Fox News is reporting that researchers from the U.K.’s Institute of Food Research have discovered that jam and jelly may have cancer-fighting properties. These surprising findings derive from the use of pectin as the gelling agent of choice in the products. The researchers discovered that pectin, under specific conditions, releases a “molecular fragment” that binds with galectin 3 (gal3), a protein that has been implicated in many aspects of carcinogenesis, such as “the growth of tumor-nourishing blood vessels and the invasion of cancer cells into body tissue.” When pectin binds with gal3, the protein’s cancer-promoting activities are inhibited.

Jam and jelly develop their potential anti-cancer properties because the manner in which pectin is prepared for use in them is likely to trigger the conditions that create the binding with gal3. Even as promising as these findings may be, much more research needs to be conducted before anything definitive can be said about the possible cancer-fighting benefits of jam and jelly.

Labels: cancer

Disease staging is one of the fundamental steps in the development of a treatment plan for patients with mesothelioma. Effective measurement of tumor spread and the identification of distant metastases are important indications of long-term prognosis and, therefore, are determinate conditions in deciding which patients are eligible for radical surgery and which patients will be treated less invasively. Generally speaking, patients who are considered Stage I-III for pleural mesothelioma may be acceptable for “curative” surgeries such as extrapleural pneumonectomy, while patients with Stage IV disease are excluded from these procedures and will be treated palliatively. Staging is designed to separate out patients so those in the disease’s later stages do not undergo operations that are associated with significant surgical complications and extended recovery time when their long-term prognosis is not hopeful.

Historically, however, there have been difficulties in the accurate determination of stage because of mesothelioma’s unique behavior and morphological form. Unlike most other cancers which present as an individualized tumor with clear boundaries (even if there are multiple tumors, they generally fit this same individualized pattern), pleural mesothelioma presents as a diffuse malignancy that grows along tissue surfaces, with little distinction between malignant and non-malignant areas. This can make determining the full extent of tumor infiltration difficult to properly image. CT is the standard technology in diagnostic imaging for mesothelioma and MRI can be used to supplement its results, but these technologies have known limitations in determining a number of important tumor states, including tumor involvement of the chest wall and diaphragm, as well as a fundamental inability to identify distant metastatic events or to determine lymph node status. PET can be used to identify distant metastases, but it has poor spatial resolution, so precise localization is difficult. Mediastinoscopy is used to determine the status of the mediastinal lymph nodes, but it is an invasive procedure and is limited in its ability to target all of the important lymph nodes.

Because of these difficulties, some of which are common to all cancers and some of which are specific to pleural mesothelioma, researchers have developed a number of new technologies to aid physicians in their ability to accurately diagnose and stage malignant events. One of these new systems is integrated PET/CT, which combines PET’s ability to identify distant metastases with CT’s high resolution imaging of internal anatomic structures. A number of studies on this technology’s use for mesothelioma have been published and the results have been quite promising. Continuing this researching, researchers in Denmark have recently published an article on their use of PET/CT in the preoperative staging of patients with pleural mesothelioma. In their article, “Preoperative Staging of Mesothelioma by 18F-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography/Computed Tomography Fused Imaging and Mediastinoscopy Compared to Pathological Findings After Extrapleural Pneumonectomy,” the authors demonstrate PET/CT’s advancements over CT for pre-operative staging and they recommend its greater use in the staging of mesothelioma, but they also show that it cannot replace mediastinoscopy for the analysis of nodal status.

Overview of the Study

42 patients were enrolled in the study between October 2003 and October 2006. All patients had histologically-confirmed mesothelioma, epitheloid subtype. All patients received neoadjuvant chemotherapy prior to their staging assessments, which were conducted by CT and PET/CT. The results of the scans were interpreted separately and blinded from the other. Patients whose PET/CT results indicated any non-resectable tumor infiltration of the chest wall or of structures in the mediastinum, or any evidence of distant metastases, were not given surgery, although patients whose results indicated possible N2 or N3 metastases were still referred for mediastinoscopy for histological determination of stage. If these results also showed positive N2 or N3 metastatic status, the patients did not undergo surgery.

All other patients were referred for extrapleural pneumonectomy.

