Why we should care about ultra-rare disease


Orphan drugs for patients with ultra-rare diseases: between cost-effectiveness and equality of access to cure.

To date, more than 7000 rare diseases have been identified which affect 30–40 million patients in the European Union (EU), and some 250 new rare diseases are described every year [1, 2]. Primary or secondary lung involvement occurs in ∼5% of rare diseases; therefore, approximately 1–2 million people in the EU are likely to be affected by rare pulmonary diseases [3]. This means that if individuals suffering from rare diseases are by definition “uncommon”, rare conditions affect a very large number of people. Arguably, in the past few years interest in rare diseases has grown, as demonstrated by the agendas of politicians and health authorities, but too little attention is still paid to ultra-rare diseases. Although no legal definition of an “ultra-rare” disease has yet been established, this subcategory was introduced by the National Institute for Health and Care Excellence for drugs with indications for diseases that have a prevalence of <1 per 50 000 persons [46]. According to EU legislation, patients suffering from a rare condition are entitled to the same standard of care as other patients [7]. In some European countries, such as Italy and the Netherlands, the right to healthcare is protected constitutionally and everyone is entitled to equal access to public healthcare [8]. Moreover, article two of the European Convention on Human Rights (ECHR) states that “Everyone’s right to life shall be protected by law” [9].

Also for these reasons, European legislation was introduced in 2000 to drive the development of orphan drugs, arriving much later than the USA Orphan Drug Act of 1983. This legislation requires that the pharmaceutical industry has a right to: 1) obtain protocol assistance at a reduced rate; 2) access the centralised authorisation procedure; 3) enjoy lower registration fees; and 4) benefit from 10 years of market exclusivity after registration [7, 1012]. This has led to the authorisation by the European Medicines Agency of 124 new orphan drugs in the EU between 2000 and 2015, of which about one-third were for ultra-rare diseases (www.ema.europa.eu/ema/). .

In the respiratory field, there are several ultra-rare diseases: lymphangiomatosis [13], pleuro-parenchymal fibroelasytosis, pulmonary alveolar microlithiasis [14], ataxia telangiectasia [15], pulmonary alveolar proteinosis, lysosomal storage diseases, pulmonary dendriform ossification, light chain deposition disorders [16], Birt–Hogg–Dubè syndrome [16], rare vascular disorders and vasculitis along with several others.

The research and development process for new drugs to treat very rare diseases requires significant investment and the allocation of highly sophisticated resources, a situation which raises ethical as well as social issues. It is indeed fair to wonder whether society and the public at large should bear the high cost of research activities benefitting a very small number of individuals, albeit affected by severe and chronic ailments, or whether this goes against the principle of equality. Strangely, patients with rare and, at times, unknown conditions tend to absorb even higher resources than patients affected by more common diseases generally described as “normal”.

As stated by Huges et al. [5], the principle of equality would argue against special consideration being given to patients with rare conditions in the allocation of healthcare resources. Investing substantial amounts of resources in rare conditions may be viewed as unethical from a utilitarian point of view, as it does not maximise the benefits for society as a whole [5]. But who should take care of this, if not the government?

A key factor underlying the failure of many orphan drugs to meet proposed standards for cost-effective­ness is that manufacturers need to generate revenues to allow them to recoup research and development expenditures for a small group of patients. This challenge inevitably leads to elevated acquisition costs.

For EU member states to make decisions on reimbursement, it is crucial to acquire greater insights into the balance between expenses and health gains for a specific drug, in order to determine the “value for money” for orphan drugs. Conversely, the public does not seem prepared to deny patients treatment merely on the basis of cost [17]. Accordingly, drug acquisition costs are inversely correlated with prevalence.

However, despite high costs and considering the rarity of these diseases, the outlay for these drugs represents only a small proportion of the global drug budget of a modern European healthcare system.

Another important issue is how research should be carried out for ultra-rare diseases, along with the issue of quality. Clinical evidence on ultra-rare drugs for chronic diseases is frequently based on observations among small numbers of patients in short-term studies utilising surrogate outcomes rather than long-term trials [18]. Typically, in such studies, the primary end-points are surrogate; the relationship between the surrogate end-point and survival or mortality or other clinically relevant end-points is not always clear [18]. For example, improved walking distance induced by drugs affecting pulmonary arterial hypertension, although statistically significant, is of questionable clinical relevance. The efficacy of anti-cancer drugs has been measured in terms of tumour response or time-to-progression rather than survival or quality of life. Joppi et al. [18] report that in some cases the trial was too short with respect to the natural history of the rare disease evaluated: 20 weeks for agalsidase-β or 18 months for agalsidase-α in the treatment of Fabry disease; 12 weeks for pegvisomant acting on resistant acromegaly and also for drugs that are active in pulmonary hypertension or epilepsy.

However, although less stringent criteria may be adopted for orphan drugs than for common drugs, this should not be a good reason not to guarantee the best available treatment to patients with rare diseases [18]. A critical step in generating data is to establish disease-specific registries including longitudinal data on all affected patients. Schuller et al. [12] suggest that ideally registries would start before drugs are marketed, so as to produce data about the natural history of the disease. Accordingly, EU countries need to work in close cooperation.

Organising care for individuals with ultra-rare conditions demands a different and highly specific approach. Recent research has shown that a well-organised, patient-centred, multidisciplinary approach is more patient friendly and generates better outcomes than the current care model [19].

National governments must develop strategies to drive clinical research, and incentives to encourage teaching hospitals to care for and investigate rare and ultra-rare diseases. Major efforts are also needed to train specialists with enough expertise to promptly recognise ultra-rare diseases, explore differential diagnoses and offer the most advanced treatment options. All this will be facilitated by supra-national partnerships between the few specialists with an interest in specific conditions, ranging from the establishment of rare diseases registries (to significantly increase patient populations) to web-based options (extremely fast contacts and real-time data sharing thanks to teleconsultations that also permit contacts among patients) [20]. Rare and ultra-rare conditions represent a major research challenge since they highlight and amplify the need for cooperation and sharing of know-how on the one hand, and for channelling efforts towards dedicated centres of excellence to develop and offer multidisciplinary skills on the other. Is this a challenge that can be met?

Beryllium disease and sarcoidosis: still besties after all these years?


Despite advances, the pathobiology of chronic beryllium disease and sarcoidosis continue to overlap more than differ .

Toxic pulmonary disease from beryllium exposure first came to light in the 1930s, soon after the emergence of industrial uses of beryllium alloys. An early manufacturing application for beryllium compounds, as phosphors in fluorescent tubes, was the cause of some of the first known cases of chronic beryllium disease (CBD) (first termed “pulmonary granulomatosis of beryllium workers”). However, the association between beryllium and granulomatous inflammation was controversial at the outset, leading to the moniker “Salem sarcoid” to describe the outbreak of “sarcoidosis” among fluorescent bulb workers at a manufacturing plant in Salem, MA, USA [1]. Despite opposition from the manufacturer and its allies in the state government, H. Hardy convincingly established the relationship between beryllium exposure and granulomatous disease with her landmark analysis of 17 workers from the Salem light bulb factory [2]. Her key insight was to identify the high frequency of latency of disease onset and progression after cessation of exposure. Nearly a century later, despite subtle clinical and radiological differences, the salient features of pulmonary sarcoidosis and CBD continue to be nearly indistinguishable, leading to occasional suggestions that CBD may be simply “sarcoidosis of known cause” [3].

Since the triggering antigen(s) for sarcoidosis remain unknown, and there is no widely accepted animal model of sarcoidosis, some investigators have proposed studying CBD to gain insights about the pathobiology of sarcoidosis [46]. The study of CBD confers some substantial advantages. The process can be dissected epidemiologically and pathologically, in a dose–response and temporal fashion, from exposure to sensitisation to overt granulomatous inflammation. A common genetic polymorphism of the human leukocyte antigen (HLA)-DP1 gene (Glu69) markedly elevates risk for beryllium sensitisation and CBD [7, 8], facilitating assessment of gene–environment relationships and identification of at-risk populations [9]. Antigen-specific immunological responses can be characterised in cells obtained by bronchoalveolar lavage [10], and there are viable animal models for some aspects of CBD [6, 11]. Furthermore, since CBD is an occupational disease spanning several sectors of the military and industrial economy, there are funding sources available for its study that are generally not accessible to researchers interested in sarcoidosis.

In practice, the features of sarcoidosis and CBD overlap dramatically. Although sarcoidosis involves extrapulmonary organs in more than half of patients [12], individuals diagnosed with isolated pulmonary sarcoidosis could easily have CBD if exposure to beryllium is not ascertained and tested [13]. Thus, in some [13, 14], but not all [15] studies, clinically significant rates of unsuspected CBD could be identified in sarcoidosis cohorts after careful screening. The anatomic location and morphology of the CBD granuloma is identical to that of sarcoidosis; except for less prominent intrathoracic lymph node enlargement in CBD, the chest imaging features are also alike. Despite all the clinical similarities in diagnosis, disease behaviour differs in a potentially important way: unlike sarcoidosis, CBD generally requires ongoing treatment [16], whereas a high proportion of sarcoidosis cases enjoy spontaneous remission. This discrepancy alone raises the possibility of fundamental differences in the pathophysiology of granuloma formation, antigen clearance and/or immune tolerance.

In the past decade, several observations have been made that suggest sarcoidosis is not simply CBD of unknown aetiology. Serum amyloid A (SAA), an acute phase reactant with innate immune properties, was found in sarcoidosis granulomas, but not in granulomas from patients with infections, vasculitis, hypersensitivity pneumonitis, inflammatory bowel disease or CBD [17]. The authors hypothesised that the variable remission rates in sarcoidosis could be the result of SAA persistence or clearance [17]. This line of evidence implies that sarcoidosis itself is a specific disease, even if more than one antigen can trigger it.

