Left- and right-sided CRC differs in prognosis and treatment response


A retrospective analysis of the phase III CALGB/SWOG 80405 trial revealed significant differences in survival and treatment response in patients with metastatic colorectal cancer (CRC) arising in the left vs right side of the colon.

First-line bevacizumab-based treatment was found to be more effective in patients with right-sided primary tumours, while first-line cetuximab-based treatment performed better in those with left-sided primary tumours. [ASCO 2016, abstract 3504]

“While previous studies suggested that tumour location may impact clinical outcomes in CRC, the effect we observed in this analysis appeared to be far greater than what we expected,” said lead investigator Professor Alan Venook of the University of California, San Francisco, CA, US.

The current analysis included 293 patients with KRAS wild-type right-sided primary tumours (caecum to hepatic flexure) and 732 patients with KRAS wild-type left-sided primary tumours (splenic flexure to rectum) from CALGB/SWOG 80405, a trial comparing the efficacy of bevacizumab- and cetuximab-based therapy as first-line treatment in metastatic CRC. [https://clinicaltrials.gov/ct2/show/NCT00265850]

Significantly longer median overall survival (OS) was observed in patients with left- vs right-sided primary tumours (33.3 vs 19.4 months; hazard ratio [HR], 1.55; p<0.0001).

Furthermore, patients with left-sided tumours who received bevacizumab-based treatment had longer OS than their counterparts with right-sided tumours (median, 31.4 vs 24.2 months; HR, 1.32; p=0.01).

“Surprisingly, a big difference in median OS of 19.3 months was observed in those with left- vs right-sided tumours who were randomized to receive cetuximab-based treatment [36.0 vs 16.7 months; HR, 1.87; p<0.0001],” pointed out Venook.

“Cetuximab was more effective than bevacizumab in improving OS in patients with left-sided tumours [HR, 0.82; p=0.01],” he reported. “In contrast, an OS trend favouring bevacizumab was noted in those with right-sided tumours [HR, 1.26; p=0.08].”

“The prognostic and predictive values of left vs right primary tumour location are not something magical. Possible explanations include differences in the distribution of mutations, transcriptional subtypes and hypermethylation,” he suggested. “Embryology may explain these differences – the midgut forms the right colon while the hindgut forms the left colon during embryonic development.”

Another interesting finding was noted in their extpolatory analysis of patients with KRAS mutant tumours. “Although cetuximab is not indicated in KRAS mutant CRC, those with right-sided KRAS mutant tumours who received cetuximab had longer OS than their KRAS wild-type counterparts [median, 23.3 vs 16.7 months],” noted Venook. “If this is eventually confirmed by other studies, we know less about RAS than we think we do.”

“First-line cetuximab and bevacizumab have different treatment effects in subgroups defined by left vs right sidedness of primary tumours,” he concluded. “The study results will influence decisions on treatment sequences, but will not preclude my use of either agent, at least for now.”

Glasgow Prognostic Score as a useful prognostic factor after hepatectomy for hepatocellular carcinoma.


Abstract

Background

Several previous studies have revealed that the Glasgow Prognostic Score (GPS) is a clinically useful scoring system to predict the prognosis of patients with various kinds of advanced cancers. However, there have been few reports on the relationship between the GPS and prognosis after hepatectomy for hepatocellular carcinoma (HCC). Therefore, we performed an analysis of the relationship between the GPS and prognosis after hepatectomy for HCC.

Methods

Between January 2005 and December 2009, 352 HCC patients underwent hepatectomy at Kumamoto University Hospital. Nineteen clinicopathologic factors were analyzed, using univariate and multivariate analyses.

Results

Univariate analysis showed that significant risk factors for poor survival included serum albumin level (<3.5 g/dL), tumor size (>35 mm), presence of ascites, portal vein invasion, operation time (>400 min), blood loss (>360 mL), requirement for blood transfusion, and GPS. Multivariate analysis revealed that tumor size [hazard ratio (HR) 3.355; p = 0.003], operation time (HR 2.634; p = 0.006), portal vein invasion (HR 2.419; p = 0.009), and GPS (HR 3.796; p < 0.001) were independent factors for poor prognosis.

Conclusion

The GPS was demonstrated to be a statistically significant prognostic factor after hepatectomy for HCC.