The study was interested in two major topics:

1. The ability of PET/CT compared to CT to detect inoperative stages of mesothelioma; and,
2. The validity of PET/CT's results for staging, when compared against mediastinoscopy and final staging determined at EPP

Results

CT vs. PET/CT for Preoperative Staging

The results of the CT vs. PET/CT analysis showed a clear benefit to PET/CT. Of the 42 patients who were screened, PET/CT discovered: T4 disease in 7 patients, while CT did not show any; 14 patients with N2 or N3 disease, while CT only showed 7 patients; and 7 cases of distant metastases, while CT, again, did not show any. These findings resulted in an “upstage migration” of 8 cases: CT disclosed only one case as Stage IV disease, while PET/CT identified nine Stage IV cases (including the one identified by CT). In total, PET/CT excluded 12 of the 42 cases as non-resectable due to T4/M1 status, while CT did not exclude any.

PET/CT vs. Mediastinoscopy

PET/CT identified 30 patients with potentially-resectable disease. Of these patients, 14 indicated possible N2/N3 status, but they were not excluded from surgical consideration without histological confirmation of the findings. All 30 patients were then referred for mediastinoscopy. 6 patients demonstrated histologically-confirmed N2 metastases, which reduced the number of patients eligible for extrapleural pneumonectomy to 24.

All of these patients then received an EPP.

PET/CT vs. Final EPP Staging Results

Of the 24 patients who underwent EPP, 2 had undiagnosed T4 disease that PET/CT missed. T-stage was lower in 1 patient, equal in 13 and higher in 10. These results led to the following stage migration: percentage of patients identified as Stage I was reduced from 63% to 21%, while Stage IV patients increased from 4% to 12%. When compared to both mediastinoscopy and EPP staging, PET/CT correctly identified a number of N-stage cases, but it was also less accurate then both: it under-staged 3 patients when compared to mediastinoscopy and 7 when compared to final staging completed during EPP.

Conclusion

Mesothelioma remains a very difficult disease to treat effectively, and only a subset of patients are eligible for the invasive procedures that are necessary to possibly extend survival times for the disease. The need for accurate staging technologies is not unique to the treatment of pleural mesothelioma, but the difficulties of the disease complicate it. CT has been used, but it has well-known limitations for mesothelioma staging. PET/CT has showed great promise in other studies and the authors of the article describing the present study conclude that PET/CT is an important advancement in the surgical staging of pleural mesothelioma, but that it doesn’t alleviate the need for invasive, yet more accurate, diagnostic techniques such as mediastinoscopy. PET/CT can improve the selection of patients for EPP, especially when compared with CT, but the authors state that more work needs to be done to develop more accurate, non-invasive techniques.

Labels: mesothelioma, pleuralmesothelioma, staging

The current system for staging cases of pleural mesothelioma is based on a TNM model, where the determination of disease stage is based on the relationship between tumor status (T stage), lymph node status (N stage) and the presence or absence of distant metastases (M stage). This system was proposed in 1995, validated through a number of reports and subsequently accepted as the standard mesothelioma staging system by the American Joint Committee on Cancer Staging System, as well as by the Union Internationale Contre le Cancer.

However, a number of questions regarding its underlying classification structure have existed since it was initially proposed. Writing in the journal The Journal of Thoracic and Cardiovascular Surgery, physicians from the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City state that the current staging system was designed to be adjusted as more and better data regarding the classification of nodal status was developed. The authors of the article note that the staging system uses the lymph node map developed for lung cancer staging, but that pleural mesothelioma may require a different pattern map because lymphatic drainage from the pleura may differ from that of the lung.

To answer these questions, as well as others regarding the nodal classification system in mesothelioma patients, the physicians from MSKCC conducted a study on patients with pleural mesothelioma who were treated at their institution and they have recently published their results in an article entitled “The Impact of Lymph Node Station on Survival in 348 Patients with Surgically Resected Malignant Pleural Mesothelioma: Implications for Revision of the American Joint Committee on Cancer Staging System.”

Overview of the Study

The staging system is only applicable to surgical patients, so the retrospective study that the physicians conducted was limited to those patients who underwent either extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D). 348 patients were finally selected for analysis. The sample population, as is common with all forms of mesothelioma, was heavily male gender with the epitheloid histological subtype. 222 patients received EPP, while 126 underwent P/D. Most patients were Stage III at time of surgery.

These patient records were analyzed on a number of fronts, including nodal status (both individual and concurrent metastases), common nodal station involvement, surgical procedures and time to survival.

Results

Overall median survival for the entire patient cohort was 15 months, with significant variations in survival when patients were analyzed for differences in nodal status, as well as histological subtype and overall stage. Patients with N0 or N1 status demonstrated a 19-month median survival time, while patients positive for N2, N2/N1 or internal thoracic node metastases demonstrated a 10-month median survival. Patients with only N2 status did not differ significantly from patients who were positive for both N2 and N1, but multiple N2 nodal stations were indicative of more restricted median survival time.

