Clinical utility of a comprehensive genomic profiling test for patient with advanced biliary tract cancer.

BACKGROUND: Biliary tract cancer (BTC) comprises a heterogeneous group of malignancies with poor prognosis because of the limited treatment options. With the recent advances of next generation sequencing technologies, comprehensive genomic profiling (CGP) tests have been widely introduced into daily clinical practice. PATIENTS AND METHODS: We performed a retrospective, multicenter, observation cohort study. The genomic and clinical data of 85 BTC patients, who underwent CGP testing from August 2021 to September 2023, were analyzed. RESULTS: There were 62 (73%) cases in which treatment recommendations were raised during expert meetings, including 34 intrahepatic cholangiocarcinoma (ICC), 20 extrahepatic cholangiocarcinoma (ECC) and 8 gall bladder carcinoma (GBC). The drug accessibility rate of the BTC patients was 15.3% (13 cases): ten ICCs, two ECCs, and one GBC. Five ICC patients (three male and two female) with the FGFR2 fusion gene were treated with pemigatinib. Those patients who received a genomically matched therapy had significantly longer median overall survival than those patients who not received. (n = 13; not reached [95% CI not reached-not reached] vs n = 72; 8.6 months [95% CI 6.6-10.0]; hazard ratio 0.24 [95% CI 0.12-0.49], p = 0.013). The median observation period of pemigatinib treatment was 15.4 months (range 10.1-27.4). The responses were classified as PR in three patients, SD in one patient and PD in one patient. The median progression free survival is 9.0 months. No patient had grade 3/4 AEs requiring discontinuation of the treatment. CONCLUSION: The drug accessibility rate of ICC is high and pemigatinib is effective and well-tolerated in ICC patients harboring FGFR2 gene fusions.

Evaluation of the associations of interlukin-7 genetic variants with toxicity and efficacy of immune checkpoint inhibitors: A replication study of a Japanese population, based on the findings of a European genome-wide association study.

AIM: Recent genome-wide association studies of European populations have identified rs16906115, a single-nucleotide polymorphism in the interleukin-7 gene, as a predictor of immune-related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single-nucleotide polymorphism in a Japanese population. METHODS: From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow-up ≥12 weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non-responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non-responders. RESULTS: In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non-responders (p = 0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p = 0.015) in the univariate analysis and 0.315 (p = 0.023) in the multivariate analysis. CONCLUSIONS: In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry with the number UMIN000043798.

BRAF-mutant mismatch repair deficient invasive colon cancer regressing to sessile serrated lesion.

A 69-year-old female was presented with a history of sigmoid colon cancer, uterine cancer, and intrahepatic carcinomas. After computed tomography revealed a disseminated nodule located in the peritoneum, colonoscopy demonstrated a rather flat-to-slightly elevated lesion with a depressed area located in the ascending colon. The flat component showed color similar to its surrounding area, and the depressed area showed redness and an expanded appearance. We obtained a biopsy specimen from the depressed area, and microscopic examination revealed well-differentiated adenocarcinoma, which was immunohistochemically positive for BRAF V600E-mutated and PMS2 proteins, and showed loss of MSH2 and MSH6 protein expressions. These findings suggested the lesion to have transformed from a sessile serrated lesion (SSL) to mismatch repair (MMR) deficient colon cancer. The patient underwent surgical removal of the nodule, which interpreted as metastasis of intrahepatic cholangiocarcinoma histopathologically. After postoperative chemotherapy, the follow-up colonoscopy revealed only the flat portion of the lesion without depressed area. Consequently, we performed an endoscopic resection, and microscopic examination confirmed the existence of BRAF V600E-mutated protein-positive and MMR protein-retained SSL without residual carcinoma. This is the first report of BRAF-mutant and MMR-deficient colon cancer, in association with SSL, showing regression.

Proton Pump Inhibitor Associated Multiple Gastric Hyperplastic Polyps With Uncontrollable Bleeding: A Case Report.