A second fundamental advance that differentiates the pathophysiology of sarcoidosis and CBD is the finding that beryllium is not the proximate antigen to which the immune response of beryllium-specific T-cells is directed [18]. Rather, the beryllium cation induces a conformational change in a susceptible HLA-DP2–peptide complex, leading to its recognition as a neoantigen. An endogenous transmembrane protein, plexin A, has been identified as one relevant antigen that becomes an autoantigen as a result of the conformational HLA changes induced by the distant binding of beryllium [19]. It seems likely that this mechanism of neoantigen generation is specific to CBD rather than other T-cell derived immune responses [18].

Interestingly, recent work suggests that autoimmune mechanisms may also be relevant in sarcoidosis. Grunewald et al. [20] demonstrated clonal expansion of a T-cell subset that binds to a specific Type II HLA molecule (DRB01*03) in a cohort of Löfgren’s patients. Modelling of the peptide-binding groove predicted that a self-antigen, probably derived from vimentin, could be the inciting antigen [20]. In prior work, the same group had demonstrated the presence of multiple self-peptides, including vimentin, bound to HLA molecules from sarcoidosis bronchoalveolar lavage cells [21]. However, the pathogenicity of vimentin or other endogenous peptides in the sarcoidosis patient remains unproven, as does the role of endogenous peptides in non-Löfgren’s patients.

Despite the presence of some fundamental differences between sarcoidosis and CBD, there is still sufficient overlap between both syndromes to justify circumspect comparison. In this issue of theEuropean Respiratory Journal, Li et al. [22] compare gene expression in peripheral blood mononuclear cells (PBMCs) from individuals with CBD, beryllium sensitisation and healthy controls. They then compared the expression profiles of the genes differentially expressed in CBD to those from sarcoidosis populations [23, 24]. Using pathway analysis and other bioinformatics tools, they were able to identify JAK/STAT signalling as the most highly upregulated pathway in the CBD patients. Their data also provided evidence for the functional importance of JAK signalling in PBMCs from CBD patients by demonstrating beryllium-induced STAT1 phosphorylation as well as a reduction in beryllium-induced lymphocyte proliferation using a JAK2 inhibitor. These data accord with similar findings in sarcoidosis, where the STAT1 pathway has been shown to be the dominant gene expression feature in both granulomatous tissue [23] and peripheral blood [25]. Canonical signalling through the JAK/STAT pathway is necessary for transcription of numerous gene products (e.g. interferon-γ and interleukin 17) known to be relevant to T-helper cell (Th)1 and Th17 immune responses, which are thought to be central to the pathogenesis of sarcoidosis and possibly also CBD [26, 27].

The similar gene profiles exhibited in CBD and sarcoidosis extend prior observations suggesting immunological parallels between the two diseases. Both are known to be caused by HLA-dependent antigen presenting cell interactions with specific T-cell receptors. Thus, HLA genotypes are thought to be the major determinant of disease susceptibility. In addition, several genetic markers of disease severity, such as transforming growth factor-β and CCR5 are identical for both diseases [2830]. Although the antigens differ, persistent antigen stimulation in both diseases may lead to CD4+ T-cell dysfunction or exhaustion. In CBD, programmed death-1 (PD-1) is most markedly upregulated on beryllium-specific pulmonary CD4+ cells, and its presence is inversely related to beryllium-induced lymphocyte proliferation [31]. Analogously, in chronic pulmonary sarcoidosis, T-cells exhibit an increased PD-1 dependent loss of proliferative response to nonspecific stimuli [32]. These data may help explain the clinical course of individuals with chronic persistent inflammation from retained antigens such as beryllium.

Reassuringly, the present data corroborate the usefulness of peripheral blood transcriptomic signatures for the study of pulmonary granulomatous inflammation [22]. They also extend support for the concept that many aspects of various pulmonary granulomatous diseases share similar immunological profiles [22]. The authors here found 33 gene products that overlapped significantly between CBD PBMCs and sarcoidosis tissue, including CXCL9, STAT1, TAP1, CCL8 and CXCL11 [20]. The most overexpressed gene in the CBD group, CXCL9, has been shown to correlate with the outcome of sarcoidosis [33]. CXCL9, a STAT1-dependent gene that is a T-cell chemoattractant, promotes granuloma formation and is likely to be an important mediator of pulmonary granulomatous inflammation [3436]. The observation that peripheral blood gene expression profiling can be used to assess pulmonary granulomatous syndromes raises the possibility that diagnostic or prognostic markers could be developed for clinical use [3739]. However, given the immunological similarities between sarcoidosis and CBD, the present study suggests that developing expression profiles that reliably discriminate the two entities will be a significant challenge. Analogous to the currently used beryllium lymphocyte proliferation test, it is possible that changes in gene expression after beryllium stimulation may be a more specific distinguishing marker.

Although there have been very significant and disparate advances in the understanding of CBD and sarcoidosis in the past decade, the pathobiology of these two granulomatous diseases continues to overlap more than differ. For now, it seems safe to state that observations in one of the two diseases are a fertile source for hypothesis development in the other.

Sildenafil for pulmonary hypertension complicating idiopathic pulmonary fibrosis: a rationale grounded in basic science


Abstract

Sildenafil may be of benefit in IPF with out-of-proportion PH and could be a step toward effective multimodal therapy .

The last few years have seen the development and approval of two drugs, pirfenidone and nintedanib, for the treatment of idiopathic pulmonary fibrosis (IPF) [13]. Both agents have been shown to slow the loss of lung function and, therefore, target progressive fibrosis. While the availability of these agents has been a welcome breakthrough, it is well recognised that they both have limited effect, and there remain many unmet needs [4] and a dire necessity for additional therapies [4, 5]. Aside from the fibrotic component of the disease, another pathophysiological consequence that may supervene in IPF patients is pulmonary hypertension (PH) [6]. PH complicating the course of patients with pulmonary fibrosis has a strong association with functional impairment and worse outcomes. The likelihood of developing PH increases over time and, in the terminal phases of the disease, most patients have developed an element of PH [7]. Therefore, in patients with more advanced disease who have established PH or are at high risk of developing PH, pulmonary vasoactive agents might represent a viable therapeutic option. Targeting PH in IPF makes intuitive sense, but the challenges lie in not only choosing the most appropriate patient population but also the right medication or class of medications.

There are data to suggest that agents targeting the nitric oxide pathway may be best suited to the task [8, 9]. The Step-IPF study of sildenafil was a negative study based on its primary end-point (proportion of patients with an increase in the 6-min walk distance of 20% or more) but it did demonstrate significant effects on a number of secondary end-points including quality of life, single-breath diffusing capacity of the lung for carbon monoxide (DLCO) and arterial oxygenation [8]. Based on a subgroup analysis, it appears that those patients with an element of right ventricular dysfunction represent the phenotype most likely to benefit from this therapy [10]. However, one always needs to view subgroup analyses with some circumspection, especially when dealing with small numbers.

In this issue of the European Respiratory Journal, Milara et al. [11] investigated the effects of the phosphodiesterase 5 (PDE5) inhibitor sildenafil on vasoconstriction and remodelling of pulmonary arteries (PAs) from healthy donors and patients with IPF (with or without PH) as well as patients with isolated PH. In separate experiments, the authors examined the effect of sildenafil on ventilation/perfusion (V′/Q′) match in a model of bleomycin-induced pulmonary fibrosis. The functional studies related to isolated PA rings were simple and elegant, and included a “relaxant” protocol where cumulative doses of sildenafil were added to PAs pre-contracted with serotonin (5-hydroxytryptamine (5-HT)) and a “contraction” protocol where sildenafil was present in the organ bath before cumulative concentrations of 5-HT were added. In the relaxant protocol, sildenafil was found to induce concentration-dependent relaxation of PA rings mainly in the PAs of control and IPF groups, and to a significantly lesser extent in the PH+IPF and PH groups. This effect was only partially dependent on the presence of the endothelium. In the contraction protocol, however, sildenafil had significant effects in PAs from IPF, and more so in PAs from PH+IPF and PH, with no effect in PAs from control donors.

These functional differences in PA vasomotor responses prompted further experiments examining markers of cell proliferation and remodelling, and mesenchymal/myofibroblast transition (e.g.smooth muscle α-actin, vimentin and transforming growth factor (TGF)-β1 expression). In general, these pathways were found to be activated in both IPF and IPF+PH but with more pronounced expression in IPF+PH, indicating a gradual activation of the processes of muscularisation and fibrosis in IPF eventually leading to the PH complication. These results are also consistent with a similar molecular signature obtained with laser capture microdissected PA profiles in combination with whole-genome microarrays from patients with chronic obstructive pulmonary disease and IPF complicated by PH [12]. In addition, Milara et al. [11] found the expression of several endothelial markers (e.g. endothelial nitric oxide synthase, vascular endothelial cadherin and vascular endothelial growth factor receptor) was downregulated in PAs from IPF and IPF+PH, suggestive of endothelial dysfunction. Importantly, PDE5 expression was significantly upregulated in PAs from IPF and IPF+PH patients, in strong support of the functional PA ring data. To tie up the results, Milara et al. [11] examined the role of sildenafil and TGF-β stimulation on cultured PA ring explants. TGF-β was found to decrease the expression of endothelial markers while increasing the expression of PDE5 and mesenchymal markers, effects that were reversed by sildenafil treatment. Similar effects of TGF-β and sildenafil were obtained using cultured human PA endothelial and smooth muscle cells obtained from patients with IPF, with sildenafil inhibiting TGF-induced endothelial to mesenchymal and smooth muscle cell to myofibroblast transition, seemingly via inhibition of extracellular signal-regulated kinase 1/2 and SMAD3 phosphorylation.