Other variations in survival were also reported: epitheloid vs. non-epitheloid histology, with non-epitheloid disease associated with worse survival; male gender vs. female gender, with men demonstrating a worse prognosis then women; Stage III/IV patients were associated with shorter survival than were Stage I/II patients.

Conclusion

In the discussion section of the article, the authors considered the importance of their findings in relation to the current staging system. Their results show that pleural mesothelioma is most likely to metastasize to N2 nodes, rather than to N1 nodes. The authors also note that because patients positive for only N1 nodes were associated with longer median survival than were patients positive any form of N2 metastases, the staging system should likely be changed to incorporate this distinction.

These results also confirmed an earlier study these physicians conducted which found that nodal metastasis is common in patients with pleural mesothelioma—nearly 50% of the patient cohort demonstrated some lymph node involvement.

Along with the differences in survival between N1 and N2 status, the results also demonstrated that metastases in multiple N2 nodal stations correlates with a worse prognosis than does N2 status in only one station. Because of this, the authors also state that the staging system could possibly be adjusted to show that multiple N2 stations reflect a higher stage than does a single N2 station.

The authors close the article with a call for larger study on the impact of nodal status on mesothelioma prognosis. Their research indicates grounds for revision of the staging system, but a larger, multicenter study would be needed to confirm these findings.

Labels: mesothelioma, pleuralmesothelioma, staging

Peritoneal mesothelioma is the second most common form of mesothelioma, appearing in 20% of all cases. The disease typically presents as a diffuse malignancy that can spread throughout large areas of the peritoneum. In its advanced stages, the disease can infiltrate the outer layers of the GI tract, as well as metastasize to abdominal organs, but the first indication of the disease as a metastatic event is quite rare. Researchers from Italy have recently published an article in the International Journal of Surgical Pathology where they describe a case report of a 64 year-old man who presented with gastric metastases as the first sign of peritoneal mesothelioma.

The authors describe this as the first such case report in the literature on mesothelioma.

Case Report

The authors describe a 64 year-old man who presented with abdominal pain and distension, with corresponding ascites and significant weight loss within the year. At time of presentation, he has awaiting a liver transplant due to liver cirrhosis and suffered from esophageal varices as well. His physicians first assumed a bacterial infection was the cause of the abdominal pain, but the standard treatments were not effective. After serum markers returned negative, the patient underwent an esophageal gastric endoscopy, which revealed a lesion in the antral mucosa, which is a lining of a specific area (gastric antrum) in the stomach. A biopsy of the lesion was performed and subsequent analysis showed peritoneal mesothelioma, epithelial sub-type. After these results were returned, a high resolution abdominal CT showed thickening of the parietal pleura. The patient was treated with single-agent pemetrexed(Alimta) and was still alive 7 months after diagnosis.

Conclusion

The authors report their article as the first description of a case of gastric metastasis as the first indication of peritoneal mesothelioma. In the disease’s later stages, metastases to abdominal organs are common, but the authors describe discovering peritoneal mesothelioma during an endoscopic GI biopsy as “exceptionally rare.” Because of this, they note serious diagnostic challenges to the clinician who encounters such a case.

Labels: mesothelioma, peritonealmesothelioma

ONCONASE is a first-in-class antitumor agent developed by Alfacell that has shown efficacy for the second-line treatment of malignant mesothelioma. Clinical trials involving ONCANASE have suggested a dual mechanism-of-action: the agent has its own specific anticancer activity and it sensitizes tumor cells to the effects of other chemotherapy agents as well. An article describing the underlying biological activity on ONCONASE has recently been published in the journal Cell Cycle. The authors show that ONCONASE derives its therapeutic effectiveness from its ability to target the role played by small interfering RNA (siRNA) in specific types of tumor genesis.

Labels: mesothelioma, treatments

Advances in our ability to diagnose mesothelioma in its earlier stages are among the most important developments in the recent fight against the disease. Along with the development of more effective treatment agents, these diagnostic advances have allowed physicians to begin treatment earlier than they have previously been able to—which is a key factor in their ability to extend patient survival and to improve issues related to a patient’s quality-of-life.

