PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer: a retrospective study.

BACKGROUND: Fluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer. METHODS: We analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates. RESULTS: We detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher's exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p < 0.005] or c.1562A > C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. CONCLUSIONS: The two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

Decision making for anti-VEGF inhibitor continuation: dip stick? or urine protein/creatinine ratio? (VERSiON UP study).

BACKGROUND: Monitoring proteinuria is important for the management of patients with cancer treated with anti-vascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR) inhibitors (VEGF/Ri). Here we investigated the difference between the urine protein/creatinine ratio (UPCR) and a qualitative value test (QV) on the decision making of treatment continuation and the usefulness of UPCR testing in patients with gastrointestinal cancer treated with anti-VEGF/Ri. METHODS: From January 2017 to December 2018, a survey was conducted based on the medical records of patients with gastrointestinal cancer with a QV of ≥2+ during the use of anti-VEGF/Ri at seven Japanese institutions participating in the Onco-nephrology Consortium. The primary endpoint was the ratio of the worst UPCR < 2.0 (low UPCR) in cases with a QV2+ at the point of the first proteinuria onset. The secondary endpoints were a comparison of low UPCR and worst UPCR ≥2.0 (high UPCR), the concordance rate between UPCR and QV in the Common Terminology Criteria for Adverse Events (CTCAE) grading, and the differences in the decision making for anti-VEGF/Ri continuation. RESULTS: Among the 71 patients enrolled, the proportion of low UPCR in onset QV2+ (n = 53) was 66% (n = 35). In a comparison between low (n = 36) and high UPCR cases (n = 24), body weight (P = 0.036), onset QV status (P = 0.0134), and worst QV status (P < 0.0001) were significantly associated with UPCR levels. The concordance rate for CTCAE Grade 2 of both the QV and UPCR was 83%. Regarding the judgment of anti-VEGF/Ri continuation, treatment was continued in 42.4% of cases when the QV became 3+, whereas only 25% continued treatment when the UPCR value became high. CONCLUSION: Urine dipstick test results may overestimate proteinuria, and the UPCR result tended to be more critical than the QV when deciding the treatment policy. TRIAL REGISTRATION: This study is a multiple institutional retrospectively registered observational trial. CLINICAL TRIAL NUMBER: University Hospital Medical Information Network (UMIN) Clinical Trials Registry (protocol ID UMIN000042545 ).

Wernicke encephalopathy in a caregiver: A serious physical issue resulting from stress in a family member caring for an advanced cancer patient.

OBJECTIVE: It is well known that the burden on the families of cancer patient extends across many aspects, but there have been no reports of family members developing delirium due to the burden of caring for a cancer patient. METHODS: We reported a caregiver who developed Wernicke encephalopathy (WE) while caring for a family member with advanced cancer. RESULTS: The subject was a 71-year-old woman who had been caring for her husband, diagnosed with gastric cancer and liver metastases, for 5 months. She visited the "caregivers' clinic" after referral by an oncologist who was worried about a deterioration in her mental condition that had appeared several weeks previously. The woman had a history of diabetes mellitus. Some giddiness was observed and, based on her inability to answer questions, her level of consciousness was checked and some disorientation was observed. She was diagnosed with delirium. A blood sample was collected to investigate the cause of the delirium, but the test data showed no hypoglycemia. Her appetite had declined since her husband was diagnosed with cancer. Thiamine deficiency was suspected as thiamine stores in the body are depleted within about 18 days and her loss of appetite had continued for 5 months. On intravenous injection of 100 mg of thiamine, her consciousness level was returned to normal in 1 h. A diagnosis of WE was supported by the patient's abnormally low serum thiamine level. SIGNIFICANCE OF THE RESULTS: The family members of cancer patients may develop a loss of appetite due to the burden of caring, resulting in WE. When providing care for signs of distress in family members, it is necessary to pay attention not only to the psychological aspects but also to their level of consciousness and physical aspects, particularly the possibility of serious illness resulting from reduced nutritional status.

[A Case of Esophagogastric Junction(EGJ)Cancer for Which Pathological Complete Response(pCR)Was Obtained by Multidisciplinary Treatment].

We report the case of a 68-year-old male with EGJ cancer, who was treated with palliative radiotherapy for persistent bleeding, and for whom, pCR was ultimately obtained by chemotherapy. Chemotherapy was planned to treat the EGJ cancer with intramural metastasis of the esophagus, but anemia due to persistent bleeding from the tumor was noted. Even with frequent blood transfusions, the anemia was difficult to control. Palliative radiotherapy was performed at 30 Gy/10 Fr for hemostasis, followed by chemotherapy. After approximately 9 months of chemotherapy, reduction of the primary tumor, a metastatic lymph node, and disappearance of the intramural metastasis of the esophagus were noted, and conversion surgery was performed. In the final histopathological examination, pCR was obtained. Radiotherapy for persistent bleeding from advanced gastric cancer is a minimally invasive treatment, and therefore could be an effective treatment to enable chemother- apy without any loss of compliance.

