‘New Organ’: Fluid-Filled Interstitial Spaces Could Allow Metastasis


A previously unrecognized contiguous organ in the form of fluid-filled interstitial spaces lining the dermis, gut, lungs, and urinary tract, as well as surrounding blood vessels and the fascia between muscles, has been identified for the first time, a new study shows.

The identification of what researchers are calling a “new organ” will significantly alter scientific understanding of how the interstitial space functions in the body and its contribution to health and disease, researchers predict.

“The interstitial space is the primary source of lymph and a major fluid compartment in the body,” Petros Benias, MD, director of endoscopic surgery, Northwell Health, New York City, and colleagues observe.

“[W]hile typical descriptions of the interstitium suggest spaces between cells, we describe macroscopic visible spaces within tissues — dynamically compressible and distensible sinuses through which interstitial fluid flows around the body,” they add.

“Our findings necessitate reconsideration of many of the normal functional activities of different organs and of disordered fluid dynamics in the setting of disease, including fibrosis and metastasis,” the investigators declare.

The research was published online March 27 in Scientific Reports.

Fixed Tissue on Slides

As the investigators explain, researchers have long relied on fixed tissue mounted on microscope slides to examine tissue histology.

This tissue is prepared by treating it with chemicals, slicing it thinly, and dyeing it to highlight features of interest — a “fixing” process that brings to light details of cells and structures but that drains away any pre-existing fluid that might have been present before the fixing process.

But removing fluid as slides are normally fixed causes the connective protein meshwork surrounding compartments once filled with fluid to pancake, like the floors of a collapsed building, the authors point out.

“This fixation artifact of collapse has made a fluid-filled tissue type throughout the body appear solid in biopsy slides for decades and our results correct for this to expand the anatomy of most tissues,” co-senior author Neil Theise, MD, NYU Langone Health in New York City, said in a statement.

The ingeniousness of the current research was how researchers overcame the artifactual collapse of these fluid-filled compartments.

To do this, the team used a new form of microscopy known as probe-based confocal laser endomicroscopy (pCLE), an in vivo imaging technique that allowed them to evaluate the histology of tissue during endoscopy in “real-time.”

“Samples were obtained from surgical specimens of bile ducts resected during twelve pancreatico-biliary surgeries,” the investigators note.

Just before the surgical specimen was resected, patients were infused with fluorescent dye (fluorescein) and then the reticular pattern was directly visualized in situ through the use of pCLE.

Embedded specimens were subsequently rapidly frozen, prepared, and then visualized under routine fluorescence microscopy.

Microscopy revealed “that the reticular pattern correlated with thick, fluorescein-stained bundles,” the researchers report.

Further staining confirmed that the presence of collagenous bands separated open, formerly fluid-filled spaces.

The researchers also note that the reticular pattern appeared within 30 seconds of dye infusion — about the same time that lymph nodes are visualized but later than when vascular structures are seen.

“This suggests that it is a form of interstitial space in which interstitial fluid or ‘pre-lymph’ accumulates or forms,” they comment.

Further study revealed that the collagen bundles observed on staining are asymmetrically lined on one side by thin, flat cells and that these cells adhere directly to the underlying collagen bundles; the opposite side, in contrast, is directly exposed to fluid in the space.

The same histologic features researchers documented in their initial bile duct specimens — spaces filled with fluid with collagen bundles lined by flat cells — were subsequently identified in many other tissues, including the dermis in resected specimens of skin and in submucosa of the entire digestive tract, the bladder, peribronchial tissue, fascia, and stroma of arteries and veins of all sizes.

Prelymphatic Spaces

As the investigators document, the prelymphatic nature of these newly observed fluid-filled spaces was further elucidated by analyzing stage T2 invasive tumors of the stomach and skin.

“Stage T2 invasion of the stomach is defined as invasion into the submucosa but not deeper,” they explain, while  “T2 invasion into the skin, likewise, indicates invasion directly into the dermis, but no deeper.”

Despite observing no lymphovascular invasion in 2 of these specimens, researchers detected metastatic disease to a draining lymph node in each of them — a sign that these prelymphatic spaces can serve as a conduit through which cancer can spread, they suggest.