BACKGROUND/AIM: The long-term use of proton pump inhibitors (PPIs) has been reported to be strongly associated with the development of fundic gland polyps (FGPs). Conversely, a few cases of gastric hyperplastic polyps (GHPs) associated with PPI use have been reported. We experienced a case of PPI-associated multiple GHPs with uncontrollable bleeding. CASE REPORT: A 64 year old man with a history of rheumatoid arthritis presented to the hospital with complaints of vertigo and black stools. Blood tests revealed anemia and hypoproteinemia. Esophagogastroduodenoscopy (EGD) showed blood and black residue accumulated in the stomach. The source of the bleeding was multiple hyperplastic polyps. Bleeding could be stopped even with fasting, and total blood transfusions amounted to 28 units of RBCs were required in 18 days. After the cessation of PPI, EGD showed that the polyps had almost disappeared. Pathological diagnosis of resected polyp was hyperplastic polyp, which was characterized by capillary hyperplasia and edema. Gastrin receptors were over-expressed in the foveolar epithelium and not in the capillaries. Methotrexate (MTX)-induced portal hypertensive gastroenteropathy was revealed during follow-up. We consider that the effect of portal hypertension may have caused the capillary hyperplasia. CONCLUSION: Although PPI-related polyps are usually fundic gland polyps and do not cause life-threatening adverse events, we experienced PPI-related GHPs in which hemostasis was difficult to control.

High-risk Patients With Colorectal Liver Metastases Assessed by the Beppu Score Can Have Excellent Survival Through Multidisciplinary Treatment Including Local Ablation.

BACKGROUND/AIM: The Beppu score assessed by the Japanese Society of Hepato-Biliary-Pancreatic Surgery nomogram helps predict postoperative disease-free survival for patients with resectable colorectal liver metastases (CRLM). Using the Beppu score, patients with resectable CRLM were divided into three groups according to recurrence risk: low (≤6 points), moderate (7-10 points), and high-risk (≥11 points). Hepatectomy following preoperative chemotherapy is recommended for high-risk patients. The surgical outcome, local recurrence rates, and long-term survival were assessed, focusing on local ablation. PATIENTS AND METHODS: Twenty high-risk and unresectable CRLM patients were enrolled between April 2016 and April 2022. Hepatectomy with or without local ablation was performed after induction chemotherapy. Local ablation was permissive for patients with effective chemotherapy (partial response and stable disease) with CRLM ≤2 cm and ≥5 mm distant from major vessels. RESULTS: The median diameters and numbers of CRLM were 26 (10-150) mm and 9 (1-46). All 18 patients who received preoperative chemotherapy were disease controls. Local ablation was performed simultaneously on hepatectomy in 14 patients. The median diameters and numbers of the ablated nodules were 12 (5-17) mm and 3 (1-21). Local recurrence was 8.5% per 82 ablative nodules. Three-year disease-free and five-year overall survival was 57.4% and 56.2%, respectively. There was no significant difference in patients with or without local ablation. CONCLUSION: Our treatment strategy for high-risk CRLM patients is feasible and can provide an excellent long-term prognosis regardless of adding local ablation to hepatectomy.

Comprehensive Cancer Genomic Profiling of Liver Metastasis Led to the Unexpected Identification of Colorectal Cancer.

Comprehensive genomic profiling (CGP) of a metastatic liver tumor biopsy specimen suggested that the patient, who was initially diagnosed with cholangiocarcinoma, had colorectal cancer. The identification of both FBXW7 and APC mutations is deemed characteristic of colorectal cancer. Indeed, subsequent colonoscopy revealed sigmoid colon carcinoma that led to tumor resection followed by systemic chemotherapy. CGP is principally used to identify agents that might potentially benefit the patient. However, results must be interpreted carefully to ensure consistency with the initial diagnosis.

M2-like tumor-associated macrophages promote epithelial-mesenchymal transition through the transforming growth factor ß/Smad/zinc finger e-box binding homeobox pathway with increased metastatic potential and tumor cell proliferation in lung squamous cell carcinoma.