A significant concern when using any vasodilator drug is the possibility of worsening V′/Q′ matching and, therefore, hypoxaemia. To address this particular issue, Milara et al. [11] tested the effect of sildenafil given by infusion in a model of bleomycin-induced pulmonary fibrosis. While this model may not be ideal for IPF, it is certainly appropriate here for the purpose of testing the effect of vasodilation on V′/Q′ matching. The finding that sildenafil did not in fact alter V′/Q′ matching is in keeping with the results of acute infusion of sildenafil in humans with IPF complicated by PH, which also showed no effect on V′/Q′ [13]. Whether this is the result of sildenafil having anticonstrictive effects while lacking vasodilatory effect (at least in normal arteries), as demonstrated in this study, is an interesting speculation proposed by the investigators. However, it is more likely that sildenafil has vasodilatory effects preferentially in areas that are well ventilated and where nitric oxide is available.

A novelty and strength of this paper relates to the direct study of sildenafil on contractile properties of PAs obtained from patients with IPF with or without PH, and on markers of proliferation and mesenchymal cell transition. The originality of the study is further strengthened by the finding of increased PDE5 expression in PAs from patients with IPF with and without PH, which, to our knowledge, has not been previously described. This important finding then provides a strong rationale for PDE5 as a therapeutic target in IPF complicated by PH.

It is unclear at this time whether PAH specific therapies are of any clinical value in interstitial lung disease complicated by PH. IPF clinical trials using vasodilators such as the endothelin receptor antagonists have thus far been negative [1416]. It appears, however, that sildenafil has pleiotropic properties beyond its traditional vasodilatory effects that may render it especially attractive as an add-on treatment for IPF. While there have been studies, anecdotal observations and subgroup analyses that have suggested a benefit to sildenafil in IPF, there have also been negative studies that have muted enthusiasm [17, 18]. Interestingly, a recent meta-analysis of 19 randomised clinical trials comparing 10 different interventions (including commonly used PH-specific therapies) with placebo and an average follow-up period of 1 year, without direct comparisons between treatment interventions, suggested that treatment with nintedanib, pirfenidone and sildenafil offered a possible survival advantage in patients with IPF [19].

Sildenafil may ultimately prove to be of benefit in IPF patients with out-of-proportion PH [20] and could be the next “step” forward in the quest toward effective multimodality therapy for IPF. Despite the enticing appeal of sildenafil as a therapy for IPF, there remain many questions that can only be answered in the context of well-planned, randomised, controlled studies [21]. Who should be targeted and at what point in their disease course? How much fibrosis and restrictive disease is permissible when targeting PH? Should the DLCO or echocardiogram suffice as a surrogate or should all trials be based on right heart catheterisation data only? What threshold of PH should be considered before initiating PH-targeted therapy? Should we limit such studies to IPF or be inclusive of all patients with fibrotic lung disease complicated by PH? Hopefully, this current paper by Milara et al. [11] will serve as a foundation to engender confidence in this specific therapeutic approach and further ignite interest in ongoing and planned studies targeting the nitric oxide pathway in patients with IPF and other fibrosing lung disorders.

When insulin has to work hard to keep the sugar at bay the upper airway collapses away


Obesity is a major risk factor for both obstructive sleep apnoea (OSA) and metabolic disease. As obesity rates continue to rise, so too does the prevalence of OSA and metabolic disorders. Indeed, recent community sample data from over 2000 adults aged 40–85 years in Switzerland indicate that up to 50% of men and almost a quarter of women have apnoea–hypopnoea indices (AHI) within the moderate to severe range (>15 events·h−1 sleep) [1]. Insulin resistance, a strong predictor for the development of type 2 diabetes [2], is being recognised earlier with prevalence rates in children varying between 3 and 44% [3]. Thus, OSA and insulin resistance are major health issues.

Given the shared link with obesity, the connection between metabolic disruption and OSA is not new. Indeed, OSA has been implicated in the pathogenesis of metabolic dysfunction [46]. Furthermore, a “bidirectional” or “reciprocal” relationship, or the possibility that OSA is a manifestation of the metabolic syndrome, has been discussed in several publications [710]. However, while evidence continues to grow that sleep-disordered breathing and sleep disruption can worsen metabolic function including insulin resistance [11], there is currently limited direct evidence to support the concept that early biomarkers of metabolic dysfunction such as insulin resistance predispose to OSA [12, 13]. Thus, the chicken or the egg causality dilemma remains.

The new study by Llanos et al. [14] in this issue of the European Respiratory Journal takes us one step closer to solving this dilemma. Specifically, the authors have provided elegant insight into this question by going to the source; evaluating the relationship between pre- diabetes (i.e. insulin resistance), and “pre-OSA” (i.e. individuals with vulnerable upper airways due to high mechanical load from morbid obesity but without frank OSA (AHI <10 events/h sleep)). This unique approach has allowed the investigators to study upper airway collapsibility during sleep, using the gold standard critical closing pressure or “Pcrit” technique, without the confounding effects of prior exposure to repetitive severe hypoxaemia and sleep fragmentation, both of which contribute to metabolic sequelae [5, 15]. Accordingly, consistent with insulin resistance preceding the decline in pharyngeal stability, the reported positive correlation between insulin resistance and upper airway collapsibility and the ∼4 cmH2O increase in Pcrit when the group was dichotomised according to high versus low insulin resistance cannot be explained by the presence of severe sleep-disordered breathing.

In addition to a causal role, these novel findings suggest that insulin resistance may also accelerate the development of OSA and its aggravation once manifested. Thus, the following question arises: what has the pancreas/insulin resistance got to do with upper airway collapsibility? As discussed below, there are several plausible mechanisms by which insulin resistance may increase pharyngeal collapsibility and possibly cause frank OSA, each of which will require careful future investigation (summarised in figure 1).

FIGURE 1

Schematic indicating the potential mechanisms by which insulin resistance might contribute to increased upper airway collapsibility and ultimately obstructive sleep apnoea (OSA). Some of the interconnections have been omitted for clarity. Refer to the text for further detail.

Pharyngeal stability is dependent on the interaction between anatomical or static properties of the upper airway and the dynamic function of the dilator muscles [16]. Static properties include: cross sectional area, pharyngeal length and structural composition. Dynamic properties include: neural drive, coordination and muscle efficiency. The anatomic features govern the static shape and size of the upper airway whereas the dynamic components mediate the ability of the pharyngeal dilators to compensate for mechanical loads to the upper airway (e.g. obesity chronically or transient repetitive narrowing and closure as occurs during sleep in OSA). The Llanos et al. study [14] used the “passive Pcrit” technique to focus on the effects of insulin resistance on the static properties. As highlighted by the authors, factors that crowd the upper airway directly such as preferential ectopic fat accumulation in the tongue or peripharyngeal tissues with insulin resistance will increase upper airway collapsibility. Indirectly, visceral fat accumulation which is closely linked to insulin resistance will lower lung volume during sleep and make the upper airway more prone to collapse via a loss of tracheal traction [17]. To determine if these regional changes in fat distribution are indeed the key mechanisms explaining the current findings, sophisticated imaging approaches of the key upper airway structures and lateral fat pads of the neck combined with respiratory physiology work is required [1820].

Although not the focus of the present study, insulin resistance may also alter the dynamic properties of the upper airway. The pharyngeal dilator muscles receive input from wakefulness active neurons, local reflex mechanisms and central drive (e.g. pattern generator neurons to the largest upper airway muscle, genioglossus) [21]. The passive Pcrit” technique used in the current study [14] was designed to reduce upper airway muscle activity by minimising local reflex input with continuous positive airway pressure. However, some individuals generate substantial reflex activation during these measurements [22, 23] and centrally controlled muscle activity remains, as evident by increases in passive Pcrit during rapid eye movement (REM) sleep [22] and anaesthesia [24] when compared to non-REM sleep. Thus, while there is currently no evidence to indicate that insulin resistance alters the central mechanisms controlling the residual dilator muscle activity during the conditions used for passive Pcrit measurement, the differences observed with insulin resistance in the current study may be, at least in part, due to impaired neuromuscular responses.

For example, obesity, primarily central obesity, is associated with increased circulating levels of inflammatory cytokines, some of which yield somnogenic central nervous system activity [25]. Obesity is also associated with blunted neuromuscular compensatory responses [25, 26]. It is conceivable that insulin resistance may augment these effects. Patients with untreated OSA are more prone to upper airway muscle fatigue [27, 28]. Insulin resistance is associated with lower leg muscle fatigue during a stair climbing task [29]. Thus, if insulin resistance also increases upper airway muscle fatigue, this could contribute to increased upper airway collapsibility.

An alternate mechanism by which insulin resistance might increase passive Pcrit and the predisposition or progression of OSA is via damage to the soft tissues surrounding the pharynx. Diabetic neuropathy may impair the ability of the dilator muscles to protect pharyngeal patency [30]. However, diabetic neuropathy usually develops after prolonged diabetes mellitus, and typically first manifests as a sensory peripheral neuropathy. The role of systematic sensorimotor impairment in OSA pathogenesis is also unclear [27, 31]. Thus, while this mechanism cannot be discounted, the occurrence of a relevant asymptomatic insulin resistance-induced neuropathy confined to the upper airways, either sensory or motor, would appear unlikely. Similarly, while obesity and OSA are associated with structural alteration and inflammatory reactions in the extracellular matrix of upper airway tissue [32], the role of insulin resistance in these processes has not been evaluated.