Source: International Journal of Clinical Oncology

The use of surgery in mesothelioma.


meso sx

Malignant pleural mesothelioma is an aggressive cancer of the pleura that is associated with exposure to fibrous minerals in the environment, such as asbestos or erionite. Because asbestos is ubiquitous in building material, the worldwide incidence of the disease continues to rise; rates in Europe are expected to increase by 5—10% per year for the next 25 years.1 Left untreated, the prognosis of malignant pleural mesothelioma is poor, with median overall survival of 7 months.1 Diagnosis of early disease is rare, because symptoms, such as dyspnoea or chest wall pain, often do not occur until later stages. Suspicion must be high to make the diagnosis, because the disease often presents as a pleural effusion or pleural thickening on imaging, or both, making it difficult to differentiate from other diseases.2

Once malignant pleural mesothelioma is suspected, a tissue sample is obtained in the operating room via pleuroscopy or video-assisted thoracoscopy, with incisions placed in a potential future thoracotomy site.1 Pleural fluid cytology and needle biopsy are often insufficient, because adequate specimens are needed to establish whether invasion is present and distinguish malignant disease from fibrous exudate or proliferating mesothelial cells. Additionally, enough tissue should be obtained to identify the histological subtype: epithelial, sarcomatoid, or mixed (biphasic).23

Prognostic factors that portend increased survival include epithelial histology, female sex, and earlier stage. In a retrospective study of 945 patients,4 longer survival was associated with these characteristics, as well as no history of smoking or asbestos exposure, and left-sided tumours. The longest survival is recorded in women younger than 50 years and those with epithelial disease, for whom median survival exceeds 30 months.5 The difference between the sexes is a consistent finding and suggests that circulating oestrogen might affect tumour biology.356

While trials assess the roles of neoadjuvant or adjuvant chemotherapy, radiation therapy, intracavitary chemotherapy, photodynamic therapy, and other systemic options, the standard of care is resection and adjuvant therapy with radiation or chemotherapy, or both.6 Most studies have suggested that patients with favourable disease characteristics benefit from surgery with curative intent in the context of multimodality therapy.127

The two options for surgical resection are extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). With EPP, the pleural envelope is resected along with its contents, including the lung, diaphragm, and pericardium. P/D is a similar radical resection, but preserves the lung. Until 10 years ago, many surgeons preferred EPP for macroscopic complete resection, even in early-stage disease, as long as the patient had adequate cardiopulmonary function. Critics of EPP suggested that it was associated with high risk and did not offer a clear survival benefit. The Mesothelioma and Radical Surgery trial8 was designed to assess the role of EPP in malignant pleural mesothelioma, but its design was not feasible due to the high morbidity associated with EPP, and subsequent exploratory analyses were done with sample sizes that did not have adequate power to draw meaningful conclusions.

Many surgeons have recognised that macroscopic complete resection can be accomplished with P/D and with less morbidity than with EPP, particularly for early-stage disease. A multi-institutional retrospective study of 663 patients9 showed that, when undertaken as part of a multimodality treatment plan with curative intent, cumulative survival for early-stage disease was higher for P/D than for EPP. For later-stage disease, survival was higher with EPP. A subsequent study3 assessed 42 patients with International Mesothelioma Interest Group stage III disease undergoing P/D and adjuvant chemoradiation. Macroscopic complete resection was possible in 26 (62%), and median survival after this procedure was 35 months compared with 13 months in the 16 patients with incomplete resections.3 These data suggest that, as long as macroscopic resection of gross disease can be achieved, which operation to undertake depends on the individual patient’s tumour and functional status.7 This conclusion is reflected in the most recent clinical guidelines that were formulated by the 2012 International Mesothelioma Interest Group Congress (panel).10 Moreover, as techniques and perioperative management have improved, the mortality rates associated with these procedures—which were once prohibitively high—are now only 2·2—7% for EPP and 1—5% for P/D.279

Panel

Surgical recommendations discussed at the 2012 International Mesothelioma Interest Group Congress10

  • Surgical macroscopic complete resection and control of micrometastatic disease have an important role in the multimodality therapy of malignant pleural mesothelioma, as for other solid malignancies.
  • Surgical cytoreduction is indicated when macroscopic complete resection is deemed achievable.
  • The type of surgery (extrapleural pneumonectomy or pleurectomy/decortication) depends on clinical factors and on individual surgical judgment and expertise.
  • All patients with the diagnosis of malignant pleural mesothelioma should be initially assessed in a multidisciplinary setting, by medical oncology, radiation oncology, and surgical teams.
  • Clinical staging (lymph-node sampling, PET, and MRI) should be done before treatment.
  • The histological subtype should be identified by tissue biopsy before initiation of treatment.

Source: Lancet

 

 

Resting state magnetoencephalography functional connectivity in traumatic brain injury.