Epithelial-mesenchymal transition (EMT) promotes primary tumor progression toward a metastatic state. The role of tumor-associated macrophages (TAMs) in inducing EMT in lung squamous cell carcinoma (LUSC) remains unclear. We aimed to clarify the significance of TAMs in relation to EMT in LUSC. We collected 221 LUSC specimens from patients who had undergone surgery. Immunohistochemistry was performed to evaluate M1-like and M2-like TAM distribution and EMT by E-cadherin and vimentin staining. Human LUSC cell lines (H226 and EBC-1) and a human monocyte cell line (THP-1) were used for in vitro experiments. M2-like polarization of TAMs and EMT marker expression in LUSC cells were evaluated by western blotting. The biological behavior of LUSC cells was evaluated by migration, invasion, and cell proliferation assays. Immunohistochemical analysis showed that 166 (75.1%) tumors were E-cadherin-positive and 44 (19.9%) were vimentin-positive. M2-like TAM density in the tumor stroma was significantly associated with vimentin positivity and worse overall survival. Western blotting demonstrated higher levels of CD163, CD206, vascular endothelial growth factor, and transforming growth factor beta 1 (TGF-ß1) in TAMs versus unstimulated macrophages. Furthermore, increased TGF-ß1 secretion from TAMs was confirmed by ELISA. TAM-co-cultured H226 and EBC-1 cells exhibited EMT (decreased E-cadherin, increased vimentin). Regarding EMT-activating transcriptional factors, phosphorylated Smad3 and ZEB-family proteins were higher in TAM-co-cultured LUSC cells than in parental cells. TAM-co-cultured H226 and EBC-1 cells demonstrated enhanced migration and invasion capabilities and improved proliferation. Overall, the present study suggests that TAMs can induce EMT with increased metastatic potential and tumor cell proliferation in LUSC.

Durable Stable Disease by Atezolizumab/Bevacizumab Can Provide Long-term Survival of Patients With Hepatocellular Carcinoma Lung Metastases.

BACKGROUND: Multiple bilateral lung metastases secondary to hepatocellular carcinoma (HCC) are mainly treated with molecular therapy. Atezolizumab plus bevacizumab can provide excellent long-term survival for patients with a good response. CASE REPORT: A 67-year-old woman underwent right hepatectomy for a primary solitary HCC, 11 cm in diameter, after portal embolization. After 2 years, she developed bilateral lung metastases with >100 nodules, <1 cm in size. She had no viral hepatitis or liver cirrhosis, and the Child-Pugh Grade was A (5 points). Lenvatinib (12 mg daily) was administered as a first-line treatment and continued for 18 months. The best response was stable disease (SD). Subsequently, intravenous atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) was administered once every three weeks. The best response was SD, which continued for 26 months. After that, cabozantinib treatment was initiated and discontinued after one cycle. Subsequently, dual immune checkpoint inhibitor treatment (durvalumab + tremelimumab) was administered. She has had multiple, but lung-only, metastases over four years. She has been well as an outpatient with the Child-Pugh Grade of A and a performance status of 0. CONCLUSION: Even if atezolizumab plus bevacizumab does not induce a good response, a durable SD could prolong survival in patients with metastatic HCC while maintaining liver function and a good quality-of-life.

Conversion Surgery After Encorafenib Plus Cetuximab for Chemorefractory BRAF V600E-mutated Colorectal Cancer With Para-aortic Lymph Node Metastases.

BACKGROUND/AIM: Mutant BRAF V600E colorectal cancer accounts for 5% of metastatic colorectal cancers, and it has a poor response to systemic chemotherapy and a poor prognosis. However, combination treatment involving MAPK pathway blockade is effective for this cancer. Herein, we report a case of a patient who underwent conversion surgery after encorafenib plus cetuximab for chemorefractory BRAF V600E-mutated colorectal cancer with para-aortic lymph node metastases. CASE REPORT: A 68-year-old woman was diagnosed with ascending colon cancer and multiple para-aortic lymph node metastases. After primary tumor resection, molecular genetic testing of the primary tumor revealed a BRAF V600E mutation. She was treated with FOLFOXIRI plus bevacizumab as first-line chemotherapy. After disease progression, the regimen was changed to encorafenib plus cetuximab, and the metastatic lesions shrank. She underwent para-aortic lymph node dissection as conversion surgery, and pathology revealed complete response of the lymph nodes. She achieved long-term survival. CONCLUSION: The development of new treatments for BRAF V600E-mutated metastatic colorectal cancer will increase opportunities for conversion therapy.

