Colorectal cancer harboring EGFR kinase domain duplication response to EGFR tyrosine kinase inhibitors.

Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare, recurrent oncogenic variant that constitutively activates EGFR in non-small-cell lung cancer. Herein, we report the case of a 70-year-old man with resectable colorectal adenocarcinoma who underwent surgery followed by adjuvant therapy. He relapsed with multiple liver metastases and received standard chemotherapy until his disease became refractory. Comprehensive genomic profiling of his postoperative colorectal cancer tissue revealed EGFR-KDD. He was treated with an EGFR tyrosine kinase inhibitor (TKI), afatinib and achieved a partial response (- 55%) after 8 weeks; however, he developed massive malignant ascites after 13 weeks. Osimertinib, another EGFR-TKI, controlled his tumors for 9 months. Patient-derived cancer organoids from his malignant ascites confirmed sensitivity to EGFR-TKIs. The findings suggest that EGFR-TKIs can be a potential treatment option for this molecular subgroup.

Lynch syndrome screening in patients with young-onset extra-colorectal Lynch syndrome-associated cancers.

BACKGROUND: Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic germline variants in mismatch repair (MMR) genes, which predisposes to various types of cancers showing deficient MMR (dMMR). Identification of LS probands is crucial to reduce cancer-related deaths in affected families. Although universal screening is recommended for colorectal and endometrial cancers, and age-restricted screening is proposed as an alternative, LS screening covering a broader spectrum of cancer types is needed. In the current study, we elucidated the rate of dMMR tumors and evaluated the outcome of LS screening in young-onset extra-colorectal LS-associated cancers. METHODS: Immunohistochemistry for MMR proteins were retrospectively performed in a total of 309 tissue samples of endometrial, non-mucinous ovarian, gastric, urothelial, pancreatic, biliary tract, and adrenal cancers in patients < 50 years of age. Clinicopathological information and the results of genetic testing were obtained from medical charts. RESULTS: There were 24 dMMR tumors (7.8%) including 18 endometrial, three ovarian, two urothelial, and one gastric cancer. Co-occurrence of colorectal cancer and family history of LS-associated cancers was significantly enriched in patients with dMMR tumors. Among the 16 patients with dMMR tumors who were informed of the immunohistochemistry results, five with endometrial and one with urothelial cancer were diagnosed as LS with positive pathogenic variants in MMR genes. CONCLUSIONS: We report the outcome of immunohistochemistry for MMR proteins performed in multiple types of young-onset extra-colorectal LS-associated cancers. Our study demonstrates the feasibility of a comprehensive LS screening program incorporating young-onset patients with various types of extra-colorectal LS-associated cancers.

Efficacy and safety of cold forceps biopsy for diminutive pharyngeal neoplasms: Single-center, prospective pilot study.

BACKGROUND: Management of diminutive pharyngeal neoplasms is controversial. Thus, we conducted a single-center, prospective pilot study to investigate the efficacy and safety of endoscopic excision with cold forceps biopsy (CFB) of these lesions. PATIENTS AND METHODS: Thirty-nine lesions endoscopically diagnosed with narrow-band imaging as pharyngeal neoplasms of 3 mm or smaller were excised with CFB using jumbo biopsy forceps (cap diameter 2.8 mm, jaw volume 12.4 mm3 ). The primary outcome was endoscopically determined local remnant/recurrence rate 3 months after CFB. The secondary outcomes were histopathologically determined local remnant/recurrence rate; risk factors associated with the endoscopic remnant/recurrence; and incidence of intraoperative or delayed bleeding and other adverse events. RESULTS: Histological diagnosis of the 39 CFB-excised lesions were: 11 high-grade dysplasia (28.2%), 22 low-grade dysplasia (56.4%), two basal cell hyperplasia (5.1%) and four atypical squamous epithelium (10.3%).Twenty-seven patients (30 lesions) underwent follow-up endoscopy 3 months after CFB; the endoscopic and pathological local remnant/recurrence rate was 20% (6/30; 95% confidence interval (CI), 7.7-36.6%) and 16.7% (5/30; 95% CI, 5.6-34.7%), respectively. Location of the lesion in the hypopharynx was a significant risk factor associated with the endoscopic local remnant/recurrence (P = 0.049). No significant adverse events occurred. CONCLUSIONS: Cold forceps biopsy with jumbo biopsy forceps appears to be a safe and effective technique for excising diminutive pharyngeal neoplasms. Although small, the excised lesions may have a remarkably high frequency of high-grade dysplasia. (Clinical trial registration number: UMIN000037980).