In summary, while many uncertainties regarding the underlying mechanisms remain, the study in this issue of the European Respiratory Journal by Llanos et al. [14] provides the first empiric evidence for a pathogenic contribution from insulin resistance to the primary cause of OSA, increased pharyngeal collapsibility. To extend the generalisability of this work beyond morbidly obese women (the average BMI of the participants was 48 kg·m−2), it will be important to determine if the reported relationships are also present in lean subjects, in men, and in longitudinal cohorts. Indeed, in light of recent findings [33, 34], morbidly obese individuals who do not have OSA likely have “supranormal” neuromuscular compensatory mechanisms that protect them from OSA. This concept is further supported by >50% of the study participants having a passive Pcrit above −2 cmH2O and elevated AHIs during REM sleep into the pathogenic range when neuromuscular compensatory mechanisms are reduced or absent. However, given the differences in OSA pathophysiology between the sexes, it will be challenging to extend the current design to obese men with insulin resistance who do not have OSA as these individuals are rare. It will also be of interest to determine if other contributors to OSA pathophysiology that have been implicated with insulin resistance such as heightened peripheral chemosensitivity [35] cause respiratory control instability during sleep and have a causal role in OSA pathogenesis and/or disease progression. Finally, the intriguing possibility that insulin “sensitisers” may improve upper airway collapsibility in patients with OSA and insulin resistance warrants further investigation.

Bronchiectasthma and asthmectasis


Respiratory disease can be considered as a species in constant evolution. Due to population growth and ageing only, and apart from the current 1.1 billion smokers, there have never been more respiratory patients ever in history than today [1]. With the latest World Health Organization (WHO) worldwide estimates of 400 million individuals with rhinitis, 334 million asthmatics, 328 million chronic obstructive pulmonary disease (COPD) patients and over 100 million with sleep apnoea, there is plenty of opportunity for the concurrence of two or more respiratory diseases in the same person. Not surprisingly, it is now commonplace in medical journals and conferences to explore for syndromes that combine two respiratory conditions, such as COPD and sleep apnoea, asthma and COPD, lung cancer and pulmonary fibrosis, emphysema and bronchiectasis, etc. A relatively new kid on the block is, perhaps, bronchiectasis and asthma. Both chronic conditions are diagnosed clinically, with or without the help of imaging and lung function, and their flares (or exacerbations) share similar symptoms.

These diseases have individually been around for a while. Asthma was documented long before Hippocrates and the Egyptian Georg Ebers Papyrus, at the least nearly 5000 years ago by the Chinese Nei Ching Su Wen (Classic of Internal Medicine), written ∼2697 BC, describing an asthma exacerbation. Conversely, bronchiectasis is as old as mankind, yet a definition was eluded until much more recently, when in 1819 René Laennec, and his stethoscope, reported it. The disease was researched in greater detail by Sir William Osler in the late 1800s, who actually died of complications from undiagnosed bronchiectasis [2].

Accordingly, asthma and bronchiectasis, or vice versa, are partners in an intense and complex, sometimes hot, relationship. They may have common aetiopathogenetic mechanisms, either genetic, environmental or immunological. Thus, certain mutations in the cystic fibrosis transmembrane conductance regulator gene are more frequent in nonallergic or neutrophilic asthma and in patients with disseminated bronchiectasis [3, 4]. Furthermore, α1-antitrypsin deficiency has also been associated with both diseases, although in the case of asthma there is no agreement on whether this relationship may be causal or simply corresponds to clinical misdiagnosis [5, 6]. With regard to environmental factors, respiratory tract infections in childhood have been considered as likely triggers of inflammatory mechanisms of the airways, which can lead to the future development of both diseases [7, 8]. Finally, several immunological mechanisms link asthma and bronchiectasis. On the one hand, the traditional association between bronchiectasis and immunodeficiencies, both primary and acquired, also includes asthma [9]. On the other hand, it has also been observed that innate immunity plays a role in the pathogenesis of some phenotypes of asthma and bronchiectasis. There are differences in neutrophilic, eosinophilic and paucigranulocytic asthma, both between these types and compared with healthy controls, in the expression of certain innate immune system receptors (Toll-like receptors 2 and 4, surfactant protein A and CD14), and in the production of certain cytokines (interleukin (IL)-8, IL-1β and tumour necrosis factor-α). Some of these differences are also present in patients with bronchiectasis [10]. Moreover, asthma and bronchiectasis share protagonism in a clinical entity, allergic bronchopulmonary aspergillosis, where both constitute two of its diagnostic criteria [11]. In view of all these links, it is not surprising that the British Thoracic Society (BTS) recommended in its guideline for management of bronchiectasis that, in the absence of other possible aetiologies, asthma can be considered as a cause of bronchiectasis [12]. It is also worth considering that a completely opposite sequence of occurrence of both diseases, with the detection of bronchiectasis before a diagnosis of asthma, has also been reported [13].

Until recently, researchers have explored the influence in asthmatics of having bronchiectasis. In this regard, Kang et al. [14] observed a higher annual rate of asthma exacerbations, courses of systemic glucocorticoids and emergency room visits in a group of 50 asthmatics with bronchiectasis compared with 50 asthmatic controls. Oguzulgen et al. [15] also detected a higher proportion of patients with a history of hospitalisation for acute asthma exacerbation in asthmatics with concomitant bronchiectasis (49%) compared with patients who only suffered asthma (17.6%). Moreover, in a recent analysis by the European Bronchiectasis Network (EMBARC) [16], involving 1258 patients and using the diagnostic criteria of the BTS, it was considered that asthma was the cause of bronchiectasis in 3.3% of cases; no significant differences in that proportion were appreciated depending on the severity of bronchiectasis. An unanswered question is whether asthma frequency is different within the newly suggested bronchiectasis phenotypes [17].

By contrast, the presence of bronchiectasis itself appears to increase depending on the severity of asthma. Comparing steroid-dependent asthma (SDA) and non-SDA (NSDA) patients, Luján et al.[18] detected the presence of bronchiectasis in 20% of the SDA group and only in 4% of the NSDA group. In other series of patients with severe persistent asthma, the percentage of patients with bronchiectasis was much higher, reaching 44% [19]. In patients with both diseases, up to 49% have severe asthma [15].

In this issue of the European Respiratory Journal, Mao et al. [20] explore the opposite association,i.e. the influence of having asthma or not in a clinical cohort of patients with bronchiectasis. Apart from the novelty, other strengths of their research include the relatively high number of cases studied and that patients with bronchiectasis secondary to other diseases were reasonably excluded. Their most notable result was to observe that the presence of asthma was independently associated with experiencing at least one exacerbation of bronchiectasis during 1 year of follow-up (odds ratio 2.6, 95% CI 1.1–5.9; p=0.02).

However, a number of limitations, many of them mentioned by the authors, are worth discussing. As with all research studying possible links between asthma and bronchiectasis, Mao et al. [20] faced two serious challenges. First were the diagnostic difficulties in clinical practice involved with confirming the simultaneous presence of both diseases in the same patient. Quite often cases with bronchiectasis and bronchial hyperresponsiveness (BHR) were clinically and functionally indistinguishable from those of patients with bronchiectasis and asthma. BHR is very common among patients with bronchiectasis (33–45%) [21, 22] and is also associated with impaired lung function, regardless of whether or not there is concomitant asthma [23]. Secondly, it is necessary to consider the complexity of deciding whether an episode of clinical and functional impairment in a patient with asthma and bronchiectasis corresponds to an asthma attack, to an exacerbation of bronchiectasis or (perhaps more likely) to both conditions simultaneously. We must bear in mind that the symptoms of both types of episodes may be similar or identical. In addition, there are several common causes of exacerbation of asthma and/or bronchiectasis, and also it is possible that any of the two exacerbated diseases can decompensate the other. Although the diagnostic criteria used by Mao et al. [20] for exacerbations of bronchiectasis seem quite robust (presence of four or more of the following symptoms/signs: change in sputum production, increased dyspnoea, increased cough, fever >38°C, increased wheezing, decreased exercise tolerance, fatigue, malaise, lethargy, reduced pulmonary function, changes in chest sounds or radiographic changes consistent with a new infectious process), it is clear that many of them also serve to diagnose asthma exacerbations. Finally, regardless of whether patients have an asthma attack or an exacerbation of bronchiectasis (or both at once), it seems logical that people with two bronchial diseases can present with “respiratory attacks” more often than subjects who only have one.

A philosophical approach to this problem could be that individuals suffering with asthma and bronchiectasis should comprise a different population and present a new syndrome worth studying and naming. The naming game in medicine has some unwritten rules. For instance, it has been recently noted that the term “syndrome” for asthma–COPD overlap syndrome is actually not well deserved [24], as some overlap may be predicted because asthma and COPD are common conditions, and there is no evidence this overlap has a distinctly known pathogenesis. However, recently, the WHO published global rules for naming new diseases [25]. In the (very unlikely) event that the overlap of asthma and bronchiectasis in the same individual were considered a new disease entity, we would present our eponym candidate to join the eminent list of doctors who helped to discover these diseases, as well as famous persons who suffered from them. Hence the Serrano–Soriano Syndrome (or the other way around) would hopefully help to identify new avenues for research, especially including those therapeutic measures that can simultaneously improve the control of both diseases, such as the treatment of airways inflammation (either with inhaled steroids [26] or macrolides [27]) or immunoglobulin replacement [28]. We will keep wondering if Laennec’s stethoscope (figure 1) and other tools will help to disentangle the overlap of asthma and bronchiectasis. Rather than suggesting bronchiectasthma and asthmectasis, we might restrain ourselves and live with asthma and bronchiectasis for the time being.

FIGURE 1

Diagnostic PET/CT should be used with caution in high-risk adrenal cases


In patients at high-risk for adrenal malignancy, 18F-fluorodeoxyglucose-PET/CT imaging should be used with clinical judgment because of suboptimal sensitivity and specificity in this population, according to study findings presented here.

In a retrospective study, Danae Delivanis, MD, a second-year endocrine fellow at Mayo Clinic, and colleagues examined the performance of 18F-fluorodeoxyglucose(18FDG)-PET/CT imaging in a population at high risk foradrenal malignancy. The researchers evaluated data from 352 patients (62.5% men; median age, 68 years; age range, 18-91 years) referred for adrenal biopsies due to suspected or confirmed extra-adrenal malignancy between 1994 and 2014. Malignant adrenal lesions were present in 223 cases and benign lesions in 129. Adrenal histopathology yielded the reference standard in all patients.