Distinct approaches (antecolic and retrocolic) according to tumor location in laparoscopic and endoscopic cooperative surgery for non-ampullary duodenum tumors.

AIM: Laparoscopic and endoscopic cooperative surgery for early non-ampullary duodenum tumors (D-LECS) is now noted because of its safety and lower invasiveness. Here, we introduce two distinct approaches (antecolic and retrocolic) according to the tumor location during D-LECS. METHODS: From October 2018 to March 2022, 24 patients (25 lesions) underwent D-LECS. Two (8%), two (8%), 16 (64%), and five (20%) lesions were located in the first portion, in the second portion to Vater's papilla, around the inferior duodenum flexure, and in the third portion of the duodenum, respectively. The median preoperative tumor diameter was 22.5 mm. RESULTS: Antecolic and retrocolic approaches were employed in 16 (67%) and 8 (33%) cases, respectively. LECS procedures, such as two-layer suturing after full-thickness dissection and laparoscopic reinforcement by seromuscular suturing after endoscopic submucosal dissection (ESD), were performed in five and 19 cases, respectively. Median operative time and blood loss were 303 min and 5 g, respectively. Intraoperative duodenal perforations occurred in three of 19 cases during ESD; however, they were successfully laparoscopically repaired. Median times until start diet and postoperative hospital stay were 4.5 and 8 days, respectively. Histological examination of the tumors revealed nine adenomas, 12 adenocarcinomas, and four GISTs. Curative resection (R0) was achieved in 21 cases (87.5%). In a comparison of the surgical short outcomes between antecolic and retrocolic approaches, there was no significant difference. CONCLUSION: D-LECS can be a safe and minimally invasive treatment option for non-ampullary early duodenal tumors, and two distinct approaches according to the tumor location are feasible.

A Laparoscopically Treated Case of Peritoneal Dissemination Mimicking Liver Metastases from Distal Cholangiocarcinoma Four Years After the Initial Pancreaticoduodenectomy.

BACKGROUND/AIM: Operable peritoneal dissemination from distal cholangiocarcinoma after pancreaticoduodenectomy is rare. Furthermore, peritoneal dissemination mimicking liver metastasis has scarcely been reported. CASE REPORT: An 81-year-old woman received pancreaticoduodenectomy for distal cholangiocarcinoma. She was diagnosed with stage IIA (T3a N0 M0) and received curative resection. She did not receive adjuvant chemotherapy. As a result of the examination in our department, she showed two tumors, 20 mm and 8 mm in segments 7/8 and 7, respectively, in the subphrenic liver surface four and half years after the initial pancreaticoduo-denectomy. The larger tumor was slow-growing, and cystic degeneration was inside. Plain computed tomography imaging revealed an isodense tumor with a marginal high ring and weak early enhancement, and prolonged peripheral enhancement was recognized at the marginal portion. Magnetic resonance imaging showed a heterogeneous mass with peripheral hypointensity ring that may be caused by fibrous tissue. Although the smaller tumor was diagnosed only after admission, it presented similar imaging findings to the larger tumor. The preoperative diagnosis was suspected to be liver metastases from DCC or inflammatory pseudotumor. Laparoscopic partial liver resection with diaphragm dissection was performed for both tumors. Pathologically, the tumors were diagnosed as peritoneal dissemination from distal cholangiocarcinoma. In the disseminated cancer cells, the expression of Ki67 was decreased, which was suspected to be one of the reasons for the long recurrence-free interval. The patient is doing well without any recurrence three months after the second operation. CONCLUSION: Laparoscopic surgery can provide excellent results for diagnosing and treating unknown subphrenic tumors.