Complete response to uracil-tegafur alone in advanced rectal cancer.

We report a case of a complete response to treatment with uracil-tegafur (UFT) alone in advanced rectal cancer. The patient was an 84-year-old woman referred to our hospital complaining of anal bleeding. A colonoscopy revealed a Borrmann type II tumor in the rectum, which was diagnosed as an adenocarcinoma. Therefore, best supportive care was initiated in April 2011 with oral administration of UFT. The anal bleeding stopped 2 months later, and the patient's general condition remains good at one year. A further colonoscopy at one year after initiation of treatment in April 2012 resulted in reclassification of the tumor as an Isp lesion, and the biopsy was negative for cancer. The patient was still alive with no sign of recurrence at 21 months after commencing UFT alone with no surgical treatment. These results suggest that chemotherapy with UFT alone can yield complete remission from advanced rectal cancer.

A Case of Bile Duct Mixed Neuroendocrine-nonendocrine Neoplasm with a Complete Response to Chemoradiotherapy.

The incidence of neuroendocrine carcinomas arising from the bile duct is low, and that of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) is even lower; therefore, there is no standard treatment for MiNENs. Choosing the appropriate treatment in clinical practice is difficult. We herein report a case of unresectable extrahepatic bile duct MiNEN in a 66-year-old man who received curative chemoradiotherapy and achieved a complete response, remaining recurrence-free for 2.5 years. We consider the findings of this case to be valuable in selecting a treatment strategy for unresectable bile duct MiNENs.

A complete response to S-1 plus cis-diamminedichloroplatinum in advanced-stage esophageal and gastric adenocarcinoma: a case report.

BACKGROUND: Complete remission from advanced-stage synchronous double primary (SDP) esophageal and gastric adenocarcinoma by chemotherapy alone is rare. We report a case of advanced-stage SDP esophageal and gastric adenocarcinoma in which a complete response to treatment was obtained with S-1 and cis-diamminedichloroplatinum (CDDP). CASE PRESENTATION: The patient was a 74-year-old man referred to our hospital complaining of dysphagia. Gastrointestinal endoscopy was performed and advanced-stage SDP esophageal and gastric adenocarcinoma diagnosed. Computed tomography revealed multiple regional lymph node metastases in the mediastinum. Neoadjuvant chemotherapy with S-1 and CDDP for advanced esophageal and gastric cancer was planned. An endoscopy following two courses of chemotherapy revealed that the esophageal cancer had been replaced with a normal mucosal lesion and the gastric tumor with a scar lesion; the results of biopsies of both were negative for cancer. Computed tomography revealed that the multiple lymph node metastases had disappeared. We diagnosed a complete response to S-1 and CDDP in advanced-stage SDP esophageal and gastric cancer. The patient is still alive with no signs of recurrence 22 months after the disappearance of the original tumor and metastatic lesions without surgical treatment. CONCLUSION: These results suggest that complete remission from advanced-stage esophageal and gastric cancer can be obtained with chemotherapy with S-1 plus CDDP.

An Autopsy Case of Late-onset Fulminant Myocarditis Induced by Nivolumab in Gastric Cancer.

Nivolumab is an immune-checkpoint inhibitor (ICI) that can induce unique treatment-related toxicities, such as immune-related adverse events (irAEs). Myocarditis is a serious irAE with an incidence between 0.06% and 1.14%. Although the peak onset of irAE is generally within three months from the start of treatment, we experienced an autopsy case of late-onset fulminant myocarditis caused by nivolumab in Epstein Barr virus-associated gastric cancer. Pathological complete remission of the primary lesion was confirmed by the autopsy. We should consider possible complications of cardiac irAEs, especially fulminant myocarditis, even beyond three months after starting ICI therapy.

Verification of the Utility of Palliative Radiotherapy for Hemostasis of Gastric Cancer Bleeding: a Case Control Study.