Danae Delivanis

Danae Delivanis

“We do have a relatively large number [of studies on PET/CT imaging for adrenal lesions] as well as an optimal reference standard,” Delivanis told Endocrine Today. “But other studies lack clinical follow-up, or they don’t mention how they defined ‘benign’ or ‘malignant,’ compared to other published studies that are characterized by small sample sizes and lack of an optimal reference standard (eg, having used only clinical follow-up or repeat imaging. Here there are only patients who had adrenal biopsy performed or adrenalectomy. So we had a good reference standard.”

Unenhanced CT revealed Hounsfield unit (HU) measurements greater than 10 HU for all malignant lesions, with 100% sensitivity, 33% specificity, 73% positive predictive value and 100% negative predictive value. In 91 patients who underwent 18FDGPET/CT, imaging revealed 44 metastases, three lymphomas, one adrenocortical carcinoma and 43 adrenal adenomas. FDG uptake was higher in malignant (SUV max: median, 10.1; range, 1.9-29.4) than in benign lesions (SUV max:  median, 3.7; range, 1.4-24.5; P < .001). Adrenal/liver ratio in malignant lesions was higher than in benign lesions (median, 3; range, 0.5-13.4 vs. median, 1.15; range 0.6-6.6; P < .001). Diagnosis of adrenal malignancy was most accurate with an adrenal/liver ratio cutoff of 1.8 and had 83.3% sensitivity, 83.7% specificity, 85.1% positive predictive value and 81.8% negative predictive value.

“From this study we can conclude that noncontract CT HU of 10 or below is a good initial imaging approach as it excludes a malignant lesion,” Delivanis told Endocrine Today. “For lesions bigger than 10 HU, PET/CT could be considered in a population at high risk for adrenal malignancy. However, both sensitivity and specificity of PET/CT is not perfect; therefore careful clinical judgement is warranted.” – by Jill Rollet

How a High-Fat Diet Helps Starve Cancer


In 1931, Dr. Otto Warburg won the Nobel Prize  Physiology or Medicine for his discovery that cancer cells have a fundamentally different energy metabolism compared to healthy cells.

Most experts consider him to be the greatest biochemist of the 20th century. His lab staff also included Hans Krebs, Ph. D., after whom the Krebs cycle1 was named.

The Krebs cycle refers to the oxidative reduction pathways that occur in the mitochondria. So just how does the metabolic inflexibility of cancer cells differ from healthy cells?

A cell can produce energy in two ways: aerobically, in the mitochondria, or anaerobically, in the cytoplasm, the latter of which generates lactic acid — a toxic byproduct. Warburg discovered that in the presence of oxygen, cancer cells overproduce lactic acid. This is known as The Warburg Effect.

Mitochondrial energy production is far more efficient, capable of generating 18 times more energy in the form of adenosine triphosphate (ATP) than anaerobic energy generation.

Warburg concluded that the prime cause of cancer was the reversion of energy production from aerobic energy generation to a more primitive form of energy production, anaerobic fermentation.

To reverse cancer, he believed you had to disrupt the energy production cycle that is feeding the tumor, and that by reverting back to aerobic energy metabolism you could effectively “starve” it into remission.

Although he was never able to conclusively prove it, he maintained this view until his death in 1970. One of his goals in life was to discover the cure for cancer. Sadly, as so typically happens in science, his theories were never accepted by conventional science despite his academic pedigree — until now.

The New York Times2 recently published a long, detailed article about the history of modern cancer research, including Warburg’s theories on cancer, which are now becoming more widely accepted.

Sugar Feeds Cancer

Another simpler way of explaining Warburg’s discovery is that cancer cells are primarily fueled by the burning of sugar anaerobically. Without sugar, most cancer cells simply lack the metabolic flexibility to survive. As noted in the New York Times (NYT) featured article:

“[T]he Warburg effect is estimated to occur in up to 80 percent of cancers. [A] positron emission tomography (PET) scan, which has emerged as an important tool in the staging and diagnosis of cancer works simply by revealing the places in the body where cells are consuming extra glucose.

In many cases, the more glucose a tumor consumes, the worse a patient’s prognosis.”

Unfortunately, Warburg’s theories quickly vanished into obscurity once scientists turned their attention toward genetics. Molecular biologists James Watson, Ph. D., and Francis Crick, Ph. D., discovered DNA in 1953 and from that point on, cancer research began to primarily focus on genetics.

The gene hypothesis gained even more momentum once Dr. Harold Varmus and Dr. Michael Bishop won the Nobel Prize in 1976 for finding viral oncogenes within the DNA of cancer cells.

At that point, the attention fell squarely on genetic mutations, and the theory that cancer cells are simply distorted versions of normal cells began to take hold.

The Warburg Revival

It would take another 30 years before the next major revision to the reigning cancer hypothesis. In 2006, the Cancer Genome Atlas project, designed to identify all the mutations thought to be causative for cancer, came to an astonishing conclusion — the genetic mutations are actually far more random than previously suspected.

In fact, they’re so random it’s virtually impossible to pin down the genetic origin of cancer. Some cancerous tumors even have NO mutations at all. Rather than offering the conclusive evidence needed to put an end to cancer, the Cancer Genome Atlas project revealed something was clearly missing from the equation.

With time, researchers began pondering whether cancer development might in fact hinge on Warburg’s theory on energy metabolism. In recent years, scientists have come to realize that it’s not the genetic defects that cause cancer.

Rather mitochondrial damage happens first, which then triggers nuclear genetic mutations. As noted by The New York Times:

“There are typically many mutations in a single cancer. But there are a limited number of ways that the body can produce energy and support rapid growth. Cancer cells rely on these fuels in a way that healthy cells don’t.

The hope of scientists at the forefront of the Warburg revival is that they will be able to slow — or even stop — tumors by disrupting one or more of the many chemical reactions a cell uses to proliferate, and, in the process, starve cancer cells of the nutrients they desperately need to grow.

Even James Watson, Ph.D. one of the fathers of molecular biology, is convinced that targeting metabolism is a more promising avenue in current cancer research than gene-centered approaches …

‘I never thought … I’d ever have to learn the Krebs cycle,’ he said, referring to the reactions … by which a cell powers itself. ‘Now I realize I have to.'”

Cancer-Causing Genes Regulate Cells’ Nutrient Consumption

The genetic component has not completely fallen by the wayside though. Scientists have discovered that a number of genes known to promote cancer by influencing cell division — including a gene called AKT — also regulate cells’ consumption of nutrients. So certain genes do appear to play a role in cancer cells’ overconsumption of sugar.

“Dr. Craig Thompson, the president and chief executive of the Memorial Sloan Kettering Cancer Center, has been among the most outspoken proponents of this renewed focus on metabolism …

His research showed that cells need to receive instructions from other cells to eat, just as they require instructions from other cells to divide.

Thompson hypothesized that if he could identify the mutations that lead a cell to eat more glucose than it should, it would go a long way toward explaining how the Warburg effect and cancer begin,” The New York Times writes.

“The protein created by AKT is part of a chain of signaling proteins that is mutated in up to 80 percent of all cancers. Thompson says that once these proteins go into overdrive, a cell no longer worries about signals from other cells to eat; it instead stuffs itself with glucose.

Thompson discovered he could induce the ‘full Warburg effect’ simply by placing an activated AKT protein into a normal cell. When that happens, Thompson says, the cells begin to do what every single-celled organism will do in the presence of food: eat as much as it can and make as many copies of itself as possible.”

Whereas healthy cells have a feedback mechanism that makes it conserve resources when there’s a lack of food, cancer cells do not have this mechanism, and feed continuously.

As noted by Dr. Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, cancer cells are “addicted to nutrients,” and “when they can’t consume enough, they begin to die. The addiction to nutrients explains why changes to metabolic pathways are so common and tend to arise first as a cell progresses toward cancer.”

Novel Treatment Offers Hope for Cancer Patients

A brilliant Korean biochemist by the name of  Young Hee Ko, Ph.D., who was working in the early 2000s with Peter Pedersen, a professor of biological chemistry and oncology at Johns Hopkins, made a remarkable discovery that offers a great deal of hope for cancer patients. Today Ko is the CEO of KODiscovery at the University of Maryland BioPark, where she continues her work in the field of cellular metabolism in cancer and neuro-degenerative disease.

I believe she has the answer to a large number of intractable metastatic cancers, and predict she’ll eventually receive a Nobel Prize for her work. I will actually be presenting with Ko at the Conquering Cancer Conference in Orlando on September 23 and 24 of this year..

What the two of them noticed was that when cancer cells overproduce lactic acid, they have to produce more pores, called monocarboxylic acid transfer phosphates, to let lactic acid out, or else the cancer cell will die from the inside out. As mentioned, lactic acid is a very toxic substance. Pondering how to best exploit this functional difference between normal cells and cancer cells, Ko remembered a compound called 3-bromopyruvate (3BP), which she’d worked with while getting her Ph.D.

This molecule looks very similar to lactic acid, but it’s highly reactive. She thought 3BP might be able to slip into the pore that’s allowing the lactic acid to be expelled from the cancer cell, thereby preventing the lactic acid from spilling out. Her hunch was correct. In over 100 lab tests, 3BP blew away all of the chemotherapy drugs she used for comparison. In a nutshell, 3BP “melts” tumors away by preventing the lactic acid from leaking out of the cancer cell, thereby killing it from the inside.