“Our data comparing rapidly-biopsied and frozen tissue with tissue fixed in a standard fashion suggest that the spaces we describe, supported and organized by a collagen lattice, are compressible and distensible and may thus serve as shock absorbers,” the investigators observe.

The function of these “shock absorbers” is to keep tissue from tearing as organs, muscles, and vessels squeeze, pump, and pulse as part of daily function, they suggest.

The researchers also note that a submucosa subjected to directional, peristaltic flow may facilitate movement of cells, including tumor cells, through the interstitium, “raising the possibility that direct sampling of the interstitial fluid could be a diagnostic tool.”

Apalutamide Slows Metastasis in Prostate Cancer


Two-year delay in metastatic progression with apalutamide

Action Points

  • Note that this study was published as an abstract and will be presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Men with non-metastatic castration-resistant prostate cancer (nmCRPC) had a 2-year delay in the time to metastatic progression when treated with the new-generation androgen-receptor inhibitor apalutamide, a large randomized trial showed.

Patients randomized to apalutamide had a median metastasis-free survival (MFS) of 40.5 months versus 16.2 months for placebo treatment. The difference represented a 72% reduction in the hazard for metastatic progression or death, according to Eric Small, MD, of the University of California San Francisco, and colleagues.

Time to metastasis (TTM), progression-free survival (PFS), symptomatic progression, and PFS after subsequent therapy (PFS2) all favored apalutamide, Small reported at a press briefing prior to the Genitourinary Cancers Symposium (GUCS).

“Apalutamide was associated with a reduced risk of death, but that was not significant at this early interim analysis and will continue to be followed. The trend was certainly encouraging,” he said. “Treatment with apalutamide was generally well tolerated with no impact on quality-of-life [QoL] scores and with low rates of discontinuation due to treatment-related adverse events. Overall, these data suggest that apalutamide should be considered as a new standard of care for men with nonmetastatic castration-resistant prostate cancer.”

The results were consistent with those of the randomized PROSPER trial with enzalutamide (Xtandi), which also will be reported at GUCS, said press briefing moderator Sumanta Pal, MD, of City of Hope in Duarte, California. The abstract for the PROSPER trial showed a median MFS of 37 months for men treated enzalutamide (Xtandi) versus 15 months with placebo. Patients in both groups continued existing androgen deprivation therapy (ADT) after randomization.

“Until the results of studies presented at this meeting, there’s really been no obvious standard of care for these patients,” said Pal.

Noting that enzalutamide already has approval for more advanced prostate cancer, Pal added, “The familiarity that oncologists already have with enzalutamide may help with clinical adoption.”

However, the patient population targeted by the SPARTAN and PROSPER studies could be shrinking, Pal continued. SPARTAN investigators used conventional imaging modalities (CT and technetium bone scan) to assess patients’ status at enrollment and during the trial. Some newer forms of PET imaging may improve the ability to detect disease spread earlier, leading to early changes in clinical management, he said.

Metastatic CRPC remains uniformly fatal, associated with a median survival of about 2.5 years, Small noted. The condition arises in two way: metastatic hormone-sensitive prostate cancer and nmCRPC. Both conditions afford opportunities for interventions that delay or prevent progression to mCRPC, although as Pal noted, nmCRPC currently has no standard of care.

The primary objective of the SPARTAN trial was to determine whether treatment with apalutamide could delay development of metastases and the transition from nonmetastatic to metastatic CRPC. Apalutamide has a three-fold mechanism of action that could help accomplish the objective:

  • Prevention of androgen binding to receptor
  • Prevention of androgen receptor translocation to the nucleus
  • Blocking androgen receptor-mediated DNA transcription

Investigators at 332 centers worldwide enrolled 1,207 patients who had a baseline PSA doubling time of less than 5 month. The patients were randomized 2:1 to daily apalutamide or placebo, in addition to continuous ADT. The primary endpoint was MFS. Treatment continued until disease progression, and then patients had the option to switch to abiraterone (Zytiga) plus prednisone.

The trial ended prematurely after a planned interim analysis showed the trial had met the primary endpoint. The results showed that treatment with apalutamide was associated with a significant reduction in the hazard for MFS (95% CI 0.23-0.35, P<0.001). Small did not report results for secondary endpoints (TTM, PFS, and symptomatic progression) but said all were significantly improved in the apalutamide group versus the placebo group.

