Ukierunkowane molekularnie leczenie chorych na raka tarczycy — przegląd badań klinicznych

Purpose of review. Several new targeted therapies with multikinase inhibitors targeting vascular endothelial growth factor (VEGF), rearranged during transfection and v-raf murine sarcoma viral oncogene homolog B1 pathways have been tested in clinical trials for radioiodine-refractory differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in the past 10 years. Recent findings. Results of the fi rst phase III trial of VEGF-targeted therapy (sorafenib) in DTC were presented in June 2013, and two phase III trials with VEGF and rearranged during transfection-targeted therapies (vandetanib and cabozantinib) in MTC have led to approval by US Food and Drug Administration in the past 2 years. Whereas such therapies increase median progression-free survival compared to placebo, there is no therapy proven to improve overall survival yet. Signifi cant potential adverse event risks associated with such therapies need to be recognized. Dissemination of knowledge about targeted therapies is critical for various medical specialists as patient care for thyroid cancers is best delivered in a multidisciplinary setting. Summary. Successful development of targeted systemic therapies in DTC and MTC in the past 5 years is incredibly exciting in the fi eld and patients with advanced DTC/MTC now have new standard-of-care therapy options.Cel przeglądu. W ciągu ostatnich 10 lat w kilku badaniach klinicznych oceniano rolę wielokinazowych inhibitorów czynnika wzrostu śródbłonka naczyń (VEGF), protoonogenu RET (REarranged during Transfection) i protoonkogennej kinazy serynowo-treoninowej BRAF (v-raf murine sarcoma viral oncogene homolog B1) w leczeniu chorych na zróżnicowanego raka tarczycy (DTC) opornego na jod radioaktywny oraz raka rdzeniastego tarczycy (MTC). Najnowsze odkrycia. W czerwcu 2013 roku przedstawiono wyniki pierwszego badania III fazy dotyczącego leczenia ukierunkowanego przeciwko VEGF (sorafenib) w DTC, a w ciągu ostatnich 2 lat wyniki dwóch innych badań III fazy analizujących leki skierowane przeciwko VEGF i RET (wandetanib i kabozantynib) w MTC, które doprowadziły do rejestracji tych leków przez amerykańską Agencję ds. Żywności i Leków. W porównaniu z placebo, leczenie ukierunkowane wydłużało medianę czasu przeżycia wolnego od progresji, jednak żaden z ocenianych schematów terapeutycznych nie wpływał na przeżycie całkowite. Planując leczenie należy brać pod uwagę ryzyko istotnych działań niepożądanych. Postępowanie terapeutyczne u chorych na raka tarczycy ma charakter wielodyscyplinarny, dlatego istotne znaczenie ma popularyzacja wiedzy na temat leczenia ukierunkowanego molekularnie wśród lekarzy różnych specjalności. Podsumowanie. Znaczący rozwój metod leczenia ukierunkowanego molekularnie sprawił, że w ciągu ostatnich 5 lat pojawiły się nowe opcje terapeutyczne dla chorych na zaawansowane DTC/MTC

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesLynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.Ohio State University (OSU) Comprehensive Cancer Center OSU Colorectal Cancer Research fund Obrine-Weaver Fund Pelotonia Fellowship Award deCODE genetic

Large Cancer Pedigree Involving Multiple Cancer Genes including Likely Digenic MSH2 and MSH6 Lynch Syndrome (LS) and an Instance of Recombinational Rescue from LS

Funding Information: This research was funded in part by a Cedars-Sinai Medical Center Precision Health Initiative Award to Megan P. Hitchins and Andrew Hendifar. Publisher Copyright: © 2022 by the authors.Lynch syndrome (LS), caused by heterozygous pathogenic variants affecting one of the mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2), confers moderate to high risks for colorectal, endometrial, and other cancers. We describe a four-generation, 13-branched pedigree in which multiple LS branches carry the MSH2 pathogenic variant c.2006G>T (p.Gly669Val), one branch has this and an additional novel MSH6 variant c.3936_4001+8dup (intronic), and other non-LS branches carry variants within other cancer-relevant genes (NBN, MC1R, PTPRJ). Both MSH2 c.2006G>T and MSH6 c.3936_4001+8dup caused aberrant RNA splicing in carriers, including out-of-frame exon-skipping, providing functional evidence of their pathogenicity. MSH2 and MSH6 are co-located on Chr2p21, but the two variants segregated independently (mapped in trans) within the digenic branch, with carriers of either or both variants. Thus, MSH2 c.2006G>T and MSH6 c.3936_4001+8dup independently confer LS with differing cancer risks among family members in the same branch. Carriers of both variants have near 100% risk of transmitting either one to offspring. Nevertheless, a female carrier of both variants did not transmit either to one son, due to a germline recombination within the intervening region. Genetic diagnosis, risk stratification, and counseling for cancer and inheritance were highly individualized in this family. The finding of multiple cancer-associated variants in this pedigree illustrates a need to consider offering multicancer gene panel testing, as opposed to targeted cascade testing, as additional cancer variants may be uncovered in relatives.Peer reviewe

What is the optimal neo-adjuvant treatment for liver metastasis?

Colorectal cancer is the third most common cancer in the Western population and has a 5-year overall survival of 5–10% when metastatic. Approximately 30% of the patients with metastatic colorectal cancer have limited disease apparently isolated to the liver and, if this can be resected, the 5-year overall survival is improved to 30–60%. Therefore, it is important to identify patients who have both resectable disease and those with initially unresectable tumors who can potentially be downsized with chemotherapy to allow resection. First-line doublet chemotherapy regimens lead to response rates of 50–60%, triplet chemotherapy regimens may result in a response rate of up to 70%, and biological agents may add to responses or induce morphologic changes that facilitate disease resection. Surgical advances in recent years have also increased resectability rates and have challenged prior rules of resectability. Local therapies including ablation and radiation, often performed in conjunction with resection, may further aid in control of disease. The aim of this article is to focus on the role of neoadjuvant therapy in the treatment of colorectal liver metastases

Krabbamein í ristli og endaþarmi - yfirlitsgrein

Colorectal cancer is the third most common cancer in the Western hemisphere and the incidence increases with increasing age. Most colorectal cancers are localized with or without lymph node metastases. Up to 20% of patients present with metastatic disease, most commonly to the liver. Surgery is the only curative therapy for localized colorectal cancer and adjuvant chemotherapy is usually recommended for patients with lymph node metastases. Surgery, radiation therapy and chemotherapy are the key components of rectal cancer therapy. Selected patients with recurrent and metastatic disease can be salvaged with surgery but chemotherapy remains the mainstay of therapy for advanced colorectal cancer. Substantial progress has been observed in the treatment of metastatic colorectal cancer in recent years

Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome.

To access publisher's full text version of this article click on the hyperlink belowLynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.Pelotonia, an annual cycling event in Columbus, Ohio National Cancer Institute, Bethesda, M