Visceral fat obesity is the key risk factor for the development of reflux erosive esophagitis in 40-69-years subjects.

BACKGROUND: Visceral fat obesity can be defined quantitatively by abdominal computed tomography, however, the usefulness of measuring visceral fat area to assess the etiology of gastrointestinal reflux disease has not been fully elucidated. METHODS: A total of 433 healthy subjects aged 40-69 years (234 men, 199 women) were included in the study. The relationship between obesity-related factors (total fat area, visceral fat area, subcutaneous fat area, waist circumference, and body mass index) and the incidence of reflux erosive esophagitis was investigated. Lifestyle factors and stomach conditions relevant to the onset of erosive esophagitis were also analyzed. RESULTS: The prevalence of reflux erosive esophagitis was 27.2% (118/433; 106 men, 12 women). Visceral fat area was higher in subjects with erosive esophagitis than in those without (116.6 cm2 vs. 64.9 cm2, respectively). The incidence of erosive esophagitis was higher in subjects with visceral fat obesity (visceral fat area ≥ 100 cm2) than in those without (61.2% vs. 12.8%, respectively). Visceral fat obesity had the highest odds ratio (OR) among obesity-related factors. Multivariate analysis showed that visceral fat area was associated with the incidence of erosive esophagitis (OR = 2.18), indicating that it is an independent risk factor for erosive esophagitis. In addition, daily alcohol intake (OR = 1.54), gastric atrophy open type (OR = 0.29), and never-smoking history (OR = 0.49) were also independently associated with the development of erosive esophagitis. CONCLUSIONS: Visceral fat obesity is the key risk factor for the development of reflux erosive esophagitis in subjects aged 40-69 years.

Impact of submucosal saline solution injection for cold snare polypectomy of small colorectal polyps: a randomized controlled study.

BACKGROUND AND AIMS: Cold snare polypectomy (CSP) of small colorectal polyps is widely used. However, the technique is still troubled by insufficient resection depth, which may prevent precise pathologic evaluation. In this study, we investigated whether submucosal injection of saline solution helps to achieve deeper resection in CSP. METHODS: The study was a single-center, prospective, randomized trial. Patients with small (3- to 10-mm diameter) nonpedunculated adenomatous or sessile serrated colorectal polyps were randomly allocated to either conventional CSP (C-CSP) or CSP with submucosal injection (CSP-SI). Primary outcome was the rate of complete muscularis mucosae (MM) resection, defined by the proportion of MM under the tumor more than 80% of the tumor's horizontal dimension. Secondary outcomes were the rates of negative lateral and vertical margins, fragmentation of resected specimens, conversion to hot snare mucosal resection, intraprocedural bleeding, delayed bleeding, and perforation. RESULTS: Two hundred fourteen patients were randomly assigned to the CSP-SI (n = 107) or C-CSP (n = 107) group. The rate of complete MM resection was 43.9% in the CSP-SI group and 53.3% in the C-CSP group, a statistically insignificant difference. The rates of negative lateral margin and vertical margin (42.3% and 56.7%, respectively) in the CSP-SI group were significantly lower than those (58% and 76%) in the C-CSP group (P = .03 and P = .006, respectively). There was no polypectomy-related major bleeding or perforation. CONCLUSIONS: Saline solution injection into the submucosa did not improve the resection depth of CSP of small colorectal polyps, and the method resulted in lower rates of negative lateral and vertical margins of resected lesions. (Clinical trial registration number: UMIN000037980.).

Post-polypectomy bleeding in hot-snare polypectomy of colonic polyps under continued warfarin or short interruption of direct oral anticoagulants.

BACKGROUND: Newly published guidelines of the Japanese Gastroenterological Endoscopy Society (JGES) suggest to consider endoscopic procedures with high risk of bleeding without stopping warfarin and with stopping direct oral anticoagulants (DOACs) only on the day of the procedure. In this study, we aimed to test the validity of these recommendations. PATIENTS AND METHODS: We retrospectively reviewed medical records of 344 patients with anticoagulant therapy who underwent hot-snare polypectomy between January 2012 and October 2018. Patients (n = 132) with interruption of anticoagulants (3-7 days for warfarin and 2-3 days for DOACs before the procedure) and without heparin-bridging were excluded. Among the remaining 212 patients, the incidence of post-polypectomy bleeding was compared between the following 2 patient groups: patients who had interruption of anticoagulants with heparin-bridging (HB group, n = 139) and patients treated according to the new JGES guideline (FG group, n = 73). RESULTS: The rate of post-polypectomy bleeding (PPB) in FG group (9.6%) was not significantly different from that in HB group (12.9%, p = 0.5). In subgroup analysis, the incidence of bleeding in patients with warfarin (12.2%) and with DOAC (6.3%) in FG group was not significantly different from corresponding figures in HB group (14.2%, 0%). In multivariate analysis, number of resected polyps was associated with PPB, but the administration of anticoagulants according to the new guidelines was not a significant risk factor for PPB (p = .98). CONCLUSIONS: Our study affirms the recommendations of JGES for the management of anticoagulants in patients who undergo colonic polypectomy regarding post-polypectomy bleeding.