After a median follow-up of 20.3 months, the survival data remained immature to determine whether apalutamide treatment would lead to improved survival, said Small. However, the interim analysis showed a favorable trend in favor of apalutamide (P=0.07).

Apalutamide was generally well tolerated, as adverse events rates were similar in the two groups. Rates of discontinuation because of adverse events were 10.7% in the apalutamide group and 6.3% in the placebo group. Baseline health-related QoL scores were similar in the two groups and maintained throughout the study.

High Ran level is correlated with poor prognosis in patients with colorectal cancer.


Abstract

Background

The Ras-like nuclear protein (Ran) is involved in the regulation of nuclear transport, microtubule nucleation and dynamics, and spindle assembly. Its fundamental function is nucleocytoplasmic transport of RNA and proteins. The expression and potential role of Ran in colorectal cancer (CRC) remain unclear. The aim of this study was to investigate the relationship between Ran expression and CRC characteristics. The potential role of Ran as a prognostic indicator was also evaluated.

Methods

We used immunohistochemistry and western blotting to detect Ran expression in 287 CRC tissues. The relationships between Ran expression and clinicopathological characteristics and overall survival rate were statistically analyzed.

Results

CRC tissues had significantly higher Ran expression than normal colorectal epithelial cells. Ran was positively correlated with depth of invasion, lymph node metastases, distant metastases, tumor differentiation, and tumor–node–metastasis stage. However, no correlation was found between Ran expression and patient age or sex. The overall survival rate was consistently and significantly lower in patients with Ran-positive tumors than in those with Ran-negative tumors.

Conclusion

Our findings emphasize the important role of Ran in differentiation, disease stage, and metastasis in human CRC. Ran may play an important role in the development of CRC and may serve as a novel prognostic indicator of CRC.

Source: International Journal of Clinical Oncology

Lymph node micrometastasis in gastrointestinal tract cancer—a clinical aspect.


Abstract

Lymph node micrometastasis (LNM) can now be detected thanks to the development of various biological methods such as immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR). Although several reports have examined LNM in various carcinomas, including gastrointestinal (GI) cancer, the clinical significance of LNM remains controversial. Clinically, the presence of LNM is particularly important in patients without nodal metastasis on routine histological examination (pN0), because patients with pN0 but with LNM already in fact have metastatic potential. However, at present, several technical obstacles are impeding the detection of LNM using methods such as IHC or RT-PCR. Accurate evaluation should be carried out using the same antibody or primer and the same technique in a large number of patients. The clinical importance of the difference between LNM and isolated tumor cells (≤0.2 mm in diameter) will also be gradually clarified. It is important that the results of basic studies on LNM are prospectively introduced into the clinical field. Rapid diagnosis of LNM using IHC and RT-PCR during surgery would be clinically useful. Currently, minimally invasive treatments such as endoscopic submucosal dissection and laparoscopic surgery with individualized lymphadenectomy are increasingly being performed. Accurate diagnosis of LNM would clarify issues of curability and safety when performing such treatments. In the near future, individualized lymphadenectomy will develop based on the establishment of rapid, accurate diagnosis of LNM.

Source: International Journal of Clinical Oncology

TIP30 Inhibits Lung Cancer Metastasis, Study Suggests. Researchers in Shanghai, China suggest that TIP30 prevents metastatic progression of lung cancer.


Researchers in Shanghai, China suggest that TIP30 prevents metastatic progression of lung cancer.

They report these findings in the May 2009 issue of The American Journal of Pathology.

TIP30 is a putative tumor suppressor with decreased expression in numerous cancers including melanoma, breast cancer, and colon cancer. Lung cancer is the most common cancer worldwide, both in terms of incidence and of mortality.

To determine if TIP30 plays a role in lung cancer progression and metastasis, Tong et al examined TIP30 expression in paired cancerous and non-cancerous lung tissue. TIP30 expression was decreased in a third of non-small cell lung cancers compared with normal controls, and reduced TIP30 expression correlated with lymph node metastasis. In addition, inhibition of TIP30 expression promoted lung cancer metastasis and angiogenesis in mice,

Tong et al conclude that “TIP30 may function as a tumor suppressor gene and play important roles in suppressing the progression and metastasis of lung cancer.” These findings highlight TIP30 as a potential new therapeutic for metastatic lung cancer.