PURPOSE: Bleeding from unresectable gastric cancer is a localized condition that adversely affects quality of life. Radiotherapy can be used to treat gastric cancer bleeding when surgery, endoscopic treatment, and intravascular embolization are ineffective. This study evaluated the utility of radiotherapy for unresectable hemorrhagic gastric cancer. METHODS: We retrospectively analyzed data from 33 patients with gastric cancer bleeding who underwent palliative radiotherapy in our hospital between April 2013 and May 2020. In this study, successful hemostasis was defined as > 1 month after starting radiotherapy with the patient alive and showing no need for blood transfusion, no drop in hemoglobin, and no evidence of melena or hematemesis. RESULTS: Patients comprised 26 men (79%) and 7 women (21%), with a median age of 71 years (range, 41-78 years). Hemostasis was achieved in 24 patients (73%). Thirty-two patients (94%) have been discharged home or transferred to the hospice. Patients with successful hemostasis from radiotherapy showed significantly longer overall survival than patients with unsuccessful hemostasis (p = 0.0026). No toxicities of grade 2 or more were encountered. CONCLUSIONS: This retrospective study found that palliative radiotherapy for gastric cancer bleeding was useful and safe and can improve remaining quality of life in patients with poor prognosis.

Expression of LAT1 and 4F2hc in Gastroenteropancreatic Neuroendocrine Neoplasms.

BACKGROUND/AIM: Little is known about the expression of L-type amino acid transporter 1 (LAT1) and 4F2hc in gastroenteropancreatic-neuroendocrine neoplasms (GEP-NENs). Hence, we conducted a study to verify the clinicopathological significance of LAT1 and 4F2hc. PATIENTS AND METHODS: Tissues from 126 patients with GEP-NENs were collected between August 2007 and August 2019 at our institution. We evaluated LAT1 and 4F2hc expression by immunohistochemistry, and examined their clinical significance. RESULTS: No statistically significant associations were observed between LAT1 expression and the different NENs. Expression of 4F2hc was significantly different between neuroendocrine tumour (NET)-G1, NET-G2, and NET-G3 (p=0.029), and was significantly associated with vascular invasion (p=0.044) and the Ki-67 index (p=0.042). CONCLUSION: No association between LAT1 expression and malignant features in GEP-NENs was observed. However, an association between 4F2hc expression and the potential of malignancy in GEP-NENs was evident.

Resection of Colorectal Cancer With Versus Without Preservation of Inferior Mesenteric Artery.

OBJECTIVE: To assess the clinical significance of preservation of the inferior mesenteric artery (IMA) in comparison with IMA ligation in surgery for sigmoid colon or rectal (colorectal) cancer. METHODS: Consecutive patients (n=862) with colorectal cancer who underwent intended surgical resection of the main tumor between 1986 and 2011 were retrospectively analyzed. The patients were divided into 2 groups: IMA preserved (n=745) and IMA ligated (n=117). RESULTS: No significant difference was observed in incidence of advanced stage III or IV disease between the 2 groups (P=0.56 and 0.51, respectively), whereas a longer operation time (287 [95 to 700] vs. 215 [60 to 900] min, respectively; P<0.001) and greater amount of intraoperative bleeding (595 [15 to 4530] vs. 235 [1 to 11565] mL, respectively; P<0.001) were observed in the IMA-ligated group. The overall incidence of surgery-related complications was higher in the IMA-ligated group than in the IMA-preserved group (53.0% vs. 38.5%, respectively; P=0.003). Urinary dysfunction and abdominal abscess were significantly more frequent in the IMA-ligated group (11.1% vs. 4.0%, P=0.001; and 6.8% vs. 2.6%, P=0.01, respectively), and postoperative hospitalization was longer (11 to 140, median 28 vs. 5 to 153, median 19 d, respectively; P<0.001). No significant difference was found in overall survival rate between the 2 groups. CONCLUSIONS: For colorectal cancer resection, IMA preservation may be no change to IMA ligation as to patient' survival, with small risk of operative morbidity.

Phase II Study of Neoadjuvant Chemotherapy With S-1 and CDDP in Patients With Lymph Node Metastatic Stage II or III Gastric Cancer.

OBJECTIVES: We conducted a phase II trial to investigate the efficacy and safety of neoadjuvant chemotherapy (NAC) comprising S-1 and cisplatin (CDDP) followed by extensive resection in the management of resectable locally advanced gastric cancer with lymph node (LN) metastases. METHODS: Patients with LN metastases from stage II or III gastric cancer received S-1 and CDDP, as NAC criteria for LN metastases were the involvement of ≥4 nodes <2 cm or ≥1 nodes ≥2 cm as confirmed by a total body computed tomography scan. All patients underwent extensive resection including D2 gastrectomy. The primary endpoint was complete resection rate and the secondary endpoints were 3-year relapse-free and overall survival. RESULTS: Fifty patients were assessable for the analysis. The complete resection rate was 87.8%. Three-year relapse-free survival was 44.9% and 3-year overall survival rate was 48.0%. CONCLUSIONS: NAC with S-1 and CDDP is safe and may improve the complete resection rate in patients with metastatic LN gastric cancer. This suggests that LN metastases would provide good target lesions in future clinical trials of NAC.