Abstract

OBJECT

Traumatic brain injury (TBI) is one of the leading causes of morbidity worldwide. One mechanism by which blunt head trauma may disrupt normal cognition and behavior is through alteration of functional connectivity between brain regions. In this pilot study, the authors applied a rapid automated resting state magnetoencephalography (MEG) imaging technique suitable for routine clinical use to test the hypothesis that there is decreased functional connectivity in patients with TBI compared with matched controls, even in cases of mild TBI. Furthermore, they posit that these abnormal reductions in MEG functional connectivity can be detected even in TBI patients without specific evidence of traumatic lesions on 3-T MR images. Finally, they hypothesize that the reductions of functional connectivity can improve over time across serial MEG scans during recovery from TBI.

METHODS

Magnetoencephalography maps of functional connectivity in the alpha (8- to 12-Hz) band from 21 patients who sustained a TBI were compared with those from 18 age- and sex-matched controls. Regions of altered functional connectivity in each patient were detected in automated fashion through atlas-based registration to the control database. The extent of reduced functional connectivity in the patient group was tested for correlations with clinical characteristics of the injury as well as with findings on 3-T MRI. Finally, the authors compared initial connectivity maps with 2-year follow-up functional connectivity in a subgroup of 5 patients with TBI.

RESULTS

Fourteen male and 7 female patients (17–53 years old, median 29 years) were enrolled. By Glasgow Coma Scale (GCS) criteria, 11 patients had mild, 1 had moderate, and 3 had severe TBI, and 6 had no GCS score recorded. On 3-T MRI, 16 patients had abnormal findings attributable to the trauma and 5 had findings in the normal range. As a group, the patients with TBI had significantly lower functional connectivity than controls (p < 0.01). Three of the 5 patients with normal findings on 3-T MRI showed regions of abnormally reduced MEG functional connectivity. No significant correlations were seen between extent of functional disconnection and injury severity or posttraumatic symptoms (p > 0.05). In the subgroup undergoing 2-year follow-up, the second MEG scan demonstrated a significantly lower percentage of voxels with decreased connectivity (p < 0.05) than the initial MEG scan.

CONCLUSIONS

A rapid automated resting-state MEG imaging technique demonstrates abnormally decreased functional connectivity that may persist for years after TBI, including cases classified as “mild” by GCS criteria. Disrupted MEG connectivity can be detected even in some patients with normal findings on 3-T MRI. Analysis of follow-up MEG scans in a subgroup of patients shows that, over time, the abnormally reduced connectivity can improve, suggesting neuroplasticity during the recovery from TBI. Resting state MEG deserves further investigation as a prognostic and predictive biomarker for TBI.

Source: JNS

 

However, the post-SRS median survival time difference, 0.9 months, between the two groups is not clinically meaningful. Furthermore, patients with 5 or more METs have noninferior results compared to patients with 1–4 tumors, in terms of neurological death, local recurrence, repeat SRS, maintenance of good neurological state, and SRS-related complications. A randomized controlled trial should be conducted to test this hypothesis.

 

Source: JNS

 

Respiratory distress syndrome in patients with advanced cancer treated with pentoxifylline: a randomized study.


Abstract

The inappropriate endogenous secretion of tumour necrosis factor (TNF) could play a role in the pathogenesis of acute respiratory distress syndrome (ARDS), one of the most frequent causes of death in cancer patients. Because of its capacity to inhibit TNF secretion in vitro, pentoxifylline (PTX) could be extremely useful in ARDS therapy. In this study 30 advanced cancer patients with ARDS were randomized to receive either the conventional care or conventional care plus PTX (100 mg i.v. twice a day for 7 days followed by an oral administration of 400 mg three times a day) to evaluate the efficacy of PTX in reducing TNF serum levels and in improving the symptoms of this syndrome. Serum levels of TNF were measured before and after 7 days of therapy. The percentage of patients alive at 7 days was significantly higher in the PTX-treated group than in the controls (12/15 versus 3/15; P < 0.001). The mean survival time was significantly higher in the PTX-treated group than in the controls. A clinical and/or radiological improvement was obtained in 11/15 patients treated with PTX and in only 2/15 patients in the conventional care group (P < 0.01). TNF mean levels significantly decrease in the PTX-treated group. These data confirm in vivo the capacity of PTX to inhibit TNF secretion in patients with ARDS. Moreover PTX therapy may improve the symptoms related to ARDS without particular toxic effects.

Source:Pubmed.

PET and Prognosis in Follicular Lymphoma.


A negative posttreatment PET scan was associated with improved survival in patients with advanced-stage disease.