Clinicopathological and molecular characterization of deficient mismatch repair colorectal cancer.

Tumors demonstrating deficient mismatch repair (dMMR) account for 12%-15% of colorectal cancers (CRCs), but their characteristics have not been fully elucidated. The aim of this study was to characterize dMMR CRCs in terms of clinicopathological findings and molecular alterations. Immunostaining for mismatch repair (MMR) proteins was performed to determine MMR status, and then MLH1 promoter methylation and genetic variants of 25 genes involved in colorectal carcinogenesis were analyzed by next-generation sequencing in dMMR tumors. Coexistence of precancerous lesions was histologically evaluated to characterize the type of precursors. Immunohistochemistry revealed 34 dMMR tumors in 492 CRCs. Among dMMR CRCs, there were 25 MLH1 methylation-positive, 16 BRAF V600E variant-positive, and 7 KRAS variant-positive tumors. Positive MLH1 methylation was associated with BRAF V600E, older age, and right-side tumor location. MLH1 methylated BRAF/KRAS wild-type tumors were distinct in that all 5 tumors possessed variants in ligand-independent WNT signaling genes including APC, AXIN2, and CTNNB1. Among 10 dMMR CRCs that presented with precancerous lesions, 4 BRAF variant-positive, 1 KRAS variant-positive, and 2 BRAF/KRAS wild-type MLH1 methylated tumors coexisted with serrated lesions, whereas 1 MLH1 methylated BRAF/KRAS wild-type tumor and 2 MLH1 unmethylated tumors accompanied conventional adenomas. The present study characterized distinct subgroups of dMMR CRCs based on molecular alterations including MLH1 methylation and variants in BRAF, KRAS, and ligand-independent WNT signaling genes. The existence of distinct precursor lesions including serrated lesion and conventional adenoma further illustrates the involvement of heterogeneous carcinogenetic pathways in the development of dMMR CRCs.

Exceptional Response of Pancreatic Acinar Cell Carcinoma and Bile Duct Cancer to Platinum-Based Chemotherapy in a Family With a Germline BRCA2 Variant.

ABSTRACT: Pancreatic cancer and its rare subtype, acinar cell carcinoma (PACC), frequently harbor germline and/or somatic variants in homologous recombinant genes, including BRCA2. Individuals possessing germline pathogenic BRCA2 variants are known to have a higher risk of developing various cancers, including breast, ovarian, pancreatic, and bile duct cancers (BDCs). It has been reported that tumors positive for BRCA1/2 variants are sensitive to platinum-based agents. Thus, BRCA1/2 germline testing and comprehensive genomic profiling are recommended to identify genetic susceptibility and to indicate optimal targeted therapy. Here, we report familial occurrence of PACC and BDC associated with BRCA2; both tumors responded exceptionally well to platinum-based chemotherapy. A 37-year-old man was diagnosed with unresectable PACC with a germline BRCA2 variant. He was treated with oxaliplatin-containing chemotherapy and conversion surgery, and remains alive without tumor recurrence after more than 36 months. His father also possessed the identical germline BRCA2 variant and was diagnosed with extrahepatic BDC with lymph node metastases. The tumors showed marked shrinkage upon treatment with cisplatin-containing chemotherapy. Our cases underscore the importance of comprehensive genomic profiling and genetic testing for BRCA2 to ensure optimal therapeutic options for PACC as well as to identify high-risk individuals with various cancers in the family.

Real-world outcome of universal screening for Lynch syndrome in Japanese patients with colorectal cancer highlights the importance of targeting patients with young-onset disease.