They report these findings in the May 2009 issue of The American Journal of Pathology.

TIP30 is a putative tumor suppressor with decreased expression in numerous cancers including melanoma, breast cancer, and colon cancer. Lung cancer is the most common cancer worldwide, both in terms of incidence and of mortality.

To determine if TIP30 plays a role in lung cancer progression and metastasis, Tong et al examined TIP30 expression in paired cancerous and non-cancerous lung tissue. TIP30 expression was decreased in a third of non-small cell lung cancers compared with normal controls, and reduced TIP30 expression correlated with lymph node metastasis. In addition, inhibition of TIP30 expression promoted lung cancer metastasis and angiogenesis in mice,

Tong et al conclude that “TIP30 may function as a tumor suppressor gene and play important roles in suppressing the progression and metastasis of lung cancer.” These findings highlight TIP30 as a potential new therapeutic for metastatic lung cancer.

Source: http://www.sciencedaily.com

 

Dose-intensive cisplatin for hepatoblastoma: have you heard?


Although survival rates for paediatric cancer have improved greatly during the past four decades, outcomes for children diagnosed with metastatic solid tumours have barely changed. These patients and their families are in desperate need of novel therapeutic approaches. Chemotherapeutic options and approaches might have come to their limit. Surgical resection of metastatic disease is largely unstudied and unproven with the exception of isolated recurrent pulmonary lesions for osteosarcoma, which can sometimes be cured with surgery alone. Radiation therapy is often used with demonstrated benefit to pulmonary metastases, although it is usually given at subtherapeutic doses because of whole lung radiotolerance.

Hepatoblastoma is the most common paediatric liver tumour in the first decade of life and is typically diagnosed in patients younger than 3 years. Surgical resection of the primary tumour is necessary as part of curative therapy whether by primary or delayed resection, including the use of orthotopic liver transplantation. Unfortunately only about a third of newly diagnosed patients are amenable to resection at diagnosis.1 Neoadjuvant chemotherapy can render tumours in many of these patients resectable, but typically a quarter to a third of such patients might never get to resection. About a quarter of newly diagnosed patients present with metastatic disease and typically have had survival rates less than 30%.1 Whether these metastatic patients have better outcomes if their pulmonary disease is eradicated by chemotherapy or by surgical resection has never been formally studied and is not clear or known.

In The Lancet Oncology, József Zsiros and his SIOPEL colleagues2 are to be congratulated for their report of improvement in outcome of patients with high-risk hepatoblastoma, many of whom had pulmonary metastases. 3-year event-free survival was 76% (95% CI 65—87) in the 62 patients studied (77%, 95% CI 63—90, in the 39 patients with metastasis). This finding is perhaps the most substantial improvement in survival that has been described for children with solid tumours and metastatic disease in decades. Because cisplatin is thought to be the most active drug in this disease, the investigators used a novel, well designed therapeutic schema that incorporated weekly dose-dense cisplatin chemotherapy—revisiting an old basic tenet of chemotherapy administration that has never been fully evaluated in paediatric malignancies.3

The use of dose intensification of chemotherapy has had some success in adult malignancies but has been used rarely in paediatric cancers.4 Interval compression of chemotherapy has been shown to be effective in acute myeloid leukemia and Ewing’s sarcoma, although with substantial costs and burden of care, and is now being explored for rhabdomyosarcoma.56Trials in patients with osteosarcoma have shown positive benefits in some trials but no effect in others.7 A previous hepatoblastoma trial from the Children’s Oncology Group (P9645)8 attempted to intensify platinum delivered therapy by alternating cisplatin and carboplatin on an every 2 week schedule. Ultimately, this regimen was inferior to the standard control group, perhaps because of decreased dose intensity of cisplatin.

