levoleucovorin and Colorectal-Neoplasms--Hereditary-Nonpolyposis

Microsatellite instability is the consequence of a deficient mismatch repair system. It has a key role in the diagnostic strategy of Lynch syndrome, where tumours are all characterized by the presence of this phenotype. Microsatellite instability is therefore essential in the selection of colorectal cancer patients in whom a germline analysis of Mismatch Repair genes is possibly indicated. Moreover, microsatellite instability tumours are associated with a good prognosis and a resistance to fluorouracil-based adjuvant chemotherapy, which has a clinical application mainly in stage II colon cancer patients in whom adjuvant chemotherapy has a less beneficial effect than in stage III and outcome in presence of microsatellite instability is excellent. Recent data suggest that impact of microsatellite instability on benefit to fluorouracil-based adjuvant chemotherapy is dependent of the molecular mechanism involved in this genetic instability since an improved survival has been reported with adjuvant fluorouracil in microsatellite instability colorectal cancers of germline origin but not in sporadic cases. Predictive value of microsatellite instability on response to fluorouracil/oxaliplatin adjuvant chemotherapy has been less evaluated but recent studies suggest that the favorable outcome of Microsatellite instability tumours is maintained in patients receiving FOLFOX.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Organoplatinum Compounds; Prognosis; Treatment Outcome

Microsatellite instability (MSI) phenotype occurs in approximately 15 to 24% of colorectal cancer (CRC) patients and may be sporadic or hereditary. It reflects a mutator phenotype in the tumor due to a lack of mismatch repair system. MSI is indeed one of the characteristics of CRCs occurring in Lynch syndrome and some sporadic cases. CRCs with MSI have a better prognosis than CRCs with microsatellite stability (MSS). This is explained partly by a more important anti-tumor immune response and by apoptosis of tumor cells in which mutations accumulate. However, in some retrospective studies, microsatellite instability in stage II CRCs was associated with no benefit to or even a deleterious effect of 5-FU alone based adjuvant therapy. Nevertheless, results obtained in stage III CRCs with FOLFOX type adjuvant chemotherapy remain favorable in retrospective studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Mutation; Neoplasm Staging; Organoplatinum Compounds; Prognosis

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, represents 5% to 7% of colorectal cancers. It is an autosomal dominant inherited disorder characterized by an early onset of colorectal tumors, predominantly proximal, and multiple and microsatellite instability. We used the Amsterdam II criteria for its identification.. To analyze the case of a patient with a family history of malignant colorectal tumors at an early age of onset.. A 40-year-old woman, from Valle de Punilla, Cordoba, Argentina, with no previous medical history, complained of mild changes in her bowel habits and was admitted to the general surgery department with the radiographic diagnosis of a tumor in the hepatic flexure of the colon. She underwent a right hemicolectomy for a Dukes B stenosing tumor (T3N0M0, stage IIa).. In this report, we present the case of a woman with HNPCC who met the Amsterdam II criteria II. Family members who meet these criteria should be screened for the mutation in MMR genes. As genetic tests are not routinely available, an annual colonoscopic surveillance of all asymptomatic relatives older than 25 to 30 years old who meet the criteria is recommended, regardless of the availability and/or the outcome of genetic testing.

Topics: Adult; Antimetabolites, Antineoplastic; Colectomy; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Treatment Outcome

It is known that colorectal cancers (CRC) are frequently seen and constitute an important part of cancer-related deaths. Lynch syndrome (LS) is responsible for 3-5% of CRCs and develops due to mutations in DNA mismatch repair (MMR) genes. The most important MMR genes are MutL homolog1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and postmeiotic segregation increased 2 (PMS2). PMS2 and MSH6 mutations are very rarely seen in LS.. We present a case that developed metastatic CRC, which we diagnosed as LS in association with a very rarely seen PMS2 and MSH6 germline mutation. Genetic counseling was recommended for the family, and screening programs were initiated for the family of the patient whose chemotherapy was continued after the diagnosis.. With the increase in daily use of next-generation sequencing (NGS) technology, it is thought that detection rate of both combined mutations and rare mutations will be increased.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA-Binding Proteins; Fluorouracil; Genetic Predisposition to Disease; Humans; Leucovorin; Male; Middle Aged; Mismatch Repair Endonuclease PMS2; Mutation; Organoplatinum Compounds; Phenotype