Despite the recommendations of the latest guidelines, the practical efficacy of universal screening for identifying Lynch syndrome (LS) among patients with colorectal cancer (CRC) may be limited in the real world due to infrequent referrals and the difficulties of genetic testing. Thus, the present study aimed to retrospectively analyze the results of universal screening of patients with CRC at a referral hospital in Japan. Immunohistochemistry was performed for mismatch repair proteins [including DNA mismatch repair protein MSH6 (MSH6), mismatch repair endonuclease PMS2 (PMS2), DNA mismatch repair protein Msh2 (MSH2) and DNA mismatch repair protein Mlh1 (MLH1)] and BRAF V600E mutation. Tumors that showed the following were considered to indicate LS and patients with such tumors were designated as genetic testing candidates (GTCs): i) Loss of MSH6/MSH2; ii) loss of MSH6 alone; iii) loss of PMS2 alone; and iv) loss of PMS2/MLH1 with negative BRAF V600E. MLH1 methylation and BRAF V600E mutation were analyzed in deficient mismatch repair (dMMR) tumors retrospectively. The frequency of dMMR and GTCs in an independent cohort of patients with young-onset CRC were also investigated. Universal screening revealed dMMR tumors, GTCs and LS probands in 7.3, 3.9 and 0.4%, respectively, of 463 patients with CRC. Although dMMR tumors were observed in both younger (<50 years) and older (≥60 years) patients, the GTCs were enriched in younger individuals. Evaluation of mismatch repair status in an independent cohort confirmed the high rate of GTCs in patients with young-onset CRC. The low detection rate of LS demonstrated in this study questions the implementation of routine universal screening in regions with low prevalence of LS. Considering the enrichment of GTCs in young-onset CRCs, age-restricted strategies may be simple and efficient practical alternatives to universal screening in the real world.

Universal antibiotic prophylaxis may no longer be necessary for patients with acute variceal bleeding: A retrospective observational study.

A few decades ago, antibiotic prophylaxis for patients with acute variceal bleeding was reported beneficial. However, endoscopic and systemic therapy for variceal bleeding has dramatically improved since then, so the necessity of prophylactic antibiotics can be questioned. In this study, we reevaluated the efficacy of antibiotic prophylaxis in acute variceal bleeding, using the most recent data in our hospital.We retrospectively analyzed the medical records of 150 patients with acute variceal bleeding who were admitted to Kurashiki Central Hospital between January 2012 and December 2016. We compared the rates of bacterial infection, in-hospital mortality, 5-day rebleeding rate, and 30-day emergency readmission between patients treated or not treated with antibiotic prophylaxis.Forty-six patients (30.7%) received antibiotic prophylaxis; 104 (69.3%) did not. The rates of the outcomes in patients with antibiotic prophylaxis were 6.5% (bacterial infection), 4.3% (in-hospital mortality), 2.2% (5-day rebleeding), and 10.9% (30-day emergency readmission) and were not significantly different form the corresponding figures in those without antibiotic prophylaxis (1.9%, 7.7%, 1.9%, and 10.6%, respectively). Moreover, these rates in our patients, even without antibiotic prophylaxis, were much lower than rates reported in past years, perhaps because of improvements in care of patients with variceal hemorrhage.Antibiotic prophylaxis was not associated with significantly better outcomes of bacterial infection, mortality, rebleeding or readmission rate in patients with acute variceal bleeding. Universal antibiotic prophylaxis for patients with acute variceal bleeding should be reconsidered.

Delivery rate of patients with advanced gastric cancer to third-line chemotherapy and those patients' characteristics: an analysis in real-world setting.

BACKGROUND: Nivolumab has recently become available for third-line chemotherapy of advanced gastric cancer in Japan. The drug is expected to provide long-term survival in some patients. However, not all patients receive third-line therapy. In this study, we investigated the frequency of prescribing and the predictive factors for prescribing of third-line chemotherapy for patients with advanced gastric cancer. METHODS: We retrospectively analyzed the medical records of 271 patients with unresected advanced gastric cancer who had started chemotherapy between January 2006 and June 2017 at Kurashiki Central Hospital. Patients' median age was 68 years, and 190 patients were male. We compared baseline characteristics of patients who did or did not receive third-line chemotherapy and, through multivariate logistic-regression analysis, identified potential predictive factors for receiving third-line chemotherapy. RESULTS: Among the 271 patients, 71 (26.2%) received third-line chemotherapy. In the univariate analysis, the rate of receiving this care was significantly related to patients' performance status, cancer histology, and several laboratory variables at baseline. Multivariate analysis revealed that performance status 0 and serum C-reactive protein levels ≤0.6 mg/dL were independent and significant predictive factors for administration of the third-line chemotherapy; adjusted odds ratios of the two factors were 4.17 (95% confidence interval, 2.13-8.15) and 2.46 (1.19-5.08), respectively. CONCLUSIONS: In this real-world study, only 26.2% of patients received third-line chemotherapy. Poor performance status and high serum C-reactive protein value at the start of first-line chemotherapy were significantly associated with lower frequency of administration of third-line chemotherapy.