These advances in these diagnostic and treatment techniques have been the result of innovative research into the disease’s underlying biological activity. As scientists and physicians have learned more about mesothelioma, they have also been able to identify prognostic indicators that have enabled them to better identify the patient classes that will respond best to aggressive treatments and those whose disease requires a more palliative therapeutic protocol. This distinction is important because aggressive treatment protocols require highly invasive surgical techniques and a significant recovery time, so patients who present with specific disease characteristics that indicate poor treatability should not be burdened with such regimens.

The quest to identify more precise prognostic indicators for mesothelioma patients has taken many forms and the variety of research that is being conducted shows the interest that international researchers are now taking in studies of pleural mesothelioma and peritoneal mesothelioma. The latest example of this research is a paper that that has been published from researchers in Turkey. In an articled entitled “Pleural Fluid Findings as Prognostic Factors for Malignant Pleural Mesothelioma,” published in the Journal of Clinical Laboratory Analysis, they report the results of a retrospective study they conducted that analyzed the characteristics of pleural fluid in patients with pleural mesothleioma for any prognostic indicators it may contain regarding overall patient survival.

Overview of the Study

The researchers report that only one previous study had analyzed pleural fluid for its prognostic benefits, but only 26 patients had been enrolled in that study. In this study, they examined 71 patient records. There were 33 males and 38 females in the study population, with a mean age of 59 years. 23 people were smokers. Even though smoking has not been shown to have any causative affect on mesothelioma genesis, it is known to be a causative factor for a number of other cardiovascular diseases.

The patients were diagnosed by cytological or histological analysis, usually with a immunohistochemical panel that tested for combinations of calretinin, epithelial membrane antigen (EMA), thrombomodulin, HBME-1, CD15, B72.3 or carcinoembryonic antigen (CEA). Pleural fluid was analyzed for a number of specific characteristics, including pleural fluid glucose levels, lactate dehydrogenase (LDH), albumin, protein-to-serum levels and pleural fluid leukocyte counts. For their reported survival figures, the authors defined survival from date of thoracentesis to time of death.

Results

When the authors analyzed the results of the entire patient cohort, they found two independent prognostic factors that were indicative of survival: the ratio of pleural fluid to serum LDH > 1.0 and total leukocyte count in the fluid. They found a mean leukocyte count of 648+-860/mm³ for the entire cohort, but a significant increase in survival for those patients with a count of >700/mm³. When patients who used diuretics were excluded from these results, they found that fluid glucose levels also achieved statistical significance as a predictor of survival.

Conclusion

This study has indicated another set of prognostic tests that physicians can use in their determination of survival and overall prognosis for patients with pleural mesothelioma. These results will need to be independently verified before their scientific and medical value can be fully validated, but this study provides valuable information about specific biological factors involved with mesothelioma. The authors also note that the low leukocyte mean suggests a “weak inflammatory reaction against the tumor” and they suggest the “stimulation of antitumor response” is a possible treatment avenue for mesothelioma patients.

Labels: diagnosis, mesothelioma, pleuralmesothelioma

Malignant Mesothelioma is most commonly a disease of the older and the elderly. The vast majority of all mesothelioma diagnoses are for men and women (although, mainly men), older that 55 or 60. However, the disease can, albeit very rarely, affect teenagers and young adults. Because mesothelioma is so rarely seen in these populations, studies are impossible to perform and little is understood about the best treatment regimens or the prognostic indicators involved in determining overall treatability. The only way to share information about these cases is through the publication of individual case reports in medical journals.

Physicians from the Dana-Farber Cancer Institute and from Brigham & Women’s Hospital have recently published an article on their treatment of four pediatric peritoneal mesothelioma cases. The case reports describe how the physcians treated these patients and how each responded to these therapies. They close the article with a number of recommendations regarding the future treatment of pediatric mesothelioma cases.

Case Reports

The authors report on four cases of pediatric mesothelioma:

1. A previously healthy 17-year-old female with a number of symptoms, including deep vein thrombosis of the left arm, a left-side pleural effusion and an unknown pelvic mass. Fluid in her peritoneum tested positive for mesothelioma.
2. A previously healthy 16-year-old male with pelvic pain and weight loss, among other symptoms, had a biopsy of a diffuse tumor mass in his pelvis which revealed peritoneal mesothelioma.
3. A previously healthy 20-year-old male with a Klebsiella pneumonia, pleural effusion and a mass in the tissue surrounding his kidneys tested positive for peritoneal mesothelioma.
4. A 16-year-old female with a prior cancer history (neuroblastoma at 12) who had achieved complete remission, presented with abdominal pain that was discovered to be caused by peritoneal mesothelioma.