Non-atrophic gastric mucosa is an independently associated factor for superficial non-ampullary duodenal epithelial tumors: a multicenter, matched, case-control study.

BACKGROUND/AIMS: The etiology of superficial non-ampullary duodenal epithelial tumors (SNADETs) remains unclear. Recent studies have reported conflicting associations between duodenal tumor development and Helicobacter pylori infection or endoscopic gastric mucosal atrophy. As such, the present study aimed to clarify the relationship between SNADETs and H. pylori infection and/or endoscopic gastric mucosal atrophy. METHODS: This retrospective case-control study reviewed data from 177 consecutive patients with SNADETs who underwent endoscopic or surgical resection at seven institutions in Japan over a three-year period. The prevalence of endoscopic gastric mucosal atrophy and the status of H. pylori infection were compared in 531 sex- and age-matched controls selected from screening endoscopies at two of the seven participating institutions. RESULTS: For H. pylori infection, 85 of 177 (48.0%) patients exhibited SNADETs and 112 of 531 (21.1%) control patients were non-infected (p<0.001). Non-atrophic mucosa (C0 to C1) was observed in 96 of 177 (54.2%) patients with SNADETs and 112 of 531 (21.1%) control patients (p<0.001). Conditional logistic regression analysis revealed that non-atrophic gastric mucosa was an independent risk factor for SNADETs (odds ratio, 5.10; 95% confidence interval, 2.44-8.40; p<0.001). CONCLUSION: Non-atrophic gastric mucosa, regardless of H. pylori infection status, was a factor independently associated with SNADETs.

A novel cell-based assay for the high-throughput screening of epithelial-mesenchymal transition inhibitors: Identification of approved and investigational drugs that inhibit epithelial-mesenchymal transition.

OBJECTIVES: Lung cancer with distant metastases is associated with a very poor prognosis, and epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Therefore, elucidation and inhibition of EMT signaling in lung cancer may be a new therapeutic strategy for improving the prognosis of patients. We constructed a high-throughput screening system for EMT inhibitors. Using this system, we aimed to identify compounds that indeed inhibit EMT. MATERIALS AND METHODS: We generated a luciferase reporter cell line using A549 human lung cancer cells and E-cadherin or vimentin as EMT markers. EMT was induced by transforming growth factor ß1 (TGF-ß1), and candidate EMT inhibitors were screened from a library of 2,350 compounds. The selected compounds were further tested using secondary assays to verify the inhibition of EMT and invasive capacity of cells. RESULTS: Values obtained by the assay were adjusted for the number of viable cells and scored by determining the difference between mean values of the positive and negative control groups. Four compounds were identified as novel candidate drugs. Among those, one (avagacestat) and two compounds (GDC-0879 and levothyroxine) improved the expression of E-cadherin and vimentin, respectively, in epithelial cells. GDC-0879 and levothyroxine also significantly inhibited the invasive capacity of cells. CONCLUSION: We systematically screened approved, investigational, and druggable compounds with inhibitory effects using a reporter assay, and identified candidate drugs for EMT inhibition.

Efficacy of a new traction method using ring-shaped thread for endoscopic submucosal dissection in the pharynx.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for pharyngeal cancers. However, pharyngeal ESD is sometimes technically challenging because of the narrow and complex space in which to work. Traction is important to complete the procedure efficiently. Here, we report the technical details and efficacy of a new traction method for pharyngeal ESD using ring-shaped thread and grasping forceps. METHODS: We analyzed pharyngeal ESD performed between January 2016 and March 2021 at our Institute. We designated cases resected using ring-shaped threads "Group R" and those resected without ring-shaped threads as conventional "Group C", and compared the technical outcomes between them. Multivariate analysis and the inverse probability treatment weighting (IPTW) method using propensity scores were adjusted by confounding variables. RESULTS: We analyzed 89 lesions from 68 patients, of which 46 were in Group R and 43 in Group C. Median procedure time and median dissection speed were significantly shorter in Group R than C (37 min vs. 55 min, and 16.0 mm2/min vs. 7.0 mm2/min, respectively, both P < 0.05). These results were confirmed by both multivariate analysis and after IPTW adjustment. All lesions were resected en bloc, and the complete resection rate was not significantly different between Group R and C (91.3% vs. 79.1%, P = 0.14). There were no treatment-related adverse events in either group. CONCLUSIONS: The traction method using ring-shaped thread increases the efficiency of pharyngeal ESD. This simple new traction method should be a useful option for pharyngeal ESD.