Old Diabetes Drug May Find New Use in War on Cancer

Interestingly, metformin, a drug that decreases serum glucose in diabetics, has also been shown to have anti-cancer effects — another nod at Warburg’s theory that cancer cannot thrive in a low-glucose environment. As noted in the featured article:

“In the years ahead, [metformin is] likely to be used to treat — or at least to prevent — some cancers. Because metformin can influence a number of metabolic pathways, the precise mechanism by which it achieves its anticancer effects remains a source of debate. But the results of numerous epidemiological studies have been striking.

Diabetics taking metformin seem to be significantly less likely to develop cancer than diabetics who don’t — and significantly less likely to die from the disease when they do.

Near the end of his life, Warburg grew obsessed with his diet. He believed that most cancer was preventable and thought that chemicals added to food and used in agriculture could cause tumors by interfering with respiration. He stopped eating bread unless it was baked in his own home. He would drink milk only if it came from a special herd of cows …

Warburg’s personal diet is unlikely to become a path to prevention. But the Warburg revival has allowed researchers to develop a hypothesis for how the diets that are linked to our obesity and diabetes epidemics — specifically, sugar-heavy diets that can result in permanently elevated levels of the hormone insulin — may also be driving cells to the Warburg effect and cancer.”

Although metformin likely has some benefit in improving mitochondrial dysfunction, I believe that there are far better options, as metformin has been associated with vitamin B12 deficiency. Berberine is a natural plant alkaloid that is far safer and works similarly. However, both will be miserable failures if one does not restrict protein to less than 1 gram/kilogram of lean body mass and net carbs to less than 40 grams per day.

From my perspective, ignoring diet as a prevention tool is foolhardy at best. Like Warburg, I’m convinced that most cancers are preventable through proper diet and nutrition, and besides optimizing your nutrient ratios, avoiding toxic exposures is another important factor. This is one reason why I recommend eating organic foods, especially grass-fed or pastured meats and animal products, whenever possible.

The Importance of Diet for Successful Cancer Treatment

The foundational aspect that must be addressed is the metabolic mitochondrial defect, and this involves radically reducing the non-fiber carbohydrates in your diet and increasing high-quality fats. You may need up to 85 percent of your dietary calories from healthy fats, along with a moderate amount of high-quality protein, as excessive protein can also trigger cancer growth.

That’s really the solution. If you don’t do that, other treatments, including 3BP, probably will not work. (However, I believe that if you’re in nutritional ketosis and then add 3BP, you may be able to reverse just about any cancer. That’s my current impression. It may be flawed, and I will revise it as necessary, but everything I’ve seen so far points in that direction.)

It’s important to remember that glucose is an inherently “dirty” fuel as it generates far more reactive oxygen species (ROS) than burning fat. But to burn fat, your cells must be healthy and normal. Cancer cells lack the metabolic flexibility to burn fat and this why a healthy high-fat diet appears to be such an effective anti-cancer strategy.

When you switch from burning glucose as your primary fuel to burning fat for fuel, cancer cells really have to struggle to stay alive, as most of their mitochondria are dysfunctional and can’t use oxygen to burn fuel. At the same time, healthy cells are given an ideal and preferred fuel, which lowers oxidative damage and optimizes mitochondrial function. The sum effect is that healthy cells begin to thrive while cancer cells are “starved” into oblivion.

For optimal health, you need sufficient amounts of carbohydrates, fats, and protein. However, ever since the advent of processed foods and industrial farming, making healthy selections has become a more complex affair. There are healthy carbs and unhealthy ones. Ditto for fats. There are also important considerations when it comes to protein, as excess protein also contributes to poor health. From my review of the molecular biology required to optimize mitochondrial function, it is best to seek to have about:

  • 75 to 85 percent of your total calories as healthy fat
  • 8 to 15 percent as carbs, with twice as many fiber carbs as non-fiber (net) carbs
  • 7 to 10 percent of your calories as protein (high-quality grass-fed or pastured meats and animal products)

Dietary Considerations: Fats

Healthy fats3 represent about 75 to 85 percent of your daily calories. The key here is HEALTHY fats as the vast majority of fats people eat are unhealthy. Avoid all processed and bottled oil with the exception of third party certified olive oils, as 80 percent are adulterated with vegetable oils.

Ideally you should have more monounsaturated fats than saturated fats. Limit polyunsaturated fat (PUFA) to less than 10 percent. At higher levels, you will increase the PUFA concentration in the inner mitochondrial membrane, which makes it far more susceptible to oxidative damage from the reactive oxygen species generated there.

Lastly, do not exceed 5 percent of your calories as omega-6 fats. Combined, your omega 6/omega 3 fats should not exceed 10 percent, and the omega 6:3 ratio should be below 2. Sources of healthy fats include:

Olives and olive oil Coconuts and coconut oil Butter made from raw grass-fed organic milk, and cacao butter
Raw nuts, such as, macadamia and pecans, and seeds like black sesame, cumin, pumpkin, and hemp seeds Organic pastured egg yolks Avocados
Grass-fed meats Lard, tallow and ghee Animal-based omega-3 fat such as krill oil

Dietary Considerations: Carbs

When it comes to carbohydrates, there are fiber-rich low net carbs, (mainly vegetables) and non-fiber carbs (think sugar and processed grains). Ideally, you want twice as many fiber carbs as non-fiber carbs (net carbs). So if your total carbs is 10 percent of your daily calories, at least half of that should be fiber.

Fiber is not digested and broken down into sugar, which means it will not adversely impact your insulin, leptin and mTOR levels.Fiber also has a number of other health benefits, including weight management and a lower risk for certain cancers.4 As noted in the featured NYT article, your insulin level plays a very important role in cancer.

“The insulin hypothesis can be traced to the research of Dr. Lewis Cantley. In the 1980s, Cantley discovered how insulin, which is released by the pancreas and tells cells to take up glucose, influences what happens inside a cell.

Cantley now refers to insulin and a closely related hormone, IGF-1 (insulin-like growth factor 1), as ‘the champion’ activators of metabolic proteins linked to cancer. He’s beginning to see evidence, he says, that in some cases, ‘it really is insulin itself that’s getting the tumor started.’

One way to think about the Warburg effect, says Cantley, is as the insulin, or IGF-1, signaling pathway ‘gone awry — it’s cells behaving as though insulin were telling it to take up glucose all the time and to grow.’ Cantley, who avoids eating sugar as much as he can … says that the effects of a sugary diet on colorectal, breast and other cancer models ‘looks very impressive’ and ‘rather scary.'”

The most important number to keep track of is your net carbs, which you’ll want to keep as low as possible. Net carbs are calculated by taking the total number of carbohydrates in grams and subtracting the amount of fiber contained in the food. The resulting number is your net carbs. For optimal health and disease prevention, I recommend keeping your net carbs below 40 or 50 grams per day.

The only way you’ll know how many fiber and net carbs you eat is to keep a diary of what you eat. Excellent sources of high-fiber carbs that you can eat plenty of include:

Chia seeds Berries Raw nuts
Cauliflowers Root vegetables and tubers, such as onions and sweet potatoes Green beans
Peas Vegetables, such as broccoli and Brussel sprouts Psyllium seed husks

Dietary Considerations: Protein

Last but not least, there’s an upper limit to how much protein your body can actually use, and eating more than your body requires for repair and growth will simply add fuel to disease processes. An ideal protein intake is likely around one-half gram of protein per pound of lean body mass. For most people this equates to about 40 to 60 grams a day, but many Americans typically consume three to five times that amount, which — just like excess sugar — can raise your risk of cancer.

Substantial amounts of protein can be found in meat, fish, eggs, dairy products, legumes, nuts, and seeds. Some vegetables, such as broccoli, also contain generous amounts of protein. To estimate your protein requirements, first determine your lean body mass. Subtract your percent body fat from 100. For example, if you have 20 percent body fat, then you have 80 percent lean body mass. Just multiply that percentage (in this case, 0.8) by your current weight to get your lean body mass in pounds or kilos.

Next, jot down everything you eat for a few days, and calculate the amount of daily protein you’ve consumed from all sources. Again, you’re aiming for one-half gram of protein per pound of lean body mass. If you’re currently averaging a lot more than what is optimal, adjust downward accordingly. The chart below will give you a general idea of the protein content of various foods.

Red meat, pork, poultry, and seafood average 6 to 9 grams of protein per ounce.

An ideal amount for most people would be a 3-ounce serving of meat or seafood (not 9- or 12-ounce steaks!), which will provide about 18 to 27 grams of protein

Eggs contain about 6 to 8 grams of protein per egg. So an omelet made from two eggs would give you about 12 to 16 grams of protein

If you add cheese, you need to calculate that protein in as well (check the label of your cheese)

Seeds and nuts contain on average 4 to 8 grams of protein per quarter cup Cooked beans average about 7 to 8 grams per half cup
Cooked grains average 5 to 7 grams per cup Most vegetables contain about 1 to 2 grams of protein per ounce

Optimizing Mitochondrial Function Is Key for Cancer Prevention and Treatment

We’re now starting to realize that mitochondrial dysfunction is at the core of virtually all diseases — cancer especially — and your lifestyle has everything to do with this situation. Hence strategies that support and optimize mitochondrial function, such as nutritional ketosis (achieved by a high-fat, low-net carb diet), intermittent fasting and high-intensity exercise are all part of the solution.

One of the basic reasons why a high-fat, low-net carb diet works so well is because it drives your inflammation down to almost nothing. And when inflammation disappears, your body can heal. It will also take the proverbial foot off the gas pedal of aging. Sadly, my guess is that over 99 percent of the population is not receiving the benefits of this approach simply because they either haven’t heard of it or don’t understand it.

This is why my next book will focus on mitochondrial optimization. I firmly believe it’s a major key to tackling not only the cancer epidemic, but many other disease epidemics as well. Ultimately, the really great news is that you have far greater control over your health, and your risk of cancer, than you might think.