None of the patients had any personal risk factors for mesothelioma, and none were smokers. However, three of them had fathers who were likely exposed to asbestos during their work in construction. None of the men had any evidence of pleural mesothelioma or peritoneal mesothelioma, but we know that the disease can affect the children and spouses of exposed workers before they are diagnosed, or even if they are never diagnosed.

Treatment Regimen and Response

After the patients were diagnosed with peritoneal mesothelioma, they all received the same basic treatments as an adult would receive. All of the patients received systematic chemotherapy using pemetrexed and cisplatin; two of the patients received surgical debulking prior to their chemotherapy.

The median survival for the group was 40.3 months. At the time the article was published, three of the four were still alive. Two of these were progression free at 45 and 57 months, respectively, while the third demonstrated some progression at 22 months, but will still alive at 24 months.

Conclusion

The authors conclude their article by raising the question as to the relationship between asbestos exposure and the development of either pleural mesothelioma or peritoneal mesothelioma, especially in pediatric cases. They note that while the incidence of the pleural disease is to be expected based on the way in which these exposures occur, the reasons for the development of peritoneal mesothelioma are still unknown. They wonder if the precise nature of the exposures—whatever they may be, as the question remains totally open for these four patients—may explain the development of peritoneal disease in place of pleural disease.

They also conclude that, where applicable, pediatric cases should be treated in the same manner as adult cases are treated: they should receive debulking surgery if possible and intravenous systemic chemotherapy. The authors also believe that these patients should be eligible for enrollment in adult-focused clinical trials.

Labels: mesothelioma, peritonealmesothelioma, treatments

Even as the introduction of combination chemotherapy using pemetrexed and cisplatin(Alimta Therapy) was a watershed event in the history of mesothelioma treatments, research into the disease’s underlying cellular activity has shown that mesothelioma cells demonstrate a natural resistance to most forms of chemotherapy, as well as a natural resistance to apoptosis. This research has postulated that the disease’s anti-apoptotic tendency may be one of the primary reasons for its aggressiveness and its ability to resist long-term management. Therapies using pemetrexed and cisplatin have certainly achieved longer median survival times than previous therapies have achieved, but they are still not a curative solution for pleural mesothelioma or peritoneal mesothelioma. At some point in a patient’s treatment, the chemo agents begin to lose efficacy and the disease eventually overcomes the treatment’s ability to manage it. If this is due to the disease’s natural resistance to apoptosis, then understanding the biological mechanisms responsible for this resistance should offer researchers the chance to develop treatments that account for these mechanisms, which could then lead to the development of more effective therapies than are currently available.

One of the leading genetic candidates for influencing mesothelioma’s apoptotic resistance is p21, a gene that regulates certain aspects of the S phase—the synthesis phase—of the cell cycle. High levels of p21 expression have been implicated in prior research regarding anti-apoptotic behavior and it has been shown to be highly expressed in mesothelioma cell tissues and cell lines.

Researchers in Italy conducted a study where they investigated the relationship between p21 expression and mesothelioma’s resistance or susceptibility to apoptosis and cytotoxic treatment. They found that p21 was expressed within in tumor cells in response to some chemotherapy agents, which may explain why mesothelioma is so resistant to chemotherapy: even as the chemo agents are being absorbed by the cancer cells, the cells are expressing a genetic agent, p21, that increases their resistance to apoptosis, and therefore, the cytotoxic effects of chemotherapy.

The researchers found that if they could disrupt the expression of p21 in these cells then the cytotoxic effects of the chemotherapy agents they were studying were greatly enhanced. Their results were so successful that they are now calling for more research into the effects of p21 expression in mesothelioma and, specifically, the study of novel therapeutic techniques to inhibit its expression among mesothelioma cells.

Labels: chemotherapy, mesothelioma, treatments

Eli Lilly has announced that its cancer drug Alimta, when used in combination with cisplatin, has received FDA approval for the first-line treatment of “locally-advanced and metastatic non-small cell lung cancer (NSCLC), for patients with nonsquamous histology.” The FDA’s new approval is the third overall approval that Alimta has received, and the second for its use in first-line therapy. The drug is most well known for the first-line treatment of pleural mesothelioma where it—again in combination with cisplatin—represents the chemotherapy standard of care for the treatment of the disease. It has also received approvals in single-agent use for the second-line treatment of NSCLC after prior chemotherapy treatment.

Labels: chemotherapy, LungCancer, mesothelioma, treatments