The SIOPEL-4 trial seems to be a success. 60 (98%) of 61 evaluable patients had at least a partial response from preoperative chemotherapy. 19 of 20 with metastatic disease who had a complete response to chemotherapy alone remain disease-free after surgery, with only one patient having a recurrence. In view of these striking results, these data need to be validated in a large trial. Zsiros and colleagues correctly point out the limitations of this study being a single arm trial that compared outcomes with historical results and therefore needing further study before the approach can be adopted as standard of care. Although the investigators state that their regimen is feasible, the study was not truly designed with parameters to answer this question. The only statistical criterion the study met was that it did not exceed the number of expected serious adverse events, although 18 occurred, which seems quite generous for this sample size. 97% of patients had grade 3 or 4 haematological toxicity. This result is consistent with some studies in adults that have used a similar approach and might be regarded as acceptable.7 However, febrile neutropenia occurred in 71% of patients and four patients had toxic deaths (two from infection, one from surgical bleeding, and one with tumour bleeding). More than 50% of patients had with significant hearing loss. Since ototoxocity is difficult to measure, notoriously under-reported, and can progress over time, the question remains as to what hearing function these very young patients will have in the long run and whether this loss is an acceptable price to pay for the survival rates observed. Lastly, during the three cycles of weekly cisplatin therapy, patients typically had average cumulative delays of 10 days (range −4 to 63 days), which resulted in dose reductions in 9% of the initial chemotherapy block A cycles. Such delays might render a regimen not feasible. Interestingly, irrespective of delays in therapy, all patients did well. This outcome somewhat contradicts the study conclusion that dose intensity was the reason for improvement, since the outstanding results were even seen in patients who had delays and reductions in therapy (unless all patients exceeded the dose-density threshold).

Importantly, the entire international paediatric oncology community, including Europe, Japan, and South and North America, are now working together to create unified approaches to liver tumour classification and treatment and there are plans for a single forthcoming trial. The results here suggest that the SIOPEL-4 regimen should be compared in a randomised trial further evaluating the toxicities of this design. As exciting as these results are, they emphasise the urgent need for new drugs that hold the promise of a cure with acceptable long-term side-effects.

Source: Lancet

Androgen-secreting adrenocortical carcinoma.


A 47-year-old woman presented with abdominal pain. She had recently noticed increased growth of facial hair and loss of scalp hair, and her menstrual cycle had become erratic. Abdominal examination revealed a right upper-quadrant abdominal mass. A CT scan of the abdomen revealed a 10 cm adrenal mass (figure, A, B; green arrows) that was well encapsulated and heterogeneous. Endocrine studies were ordered to exclude a functioning adrenal neoplasm. The serum total testosterone concentration was 8·6 nmol/L (reference range 0·13—2·53 nmol/L) and the serum dehydroepiandrostenedione sulphate (DHEAS) concentration was 22 μmol/L (reference range 1·0—11·6 μmol/L). The free androgen index (ratio of testosterone to sex-hormone-binding globulin) was 30·2% (reference range <0·8%). The serum concentrations of oestradiol, progesterone, luteinising hormone, follicle-stimulating hormone, and prolactin were within normal limits. The remaining endocrine studies (thyroid function tests, serum cortisol, aldosterone-to-renin ratio, plasma free metanephrines and normetanephrines, and urine biogenic amines) were also within normal limits. The increased concentrations of DHEAS and testosterone suggested an androgen-secreting adrenal neoplasm with virilising symptoms. 18F-fluorodeoxyglucose PET (FDG-PET) showed no evidence of metastatic disease.

An open right adrenalectomy was undertaken. Histology showed a neoplasm arising from the adrenal gland, fulfilling both macroscopic (460 g and 105 cm) and four of nine microscopic (Weiss) criteria for adrenocortical adenocarcinoma (high Fuhrman nuclear grade, more than five mitoses per 50 high-power fields, eosinophilic cytoplasm >75% of tumour cells, and necrosis; figure, C [haematoxylin and eosin staining]). Immunohistochemistry was positive for melan-A, vimentin, synaptophysin, and epithelial membrane antigen. Cytoplasmic staining was positive with calretinin (figure, D) and inhibin (figure, E). The Ki-67 proliferative index was 32%. Mitotane was recommended as adjuvant therapy for 2 years. No evidence of recurrence or metastatic disease was recorded 12 months postoperatively and androgen concentrations remain suppressed.

Women presenting with hirsutism or virilisation are more likely to have polycystic ovarian syndrome than an androgen-secreting adrenal neoplasm. Assessment of patients requires thorough hormonal investigation and imaging, including CT, MRI, and FDG-PET.

Source: Lancet

A different view of cancer cells.


New study measures physical changes in tumor cells as they become metastatic.

Most cancer deaths are caused by metastatic tumors, which break free from the original cancer site and spread throughout the body. For that to happen, cancer cells must undergo many genetic and physical changes.