Great Britain’s Most Outspoken Cardiologist Sets the Record Straight on Saturated Fats


Is saturated fat really the health hazard it’s been made out to be? Dr. Aseem Malhotra is an interventional cardiologist consultant in London, U.K., who gained quite a bit of publicity after the publication of his peer-reviewed editorial1 in the British Medical Journal (BMJ) in 2013.

In it, he seriously challenges the conventional view on saturated fats, and reviews how recent studies have failed to find any significant association between saturated fat and cardiovascular risk.

In fact, Malhotra reports that two-thirds of people admitted to hospitals with acute myocardial infarction have completely normal cholesterol levels. Malhotra, founder of Action on Sugar, also works as an adviser to the U.K.’s National Obesity Forum.

“My focus has been, ‘what can we do as individuals collectively (the medical profession) to help curb demand on the health system?’” he says. “A lot of that is being driven by diet-related diseases.

According to the Lancet Global Burden of Disease Reports, poor diets now contribute to more disease and death than physical activities — smoking and alcohol combined …

As an interventional cardiologist, we can do life-saving procedures with people who have heart attacks through heart surgery. But to be honest, rather than saving them from drowning, I’d rather they wouldn’t be thrown into the river in the first place. This is really where my focus has shifted.

I think for many of us, as clinicians moving more towards intervention, I think the realization that what we can do in medicine is really quite limited at the treatment end and actually the whole ‘prevention is better than cure’ phrase is very true.”

Hospitals and Medical Personnel Are Far From Paragons of Health

Malhotra’s epiphany that something was wrong with the system came rather early. While working as a resident in cardiology, he performed an emergency stenting procedure on a man in his 50s who’d recently suffered a heart attack.

The following morning, Malhotra spoke to the man, giving him the usual advice about quitting smoking and improving his diet.

“Just when I was telling about healthy diet, how important that was, he was actually served burger and fries by the hospital. He said to me, ‘Doctor, how do you expect me to change my lifestyle when you’re serving me the same crap that brought me in here in the first place?’”

Looking around, he realized that a lot of healthcare professionals are overweight or obese, and hospitals serve sick patients junk food. He believes one of the first things that really needs to happen is to set a good example in hospitals.

“The hospital environment should be one that promotes good health, not exacerbates bad health,” he says. His journey began with an email to celebrity chef Jamie Oliver, who did a lot of work campaigning for improved food in school canteens. Malhotra asked Oliver for ideas on how to improve hospital food.

“A couple of years later, I ended up going to the British Medical Association Annual Conference. I put a motion forward saying there should be a policy from the BMA to ban the selling of junk food in hospitals. It got an overwhelming majority vote.”

Diet and lifestyle changes are particularly important in light of the fact that medical errors and properly prescribed medications are the third most common cause of death after heart disease and cancer. Overmedication is a particularly serious problem among the elderly, who tend to suffer more side effects.

“Part of that is because there are very powerful vested interests that push drugs,” Malhotra says. “They even coax academic institutions and guideline bodies. People aren’t getting all the information to make decisions, whether or not they should take medications …

This is a major problem, especially [since] we’ve neglected or detracted from lifestyle changes, which are going to be much more impactful on your health and without side effects.”

For Past 60 Years, the Wrong Fats Have Been Vilified

For the past 60 years, the conventional wisdom has dictated that saturated fat is dangerous and should be avoided. This flawed notion was originally promoted by Dr. Ancel Keys, whose Seven Countries Study laid the groundwork for the myth that saturated fat caused heart disease.

It’s true that heart disease rates began spiking in the beginning of the 20th century, and for 50 years, heart disease has been progressively increasing. It really wasn’t an issue prior to the 20th century. But were saturated fats really to blame?

My belief is that it was in fact due to fats, but contrary to popular belief, saturated fat wasn’t the problem. It was all the other harmful fats people were eating.

In the 20th century, the average person probably had less than 1 pound a year of refined, processed omega-6 vegetable oils. By the 1950s, probably about 50 pounds a year, and by year 2000, it increased at about 75 pounds a year. It seems “fat” in itself isn’t the issue; it’s the type of fat that’s crucial.

This massive amount of highly refined polyunsaturated fat is far in excess of what we were designed to eat for optimal health. And I suspect that’s what catalyzed Keys to devise his research to come up with a justification for his recommendation to lower fat intake.

“What’s interesting is if you look in the United States, between 1961 and 2011, 90 percent of the calorie intake has been carbohydrates and refined industrial vegetable oils,” Malhotra says. “I think you’re absolutely correct.

The heart disease epidemic peaked between 1960 and 1970. It started to rise about 1920. When we look at our data, it’s quite clear that the so-called fats responsible for that are trans fats and very likely polyunsaturated vegetable oils high in omega-6 fatty acids.

We know now that they oxidize LDL and are pro-inflammatory. The other issue was smoking. Smoking was very high. When smoking reduction occurred from regulatory efforts, heart attack admissions dropped very rapidly. That’s because just 30 minutes after smoking, platelet activity increases.

A quick example: Helena, Montana 2002 brought in a public smoking ban. Within six months, there was a 40 percent reduction in hospital admissions for heart attack. When the law was rescinded, the hospital admissions came back to preceding levels.

When you combine all those things, it’s very clear. The dietary factors — trans fats, refined polyunsaturated vegetable oils, and smoking — are probably the three most important factors.”

What Are the Real Risk Factors for Heart Disease?

By failing to differentiate between trans fats and saturated fats, massive confusion has arisen. There’s also confusion about the relationship between saturated fat and cholesterol. Adding to the complexity, there are also different types of saturated fats, which may have different biological effects.

Many saturated fats will raise LDL, the so-called “bad” cholesterol. But LDLs come in various sizes. Large type A particles are less atherogenic and are influenced by saturated fat. Saturated fat also increases HDL, the “good” cholesterol.

“What’s interesting is the saturated fat, even though it may raise LDL, your lipid profile may actually improve [when you eat more saturated fat], especially when you cut the carbs. On top of that, LDL has been grossly exaggerated as a risk factor for heart disease, with the exception of people who have a genetic abnormality (familial hypercholesterolemia),” Malhotra says.

“Certainly when you get over the age of 60, the cardiovascular association between LDL cholesterol and cardiovascular mortality diminishes. It becomes almost negligible. For overall mortality, there is an inverse association with LDL. The higher your LDL, if you’re over 60, the less likely you are to die.

So what is the major issue when you look at heart disease and heart attacks? Insulin resistance … The reason it’s being neglected is partly this flawed science on cholesterol. But also because there’s never been any effective drugs that target insulin resistance.

Therefore, because [there isn’t a] big market around something to sell, there aren’t many people that know about it. As you and I know, if you target insulin resistance through the right kind of diet and lifestyle changes, stress reduction, right kind of exercise, that’s going to have the biggest impacts on your health.”

Gauging Your Heart Disease Risk

Factors that can help gauge your heart disease risk include:

If you have 3 out of the following 5 indications of metabolic syndrome: insulin resistance, high triglycerides, low HDL, hypertension and increased waist circumference, then you are at high risk for heart disease. Another major risk factor for heart disease that receives virtually no attention is high iron levels.

In menstruating women, this is not an issue since they lose blood on a monthly basis. This is actually part of why premenopausal women have a decreased risk of heart disease.

In men, iron levels can rise to dangerously high levels. In my experience, the majority of adult males and postmenopausal women have elevated levels that put their health at risk. Checking your iron levels is easy and can be done with a simple blood test called a serum ferritin test.

I believe this is one of the most important tests that everyone should have done on a regular basis as part of a preventive, proactive health screen. If your levels are high, all you have to do is donate blood a few times a year.

The Connection Between Saturated Fats and Diabetes

Malhotra cites a 2014 Lancet study looking at the association between dietary saturated fat, plasma saturated fat and type 2 diabetes. Interestingly, while dietary saturated fats found in dairy products were strongly inversely associated with the development of type 2 diabetes (meaning it was protective), endogenously-synthesized plasma-saturated fat was strongly associated with an increased risk.

Endogenously-synthesized plasma-saturated fats are fatty acids produced by your liver in response to net carbohydrates, sugar and alcohol. These findings suggest eating full-fat dairy products may protect you against type 2 diabetes, whereas consuming too many net carbs (total carbs minus fiber) will increase your risk of type 2 diabetes — in part by raising the saturated fat levels in your bloodstream.

That said, I believe a caution may be warranted. Milk, even raw milk, is actually high in net carbs, which your body converts to glucose. So as a general rule, I recommend avoiding milk. Butter is an exception, as it’s almost pure fat and has virtually no net carbs.

Healthy Fat Tips

Here are a few tips to help ensure you’re eating the right fats for your health:

  • Use organic butter made from raw grass-fed milk instead of margarines and vegetable oil spreads.
  • Use coconut oil for cooking. It is primarily a saturated fat and more resistant to heat damage than other cooking oils. It will also help improve your ability to burn fat and serve as a great source of energy to help you make the transition to burning fat for fuel.
  • Sardines and anchovies are an excellent source of beneficial omega-3 fats and are also very low in toxins that are present in most other fish.
  • To round out your healthy fat intake, be sure to eat raw fats, such as those from avocados, raw dairy products, and olive oil, and also take a high-quality source of animal-based omega-3 fat, such as krill oil.

Why Statins Are a Bad Idea for Most People

In addition to the recommendation to follow a low-fat diet, many doctors are still avid prescribers of statins, which help lower your cholesterol. In fact, 1 in 4 Americans over the age of 40 are on these drugs; soon to be 1 in 3. Malhotra is greatly troubled by these kinds of statistics.

“This is a drug that was marketed over the last three decades as being a wonder drug. It’s driven a multi-trillion dollar industry. We’re only now realizing that the benefits of statins have been grossly exaggerated and the side effects underplayed. One of the reasons for that is that most if not all of the studies that drove the guidelines, and the information around statin prescription, were industry-sponsored studies.