Complete remission with a negative positron emission tomography (PET) scan after front-line induction chemotherapy is associated with improved outcomes in Hodgkin lymphoma and diffuse large B-cell lymphoma. To assess the prognostic value of PET in follicular lymphoma (FL), European investigators conducted a prospective, multicenter trial involving 117 patients with advanced-stage, high–tumor burden FL who were treated with six cycles of R-CHOP (rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone) followed by two additional doses of rituximab. PET scans were performed at baseline, after cycle four (PETC4), and at completion of therapy (PETC8). Independent central review of PET response was performed by three nuclear medicine radiologists and classified by established criteria (Deauville 5-point scale). No treatment modifications were made based on PET findings.

Results were as follows:

  • Of 106 patients who underwent PETC8 imaging, 83 (78%) had negative results.
  • Of 78 patients with negative PETC4 results, 6 (8%) reverted to a positive posttreatment scan.
  • Of 26 patients with positive PETC4 results, 17 (65%) remained positive on PETC8.
  • When comparing PET response to standard computed tomography–based assessment, 53 of 54 patients (98%) with complete remissions were PET-negative, whereas 10 of 20 patients (50%) with complete remissions unconfirmed (CRu) and 9 of 26 patients (35%) with partial remission (PR) remained PET-positive.
  • Patients with negative posttreatment PET had improved 2-year overall survival versus those with a positive scan (100% vs. 88%; P=0.01).
  • Progression-free survival was improved for those with negative versus positive PETC4 or PETC8.

Comment: This is the first prospective study to demonstrate a prognostic benefit for negative posttreatment PET in FL. The predictive value was independent of both low-risk and high-risk FLIPI (Follicular Lymphoma International Prognostic Index) scores. The authors recommend that only posttreatment PET rather than interim PET be used and that scan use be reserved for CRu and PR patients. Confirmation of these results in additional prospective trials will be important, as will careful application of standardized PET response criteria and PET response–based treatment algorithms.

Source: Journal Watch Oncology and Hematology

 

Common Breast Tumor with Good Prognosis Still Dangerous at 10-Year Mark .


A long-term follow-up of breast cancer cases finds that even women with a tumor subtype thought to carry the best prognosis — luminal A — show steady declines in survival after 10 years. The study appears in Cancer Epidemiology, Biomarkers & Prevention.

Researchers followed some 900 women from a community-based managed care system whose invasive tumors were classified according to molecular subtypes: luminal A, luminal B, basal-like, and HER2-enriched. Median follow-up was 13 years; some patients were followed for over 20 years.

Compared with luminal A tumors, luminal B and HER2-enriched tumors carried a twofold higher risk for breast cancer mortality. However, the authors observe: “Despite its markedly higher survival probabilities in earlier years of follow-up, luminal A subtype was the only subtype that continued a steady drop in survival over the 20-year period with little leveling off in later years.”

Source: Cancer Epidemiology, Biomarkers & Prevention

Lactate Level Correlates with Prognosis in Patients with Suspected Infection.


This large study identified a nearly linear relationship between lactate level and mortality.

To analyze the relationship between blood lactate levels and mortality in patients with suspected infection, researchers reviewed charts from 2596 patients who were admitted from the emergency department (ED) with suspected infection (inferred from administration of antibiotics in the ED) and who had blood lactate levels measured in the ED.

Overall in-hospital mortality was 14.4%, and the median initial lactate level was 2.1 mmol/L. The initial lactate level was >4 mmol/L in 17.6% of patients. Mortality rose continuously across a continuum of incremental lactate elevations, ranging from 6% in patients with lactate levels <1.0 mmol/L to 39% in patients with levels of 19 to 20 mmol/L.

Comment: We can draw two important conclusions from this study. First, patients with suspected infection who have lactate levels <4 mmol/L still are at risk of dying, so physicians should not base their evaluation of illness severity and patient risk solely on lactate level. Second, mortality risk increases with increasing lactate level, making resuscitation of patients with higher levels a priority.

Source: Journal Watch Emergency Medicine

 

Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis.


In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs).

Methods

Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000–August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded).

Results

Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP-positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein–positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40–0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53–0.96; p = 0.02).

Conclusions

Neurofilament protein–positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein–GBM’s unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapies.

Source: Journal Of Neurosurgery.

 

 

 

Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis.


In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs).

Methods

Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000–August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded).

Results

Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP-positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein–positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40–0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53–0.96; p = 0.02).

Conclusions

Neurofilament protein–positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein–GBM’s unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapies.

Source: Journal Of Neurosurgery.