Many of those genetic changes have been studied extensively, but it has been more difficult to study the physical changes. Now, MIT researchers have developed a way to study three key physical properties of cancer cells — their mass, stiffness and friction — on a large scale.

Using this system, the researchers have analyzed how changes in those traits may allow cancer cells to migrate to new sites: Scientists have previously observed that cell lines with higher metastatic potential are generally more deformable, but the MIT team found that decreased friction also appears to help cancer cells traverse narrow channels, suggesting that friction may play a role in the ability of cancer cells to travel in blood vessels and reach new tumor sites.

“Our measurements provide an additional perspective on cell properties that may complement genomic and proteomic approaches,” says Sangwon Byun, an MIT postdoc and lead author of a paper describing the findings in the Proceedings of the National Academy of Sciences the week of April 22.

The system that Byun and colleagues used to study the cancer cells is based on a device previously developed by Scott Manalis, a member of MIT’s Koch Institute for Integrative Cancer Research and an MIT professor of biological engineering. Manalis, the senior author of the PNAS paper, has previously demonstrated that this system, known as a suspended microchannel resonator (SMR), can very accurately measure the mass and density of individual cells.

Inside the SMR, cells flow through a channel carved into a tiny slab that vibrates at a resonant frequency that can be measured with a laser beam. As each cell flows through the channel, the slab’s resonant frequency changes, allowing the researchers to calculate the cell’s mass and density.

Putting the squeeze on cells

For the new study, the researchers modified the system so they can also track each cell’s velocity as it passes through a narrow constriction in the channel. This allows them to estimate both the cell’s deformability and how much friction it experiences as it travels through the constriction, which is slightly smaller than the diameter of the cells under study. Cells that squeeze through this opening faster are more deformable.

In one set of experiments, the researchers compared the deformability of two types of mouse lung-cancer cells. The two cell types differ in the expression of only one transcription factor, known as NKX2-1: Cancer cells not expressing this factor are more aggressive and likely to metastasize. The researchers found that cells that do not express NKX2-1 entered the narrow channel more rapidly, confirming previous studies showing that metastatic cells are more deformable.

The researchers then compared nonmetastatic and metastatic cells from the same mouse model, and found that these metastatic cells were not only more deformable, but they also traveled faster through the length of the constriction (about 50 microns). A similar observation was made when comparing nonmetastatic to metastatic human lung-cancer cell lines. “It seems that the cells experience less friction, making it easier for them to get through the channels,” Byun says.

This phenomenon has not been seen before, in part because scientists haven’t had a good way to simultaneously define the size, deformability and friction of individual flowing cells. Many factors could influence the friction between the cell and the channel wall, including changes in cell-surface expression. For example, metastatic cancer cells often have an increased amount of sialic acid molecules on their surfaces, which may alter friction, the researchers say.

The new MIT system is “probably the world’s most sensitive instrument for measuring a number of different biophysical properties of individual cells,” says Mehmet Toner, a professor of biomedical engineering at Massachusetts General Hospital and Harvard Medical School who was not part of the research team. “It’s very important to know whether metastatic cells have biophysical properties different than normal or nonmetastatic cancer cells, allowing them to go through narrow spaces.”

Circulating tumor cells

The researchers are now using their system to detect circulating tumor cells (CTCs) in cancer patients’ blood samples. The current approach to finding CTCs, which can range in number from a few to several thousand per milliliter of blood, is by looking for a marker (a molecule found on a cell’s surface) that is preferentially expressed by epithelial cells. However, that approach may miss CTCs that don’t express the chosen epithelial markers.

“When you use a specific marker to look for these cells, you find the cells that you’re looking for, but you may be missing a whole population of cells,” says Josephine Shaw, an MIT graduate student and a co-author of the paper. “It’s possible that by using a more holistic and physical approach, we may be able to find certain cells that we wouldn’t be able to find molecularly, because we wouldn’t be able to guess ahead of time what these cells would be expressing.”

Once those cells were captured, scientists could do many more types of tests on them, including analysis of genes expressed and proteins produced, to learn more about how they break free from tumors.

The researchers also plan to study physical changes that occur in cells as they go through the epithelial-mesenchymal transition — a process that allows cancer cells to lose their adhesion and become mobile, helping them metastasize.