Comparison of endoscopic submucosal resection with ligation and endoscopic submucosal dissection for small rectal neuroendocrine tumors: A multicenter retrospective study.

Objectives: Endoscopic submucosal resection with band ligation (ESMR-L) and endoscopic submucosal dissection (ESD) are both standard endoscopic resection methods for rectal neuroendocrine tumors (NETs) <10 mm in size. However, there is no definitive consensus on which is better. Here, we compared the efficacy of ESMR-L and ESD for small rectal NETs. Methods: This was a multicenter retrospective cohort study including 205 patients with rectal NETs who underwent ESMR-L or ESD. Treatment outcomes were compared by univariate analysis, multivariate analysis, and inverse probability treatment weighting (IPTW) using propensity scores. Subgroup analysis evaluated the impact of the endoscopist's experience on the technical outcome. Results: Eighty-nine patients were treated by ESMR-L and 116 by ESD. The R0 resection rate was not significantly different between the two (90% vs. 92%, p = 0.73). The procedure time of ESMR-L was significantly shorter than for ESD (17 min vs. 52 min, p < 0.01) and the hospitalization period was also significantly shorter (3 days vs. 5 days, p < 0.01). These results were confirmed by multivariate analysis and also after IPTW adjustment. The procedure time of ESD was significantly prolonged by a less-experienced endoscopist (49 min vs. 70 min, p = 0.02), but that of ESMR-L was not affected (17 min vs. 17 min, p = 0.27). Conclusions: For small rectal NETs, both ESMR-L and ESD showed similar high complete resection rates. However, considering the shorter procedure time and shorter hospitalization period, ESMR-L is the more efficient treatment method, especially for less-experienced endoscopists.

Evidence of an oceanic impact and megatsunami sedimentation in Chryse Planitia, Mars.

In 1976, NASA's Viking 1 Lander (V1L) was the first spacecraft to operate successfully on the Martian surface. The V1L landed near the terminus of an enormous catastrophic flood channel, Maja Valles. However, instead of the expected megaflood record, its cameras imaged a boulder-strewn surface of elusive origin. We identified a 110-km-diameter impact crater (Pohl) ~ 900 km northeast of the landing site, stratigraphically positioned (a) above catastrophic flood-eroded surfaces formed ~ 3.4 Ga during a period of northern plains oceanic inundation and (b) below the younger of two previously hypothesized megatsunami deposits. These stratigraphic relationships suggest that a marine impact likely formed the crater. Our simulated impact-generated megatsunami run-ups closely match the mapped older megatsunami deposit's margins and predict fronts reaching the V1L site. The site's location along a highland-facing lobe aligned to erosional grooves supports a megatsunami origin. Our mapping also shows that Pohl's knobby rim regionally represents a broader history of megatsunami modification involving circum-oceanic glaciation and sedimentary extrusions extending beyond the recorded megatsunami emplacement in Chryse Planitia. Our findings allow that rocks and soil salts at the landing site are of marine origin, inviting the scientific reconsideration of information gathered from the first in-situ measurements on Mars.

Vater Papilla-preserving Strategy for Advanced Hepatocellular Carcinoma With Excessive Bile Duct Tumor Thrombus.