One of the things we have neglected in medicine is this issue around absolute risk and relative risk. The reality is if you look at the published data … if you have heart disease and you’ve had a heart attack, then taking a statin every day for five years, there’s a 1 in 83 chance that [statin] will save your life.

That means in 82 of 83 cases, it’s not going to save your life. That information isn’t given to patients, but it’s really important. Actually that’s a much more informative and transparent way to understand the benefit they’re going to get.

On top of that when you look at people with lower risk, otherwise healthy people, there is no mortality benefit. People should know that if they haven’t had a heart attack, according to the published literature, they are not high risk and they’re going to live one day longer from taking statins.”

Statins Are Associated With Serious Side Effects

Then there’s the issue of side effects. According to Malhotra, between 1 in 3 and 1 in 5 patients suffer unacceptable side effects (which he qualifies as side effects that interfere with or diminish the quality of your life). Muscle pain is the most significant side effect reported followed by fatigue (mostly in women). This isn’t very surprising, considering the fact that statins are essentially a metabolic blocker and mitochondrial poison.

They inhibit an enzyme called HMG-CoA reductase. This is how they lower cholesterol. But that same enzyme is also responsible for a number of other things like making coenzyme Q10, which is why muscle pain and fatigue are so common. This is in fact a sign that your CoQ10 is being depleted, and you don’t have enough cellular energy.

Statins also block the formation of ketones, which are an essential part of mitochondrial nutrition and overall health. If you can’t make ketones, you impair the metabolism in your entire body, including your heart, thereby raising your risk for heart problems and a variety of other diseases. It’s also recently been established that within a few years of taking statins, the drug causes type 2 diabetes in one out of 100 patients.

That too can be a significant tradeoff that needs to be taken into account, as diabetes is a risk factor for heart disease and other chronic diseases. Dr. Michel De Lorgeril, a well-respected French cardiologist at Grenoble University recently reopened the debate about statins after publishing a review in which he questions whether statins actually have any benefit at all.

“He pointed out several discrepancies in the original trials … statistical manipulation, conflict of interest … ” Malhotra says.”He’s actually suggested that maybe nobody benefits from statins; even people on statins for prevention.

He says that unless we get access to the raw data, independent analysis, the actual claims about the benefits of statins are not evidence-based. Now, I’m not personally saying that. I’m saying this is really intriguing and certainly raises as many questions … This is something that people need to know about. Even if we use the published literature at face value properly, people would be better informed. That’s the way forward in my view.”

More Information

Malhotra is currently finalizing a film called “The Big Fat Fix,” which will present a dietary protocol that incorporates many of the components of the Mediterranean lifestyle to help you reduce your risk of obesity, reverse type 2 diabetes and improve your cardiovascular health.

“We went to visit the village where Ancel Keys spent six months each year for 30 years doing his research. They had very high longevity. We try and find out what the secrets were and how things got misinterpreted,” Malhotra says. “This is really what the film will show. Where did things go wrong and where do we go from here?”

3 Thoughts on Cancer Research: What the ASCO Annual Meeting Means for You


No time is more special for the cancer community than the first weekend in June, which is when the American Society of Clinical Oncology (ASCO) Annual Meetingconvenes in Chicago. This meeting regularly draws more than 30,000 attendees from around the world, including experts, clinicians, and patient advocates. It’s important to remember that cancer research is a joint enterprise between scientists and patients, with the common goal of improving available treatments and, in so doing, lessening suffering and loss. ”share

The ASCO Annual Meeting, and other research conferences that occur around the world, provides a forum for the presentation of findings of research studies. It also gives researchers and clinicians a chance to exchange ideas and to network, and this provides an important stimulus for the creation of ideas that lead to new research. But why is there a meeting? Let’s review what happens at these meetings and why they are they important. This context can show what this meeting means for you.

#1. Research answers questions in safer ways

Large numbers of cancer research studies are conducted each year. These studies are designed to answer a question that scientists don’t know the answer to. Studies that are testing a new drug go through many phases of research. Doses are carefully determined during an early stage of the study with a small group of patients. After that, the new drug is compared to the standard therapy for that condition or disease. If the study results eventually show that this drug safely benefits patients, it can be made available for prescription.

The design of research studies must follow a very strict format, and their results must be reported in a specific way.If you have participated in a clinical trial, you know that there are a lot of steps involved in clinical trials. Each study has specific criteria, called eligibility criteria, that are designed to keep patients safe and also to ensure that the data collected is informative. If a patient does not meet these criteria, he or she cannot participate in the study. And participants must go through a long process to become familiar with the trial, provide informed consent, and understand what tasks and processes are involved.

#2. Meetings play a central role in reporting research results

Researchers first report their study results at scientific meetings like the ASCO Annual Meeting. Then, they may choose to publish the study results in peer-reviewed journals. Peer review is a process by which a study is examined by other experts in the field who have no ties to the study or the study authors. This ensures that the study results receive an objective, unbiased evaluation. The study authors must submit a detailed report of how they conducted their research, called the methods section, and how they analyzed the data using statistics.

It must be mentioned that if a study shows that a new treatment is not better than the current treatment, those results are just as important and are presented at meetings and published in scientific journals. When it comes to scientific research, we can learn just as much from failure as from success.

People who participate in clinical trials often want to know the results of their trials. Researchers usually do provide updates to their study participants.

#3. Patient participation is essential

Patient participation in studies is essential to advancing cancer research. But patients who are thinking about joining a clinical trial often have many questions, and they should feel empowered to ask the research team these questions. Researchers try to reduce the risk to study participants as much as possible, but there still is risk when a new treatment is involved. This is why I think of clinical research as a contract between the patient and the researchers. Both parties have responsibilities and expectations that need to be clearly stated and agreed to before the research begins.

When you see the research reported at the Annual Meeting and other big research conferences, now you know what it means for you. Researchers have spent a long time figuring out what questions they need to ask. Then they study how they’ll answer the question and present it at a meeting. If the results are well received, they may also publish their results in a journal. But none of this could ever happen, without the contribution of patients.

Biopsy: 5 Things Every Patient Should Know


There is a member of your health care team who plays a vital role in your diagnosis and cancer care who you may never meet face to face: the pathologist. This is the doctor who analyzes the sample of tissue removed during a biopsy to make the correct diagnosis.

Here are 5 things this pathologist wants every patient to know about biopsy. ”share

1. Biopsy sample size and location matter.

Pathologists are trained to evaluate many different types of tissue. They use powerful microscopes to evaluate the cells within each tissue sample.

Sometimes a biopsy sample might not be big enough to evaluate. Other times, the pathologist can see that the sample was not taken from the correct area. In these cases, the pathologist will ask your doctor to repeat the biopsy, so the pathologist can make a conclusive and accurate diagnosis.

2. The time required for biopsy results will vary.

Some biopsies can be performed in a doctor’s office or an outpatient clinic. These include shave biopsies, punch biopsies, Pap tests and cervical biopsies, and even some fine needle aspiration biopsies (FNABs) for the thyroid or lymph nodes. These procedures are usually fairly quick and might take 15 to 30 minutes to perform, depending on the part of the body being biopsied.

Typically, the biopsy sample is then saved in a special type of preservative and sent to the pathology lab for processing. Tissue processing takes several steps, but it starts with making sure the correct test was done on the correct patient. Depending on the type of evaluation needed, the next steps might take a few hours or several days.

If your pathologist suspects certain types of cancer, such as lymphoma, he or she might need to perform additional testing to determine the subtype. This process takes an additional 24 to 96 hours, depending on the complexity of the cancer.

It can be agonizing to wait for biopsy results. But be assured that the pathologist is using his or her specialized expertise to make sure you get an accurate diagnosis.

3. Pathologists make sure biopsy tissue is used effectively to determine an accurate diagnosis.

Pathologists are the caretakers of tissue samples and must exercise good judgment with them. Samples allow us to make a correct diagnosis. But we can also use the samples to perform additional tests, such as immunostains, which can identify where a tumor started. This is really valuable in treating cancer that has spread from another part of the body, called metastasis.

Your pathologist will also make sure that biopsy samples are used to identify other factors affecting your treatment and recovery. These can include genetic changes that could guide treatment options or predict your chance of recovery. For example, in breast cancer, pathologists use the biopsy sample to identify hormone receptors such as estrogen and progesterone receptors (ER and PR) and human epidermal growth factor receptor (HER2). As we identify more precise characteristics of cancer from the biopsy sample, we can identify a growing number of patients who may benefit from new, more effective targeted therapies.

4. Biopsy samples are safely stored and secured to help manage future treatment.

Federal law requires laboratories to safely store specimens for a set amount of time. For example, cytology slides, like Pap tests, are usually stored for at least 5 years. Other types of stained tissue slides are typically kept for 10 years or more. Paraffin blocks (material where tissues are usually processed) are retained for at least 10 years. Some states may require even longer storage periods.

By saving biopsy tissue for a long time, the pathologist may review the primary tumor if a patient has that cancer come back or spread in the future. By looking at the sample again, we can find out if the original primary tumor has come back or if it is a new cancer. We also may review the samples again if new treatments based on a tumor’s genetics become available. At other times and only if the patient gives permission, biopsy samples may be used in research to help discover new treatments and targeted therapies.

5. Pathologists seek multiple opinions, and patients can, too.

Typically, pathologists share all cancer diagnoses with their associates, especially when a patient has a cancer that is difficult to diagnose or treat. Most accredited labs require a second pathologist to confirm the diagnosis for all cancers.

In addition, pathologists participate in tumor board review. Tumor board review is an approach to planning cancer treatment in which a team of doctors from different specialties work together to reach an opinion.

This multilayered team evaluation helps ensure that patients receive a detailed and accurate diagnosis. And because we understand the value of gaining a second opinion, all laboratories are willing to give patients their biopsy samples if they want a second opinion or treatment from another cancer center.