Other authors of the paper are MIT postdoc Sungmin Son; Stanford University postdoc Dario Amodei; MIT grad students Nathan Cermak, Joon Ho Kang and Vivian Hecht; former MIT postdoc Monte Winslow; Tyler Jacks, the David H. Koch Professor of Biology at MIT and director of the Koch Institute; and Parag Mallick, an assistant professor of radiology at Stanford.

The research was funded by the National Cancer Institute, through MIT’s Physical Sciences Oncology Center and Stanford’s Center for Cancer Nanotechnology Excellence and Translation, and Stand Up to Cancer.

Source: http://web.mit.edu

 

Everolimus Improves Progression-Free Survival.


Inhibition of the mammalian target of rapamycin (mTOR) is important for overcoming endocrine resistance in ER-positive breast cancer, and positive results from the BOLERO-2 trial (N Engl J Med 2012 Feb 9; 366:520) led to the approval of the mTOR inhibitor everolimus in combination with exemestane for patients who develop progressive disease after treatment with a nonsteroidal aromatase inhibitor. The importance of the mTOR signaling pathway is not restricted to endocrine-sensitive breast cancer. Preclinical data suggest that targeting human epidermal growth factor receptor-2 (HER2) and mTOR may overcome trastuzumab resistance.

Now, O’Regan and colleagues have conducted the multicenter, phase III, randomized, controlled, double-blind BOLERO-3 trial (Abstract 505) to evaluate the combination of the mTOR inhibitor everolimus, the chemotherapy agent vinorelbine, and the HER2 inhibitor trastuzumab versus vinorelbine and trastuzumab in 569 patients with HER2-positive advanced breast cancer; 84% of patients received trastuzumab in the metastatic disease setting and developed disease progression, whereas 16% developed disease progression while receiving adjuvant trastuzumab or within 12 months of receiving it. Patients could have received up to three treatment regimens for metastatic disease; 27% of patients received prior lapatinib.

The inclusion of everolimus conferred a significant improvement in progression-free survival (7.0 vs. 5.8 months; P=0.0067) but no improvement in rates of overall survival (at current follow-up), objective response, or clinical benefit. The addition of everolimus to chemotherapy (5 mg daily) was associated with toxicities similar to that seen when everolimus was combined with the AI exemestane: stomatitis, fatigue, rash, hyperglycemia, and rare pneumonitis.

The combination of everolimus, vinorelbine, and trastuzumab may provide yet another option for patients with HER2-positive metastatic breast cancer. But, if approved, it will likely be positioned after both first-line trastuzumab, pertuzumab, and a taxane and second-line trastuzumab emtansine (T-DM1; JW Oncol Hematol Feb 26 2013). Other treatment considerations in this space include lapatinib and capecitabine, alternative trastuzumab/chemotherapy combinations, and the combination of trastuzumab and lapatinib.

Source: Journal Watch Oncology and Hematology

 

 

Current status on the diagnosis and evaluation of pancreatic tumour in Asia with particular emphasis on the role of endoscopic ultrasound.


In Asia, the incidence of pancreatic cancer in some countries has been increasing. Owing to most cases being diagnosed late, prognosis for pancreatic cancer remains dismal. It is clear the future for pancreatic cancer is early detection. While the possible presence of pancreatic masses is often first raised by non-invasive abdominal imaging such as computerized tomography (CT) and magnetic resonance imaging (MRI), smaller lesions and locoregional lymph node metastases are often not detectable by these means. Endoscopic ultrasonography (EUS) offers a higher sensitivity (93-100%) for the detection of small potentially curable pancreatic masses than other existing imaging modalities. It is also recommended to evaluate portal vein confluence, portal vein, celiac axis and SMA origin, and exclude respectability. Due to the closer proximity of EUS to the target structure, and lower rate of needle tract seeding, EUS-guided fine needle aspiration (FNA) of pancreatic mass is considered the most suitable tissue acquisition technique. Lastly, EUS also enables the performance of endoscopic interventions. Its performance can be further enhanced with newer techniques, including contrast enhanced ultrasound and elastrography. It is anticipated that in the near future, molecular technologies may make it possible to detect microscopic amounts of cancer in tissue or blood, predict relapse and survival after therapy, as well as determine optimal therapy.