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) is highly malignant; therefore, continual, multidisciplinary treatments are essential. CASE REPORT: In this study, two 78- and 81-year-old men were treated with the Vater papilla-preserving strategy. Case 1 had advanced HCC with BDTT expanding to the common bile duct (B4) and portal vein tumor thrombus (PVTT) of the umbilical portion. He showed triple-positive tumor markers. He underwent an extended left hepatectomy without bile duct resection following percutaneous transhepatic biliary drainage and transarterial chemoembolization (TACE). Later, TACE in combination with percutaneous microwave ablation was performed to treat four intrahepatic recurrent HCCs. Case 2 had diffuse-type HCCs accompanied by BDTT (B4) and PVTT to the right portal vein. He underwent liver partition associated with portal vein ligation for staged hepatectomy without bile duct resection. Six months later, he developed a solitary recurrent BDTT with obstructive jaundice. After percutaneous transhepatic biliary drainage, he was treated with two TACE from the various feeding arteries. Both patients achieved complete responses and are doing well without viable tumors approximately 2 years after the initial treatment. CONCLUSION: The Vater papilla-preserving strategy is essential for obtaining long-term survival and recurrent-free status for patients with HCC with highly extended BDTT.

Nrf2/p­Fyn/ABCB1 axis accompanied by p­Fyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non­small cell lung cancer.

Adjuvant cisplatin­vinorelbine is a standard therapy for stage II/III lung cancer. However, a poor survival rate of patients with lung cancer is attributed to vinorelbine resistance arising from ATP­binding cassette (ABC) sub­family B member 1 (ABCB1) and phosphorylated Fyn (p­Fyn) overexpression. However, the underlying mechanisms remain unclear. NF­E2­related factor 2 (Nrf2) regulates the ABC family and activates the nuclear transport of Fyn. The present study evaluated the roles of the Nrf2/p­Fyn/ABCB1 axis in vinorelbine­resistant (VR) cells and clinical samples. To establish VR cells, H1299 cells were exposed to vinorelbine, and the intracellular reactive oxygen species (ROS) level in the H1299 cells was determined using a DCFH­DA assay. The total and subcellular expression of Nrf2, ABCB1 and p­Fyn in VR cells was evaluated. Immunofluorescence was used to detect the subcellular localization of p­Fyn in VR cells. A cell viability assay was used to examine whether the sensitivity of VR cells to vinorelbine is dependent on Nrf2 activity. Immunohistochemistry was performed on 104 tissue samples from patients with lung cancer who underwent surgery followed by cisplatin­vinorelbine treatment. The results revealed that persistent exposure to vinorelbine induced intracellular ROS formation in H1299 cells. p­Fyn was localized in the nucleus, and ABCB1 and Nrf2 were overexpressed in VR cells. ABCB1 expression was dependent on Nrf2 downstream activation. The decreased expression of Nrf2 restored the sensitivity of VR cells to vinorelbine. In the surgical samples, Nrf2 and ABCB1 were associated with disease­free survival, and p­Fyn was associated with overall survival (P<0.05). On the whole, the present study demonstrates that Nrf2 upregulates ABCB1 and, accompanied by the nuclear accumulation of p­Fyn, induces vinorelbine resistance. These findings may facilitate the development of drug resistance prevention strategies or new drug targets against non­small cell lung cancer.

Early-stage reconstruction of flexor pollicis longus using palmaris longus in a patient with compartment syndrome of forearm: a case report.

BACKGROUND: The flexor pollicis longus is the most vulnerable muscle in acute compartment syndrome of the forearm. Reconstruction of a dysfunctional flexor pollicis longus is occasionally necessary following compartment syndrome of the forearm. CASE PRESENTATION: A 42-year-old Japanese man injured his left forearm in a motor vehicle accident. Open radial shaft fracture and acute compartment syndrome of the left forearm was diagnosed. We performed a fascial release of the forearm and debridement of the involved myonecrosis of the flexor pollicis longus. At second-look operation (3 days after the initial release), we performed palmaris longus tendon transfer to the flexor pollicis longus tendon. At 6-month follow-up, the patient had no complaints and returned to his job. At 2-year follow-up, the patient had achieved 88% of pinch strength, compared with the contralateral hand, and scored 11.4 on the QuickDASH score. CONCLUSIONS: Palmaris longus transfer performed immediately after injury is simple and does not require an additional surgical approach. Hence, early palmaris longus tendon transfer, which can provide satisfactory outcomes, could be considered as a potential choice for flexor pollicis longus reconstruction in patients with compartment syndrome of the forearm.