BACKGROUND Pancreatic adenocarcinoma (PDA) is associated with an 8.6-fold increased risk in Lynch syndrome patients. Here, we report the case of a Lynch syndrome PDA patient with an exceptional response to a single cycle of pembrolizumab immunotherapy. CASE REPORT A 65-year-old male patient with Lynch syndrome mismatch repair (MMR) deficient PDA with metastatic liver disease, received 1 cycle of pembrolizumab (200 mg) after progressing on 2 standard lines of treatment. His initial computed tomography (CT) showed 3×2.5 cm PDA. At that time, the disease was considered borderline resectable, and the patient received 6 cycles of FOLFIRINOX followed by chemoradiotherapy with capecitabine. A follow-up CT scan showed multiple new liver lesions. The biopsy showed metastatic PDA and tumor tissue demonstrated high microsatellite instability with abnormal/lost expression of MLH1 and PMS2 proteins. The patient was started on pembrolizumab. Only 1 cycle was given due to the development of thromboembolic complications: pulmonary embolism and myocardial infarction. His thrombophilia workup was negative. Restaging CT scans at 3, 6, and 9 months after 1 cycle of pembrolizumab revealed an excellent response with shrinkage of liver lesions. Restaging at 11 months showed the eventual resolution of most liver lesions. No new metastatic disease developed. A repeat biopsy of the dominant liver lesion showed no morphological evidence of PDA. CONCLUSIONS Only 1 cycle of pembrolizumab resulted in clinical complete response and pathologic response in metastatic PDA. We emphasize the importance of testing for MMR status and treating with immunotherapy in metastatic PDA patients with MMR deficiency.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms, Hereditary Nonpolyposis; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Oxaliplatin; Pancreatic Neoplasms

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds

Mutations in the DNA mismatch repair (MMR) gene MSH2 cause Lynch syndromes I and II and sporadic colorectal cancers. Msh2(null) mice predominantly develop lymphoma and do not accurately recapitulate the colorectal cancer phenotype.. We generated and examined mice with a conditional Msh2 disruption (Msh2(LoxP)), permitting tissue-specific gene inactivation. ECMsh2(LoxP/LoxP) mice carried an EIIa-Cre transgene, and VCMsh2(LoxP/LoxP) mice carried a Villin-Cre transgene. We combined the VCMsh2(LoxP) allele with either Msh2(Delta7null) (VCMsh2(LoxP/null)) or Msh2(G674D) mutations (VCMsh2(LoxP/G674D)) to create allelic phase mutants. These mice were given cisplatin or 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX), and their tumors were measured by magnetic resonance imaging.. Embryonic fibroblasts from ECMsh2(LoxP/LoxP) mice do not express MSH2 and are MMR deficient. Reverse transcription, polymerase chain reaction, and immunohistochemistry from VCMsh2(LoxP/LoxP) mice demonstrated specific loss of Msh2 messenger RNA and protein from epithelial cells of the intestinal tract. Microsatellite instability was observed in all VCMsh2 strains and limited to the intestinal mucosa. Resulting adenomas and adenocarcinomas had somatic truncation mutations to the adenomatous polyposis coli (Apc) gene. VCMsh2(LoxP/LoxP) mice did not develop lymphoma. Comparison of allelic phase tumors revealed significant differences in multiplicity and size. When treated with cisplatin or FOLFOX, tumor size was reduced in VCMsh2(LoxP/G674D) but not VCMsh2(LoxP/null) tumors. The apoptotic response to FOLFOX was partially sustained in the intestinal mucosa of VCMsh2(LoxP/G674D) animals.. Msh2(LoxP/LoxP) mice in combination with appropriate Cre recombinase transgenes have excellent potential for preclinical modeling of Lynch syndrome, MMR-deficient tumors of other tissue types, and use in drug development.

Topics: Adenocarcinoma; Adenoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cisplatin; Colorectal Neoplasms, Hereditary Nonpolyposis; Disease Models, Animal; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, APC; Genotype; Immunohistochemistry; Integrases; Intestinal Neoplasms; Leucovorin; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Microsatellite Instability; Mutation; MutS Homolog 2 Protein; Organoplatinum Compounds; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tumor Burden

Topics: Adaptor Proteins, Signal Transducing; Adenosine Triphosphatases; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA Repair Enzymes; DNA-Binding Proteins; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Nuclear Proteins; Organoplatinum Compounds

Gastrointestinal carcinoid tumors are often associated with other tumors, particularly colon adenocarcinomas; but the association between carcinoid tumors and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has not yet been explored. We report an unusual case of a 28-year-old woman with HNPCC who underwent surgery for a transverse colon adenocarcinoma in whom an appendix carcinoid tumor was incidentally found. To assess whether the carcinoid tumor displayed the characteristic molecular features of HNPCC tumors, we investigated the expression of mismatch-repair (MMR) proteins and microsatellite instability (MSI) status in both tumors. Both tumors demonstrated normal expression of the MMR proteins hMLH1, hMSH2, hMSH6, and hPMS2. Interestingly, the adenocarcinoma exhibited an MSI phenotype but the carcinoid tumor did not, indicating that these 2 tumors arose through different molecular pathways.

Topics: Adult; Antimetabolites, Antineoplastic; Appendiceal Neoplasms; Carcinoid Tumor; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA-Binding Proteins; DNA, Neoplasm; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Microsatellite Repeats; MutS Homolog 3 Protein; Treatment Outcome