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Vulvar & Vaginal Neoplasia in Women With Inflammatory Bowel Disease

In a new retrospective study, researchers found that the use of immunosuppressive therapy does not increase the occurrence or recurrence of vulvar or vaginal cancer in women with inflammatory bowel disease (IBD) (Dig Liver Dis 2020; doi: 10.1016/j.dld.2019.10.002). However, earlier onset of cancer was reported, and lymphomas were found in some patients, which is very rare in the genital tract. Immunosuppressive drugs are the cornerstone for treatment of IBD, but they have been associated with an increased risk of certain cancers, including lymphoma and urinary tract cancer. A team of researchers investigated whether the use of these drugs also increases the risk of vulvar and vaginal cancer. The researchers retrieved histopathological data of all IBD patients with vulvovaginal malignancies from the nationwide network and registry of histopathology and cytopathology reports in the Netherlands (PALGA) over a 24-year period, from 1991 to 2015. Medical histories for these patients were obtained from their treating physicians, including demographics, medication history, HPV status, smoking, and use of immunosuppressive drugs. The rate of vaginal and vulvar carcinoma or pre-stage neoplasia in IBD patients did not differ significantly from that of the general population, the researchers found. In addition, in patients with IBD, the use of immunosuppressive drugs did not increase the rate of these diseases. However, IBD patients who were treated with immunosuppressive therapy were, on average, 11 years younger than other IBD patients when their vaginal or vulvar cancer was diagnosed. Sixty-seven percent of the women with vulvovaginal cancers had Crohn's disease versus 33 percent with ulcerative colitis.



Anti-Angiogenic Effects of VEGF Stimulation on Endothelium Deficient in Phosphoinositide Recycling

Scientists have devised a new strategy to stop tumors from developing the new blood vessels they need to grow. Once thought to be extremely promising for the treatment of cancer, blocking molecules that stimulate new blood vessel growth (angiogenesis) has proven ineffective because tumor cells respond by producing more stimulatory molecules. The new strategy involves disabling key enzymes that replenish the molecule that cells need for the reactions that sustain new vessel growth (Nat Commun 2020; doi: 10.1038/s41467-020-14956-z). Among the angiogenesis factors that stimulate new vessel growth is vascular endothelial growth factor (VEGF), which binds to a receptor on cell surfaces. This binding sets off a sequence of chemical reactions inside the cells lining the inside of blood vessels, culminating in new vessel growth. Previous attempts have sought to prevent this binding by targeting VEGF with antibodies or drugs, or by blocking the receptor so VEGF can't bind to it. However, tumors respond by producing more VEGF, overwhelming such efforts. After binding occurs, an enzyme that converts the compound phosphatidylinositol-(4,5)-bisphosphate (PIP2) into inositol triphosphate, which is needed for the reactions that fuel new blood vessel growth, and diacylglycerol (DAG). Through a series of enzyme-assisted steps, DAG is converted back into PIP2, allowing it to be recycled, as needed. The researchers showed that they could stop angiogenesis by blocking any of the enzymes in this PIP2 recycling series. They first halted angiogenesis in human cell cultures and zebrafish embryos by disabling the genes for one or more of the enzymes. They then targeted tumors in mice with drugs that block the recycling enzymes. Compared to normal mice, the treated mice had less tumor and tumor blood vessel growth. Moreover, adding more VEGF depleted any remaining PIP2, further reducing blood vessel growth.



Predicting Ultrahigh Risk Multiple Myeloma By Molecular Profiling: An Analysis of Newly Diagnosed Transplant Eligible Myeloma XI Trial Patients

A new genetic test could help doctors pick out patients with multiple myeloma who are at "ultra-high risk" of their cancer progressing aggressively early on (Leukemia 2020; doi: 10.1038/s41375-020-0750-z). Researchers showed that patients whose cancers display particular genetic patterns have a much poorer survival than average and are unlikely to benefit from a drug called lenalidomide on its own. Scientists studied 329 patients across UK hospitals from the phase III Cancer Research UK Myeloma XI trial, which looked at the effectiveness of a range of targeted drugs, including lenalidomide, in people newly diagnosed with multiple myeloma. Researchers looked for people at ultra-high risk by analyzing patterns of abnormal gene activity and genetic mutations of their cancers-to find out if these signatures could provide clues as to how aggressive their cancer is, how quickly it spreads, and if it is likely to respond to treatment with lenalidomide on its own. One quarter of the patients, 81 in total, had cancers with the so-called SKY92 signature linked to high-risk status. On average, patients with cancers that had the SKY92 high-risk gene expression signature had an up to three-fold increased risk of their cancer returning early. Those with heavily genetically mutated cancers had a two-fold increased risk of death. Combining information about these two risk features, which had before been regarded as an "either/or" test, improved the researcher's ability to predict disease outcome. Around 10 percent of the total patient group had both the SKY92 signature and double-hit genetic features. People in this group were at ultra-high risk of early, aggressive disease relapse, with all cancers in this group progressing within 4 years with current standard therapies-as opposed to much longer responses in other groups. Patients with ultra-high risk disease had an 11-fold increased risk of death compared with other patients. The researchers found that patients in this ultra-high risk group were highly unlikely to benefit from lenalidomide as ongoing or maintenance therapy. People with ultra-high risk myeloma have a high unmet need for new treatment approaches, including cocktails of novel immunotherapy drugs in combination with chemotherapy.



Prognosis Based Definition of Resectability in Pancreatic Cancer: A Road Map to New Guidelines

New research published offers a roadmap to new guidelines for physicians in prioritizing pancreatic cancer treatments and improving outcomes through surgery (Ann Surg 2020; doi: 10.1097/SLA.0000000000003859). The study suggests a new concept of resectability and identifies objective pre-operative prognostic factors that can predict long-term survival of patients affected by pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. In the study, researchers analyzed nearly 8,000 patients who underwent pancreatic resection for PDAC from January 2010 to December 2016. The research found that the main prognostic factors for survival were age, sex, levels of carbohydrate antigen CA 19-9, tumor size, primary site, neoadjuvant treatment, Charlson/Deyo score, and facility type. For example, academic facilities were associated with better survival rates. The strength of the findings were validated by a high significant randomized test, log-rank test and simple hazard ratio. One of the most critical findings is that the tumor engagement of peri-pancreatic arteries at pre-operative scans, historically considered by several centers a contraindication for surgery, does not have a negative impact on survival rates after resection. The study offers the advantage of estimating the outcome of each patient before an operation, and regardless of local anatomic features of the tumor, to understand if a patient qualifies or not for an operation based on his or her long-term predicted survival. The use of the nomogram in clinical practice should be proposed after a prospective validation.