Gastric cancer developing in the stomach after pylorus-preserving pancreaticoduodenectomy with pancreaticogastrostomy: case report and review of the literature.

A 59-year-old woman underwent surgery for uterine corpus cancer in March 1998. She also underwent pylorus-preserving pancreaticoduodenectomy with pancreaticogastrostomy for common bile duct cancer in November 1998. She was followed up at our outpatient clinic after pylorus-preserving pancreaticoduodenectomy. In November 2002, her carcinoembryonic antigen level became elevated and abdominal ultrasound revealed a huge tumor. Gastroscopy showed a Borrmann type 3 tumor at the anastomosis of the pancreaticogastrostomy, and a biopsy revealed adenocarcinoma. With a diagnosis of advanced gastric cancer, she underwent total gastrectomy, splenectomy, and residual pancreatectomy in January 2003. The pathologic findings revealed that the gastric cancer was separated from the pancreas, suggesting that the cancer had developed from the stomach. The present report describes a rare case of gastric cancer that had developed at the anastomosis of a pancreaticogastrostomy.

Successful treatment for rupture of pancreaticoduodenal artery aneurysm: two case reports.

We report 2 cases of ruptured pancreaticoduodenal artery aneurysm (PDAA) treated by transcatheter embolization (TAE). In the first case, a 63-year-old man complained of sudden abdominal pain and was transferred to our hospital because he collapsed in a state of shock. Abdominal computed tomography (CT) revealed retroperitoneal hematoma and ascites. Abdominal angiography showed bleeding from one of the branches of the inferior pancreaticoduodenal artery. The ruptured PDAA was terminated by TAE. In the second case, a 65-year-old man experienced sudden abdominal pain. Abdominal CT revealed a retroperitoneal hematoma. He received TAE to terminate bleeding from a PDAA, but his abdominal pain worsened. At operation, ileus caused by the hematoma compressing the transverse colon was diagnosed, and cecostomy was performed. He recovered well and was discharged a few days later. In summary, a patient with a ruptured PDAA should first be treated by TAE, followed if necessary by surgery.

Total intraoperative enteroscopy using a colonoscope for detecting the bleeding point.

We report a case of bleeding in the small intestine of a 59-year-old man that was successfully diagnosed and treated by total intraoperative enteroscopy. The patient was admitted to our hospital because of gastrointestinal bleeding. Gastroscopy, colonoscopy and mesenteric arteriography could not identify the bleeding point. Technetium-99m-labeled red blood cell scintigraphy suggested bleeding from the small intestine but could not reveal the precise lesion. As the patient presented melena and went into a state of shock, we performed emergency laparotomy with total intraoperative enteroscopy using a colonoscope. A small ulceration was found at the jejunum, and subsequently partial resection of the jejunum was performed. The lesion was diagnosed histopathologically as angiodysplasia. The patient recovered uneventfully and was discharged on the 24th postoperative day. Bleeding in the small intestine is rare and difficult to diagnose but it sometimes induces a severe condition. Total intraoperative enteroscopy using a colonoscope is effective for detecting the bleeding point in the small intestine and can be performed at most centers without special fiberscopes and techniques.

D2 gastrectomy with versus without bursectomy for gastric cancer.

OBJECTIVES: The purpose of this study was to determine the survival benefit of bursectomy by retrospectively comparing the prognosis in patients undergoing D2 lymphadenectomy and gastrectomy (D2 gastrectomy) with bursectomy for gastric cancer with that in patients undergoing D2 gastrectomy alone. METHODS: A total of 254 consecutive stage IA to IIIC gastric cancer patients undergoing curative intent surgery between 2004 and 2009 were enrolled. The patients were divided into 2 groups: a bursectomy group, which included patients undergoing curative D2 gastrectomy with bursectomy by one surgeon, and a nonbursectomy group, which included those undergoing curative D2 gastrectomy alone by other surgeons. RESULTS: No statistically significant difference was observed in the number of metastatic nodes or penetration of the serosa between the 2 groups. The overall incidence of surgery-related complications was 24.0% in the bursectomy group (29 of 121 patients) and 25.6% in the nonbursectomy group (34 of 133 patients). The 5-year overall survival rate was 85.8% in the bursectomy group and 80.8% in the nonbursectomy group (hazard ratio 0.82; 95% confidence interval, 0.37-1.74; P=0.60). CONCLUSIONS: The results of this retrospective study indicate no survival benefit for bursectomy plus D2 gastrectomy over D2 gastrectomy alone.

Differing deregulation of HER2 in primary gastric cancer and synchronous related metastatic lymph nodes.

BACKGROUND: The aim of this study was to investigate how differences in expression of HER2 between primary gastric cancers (PGCs) and their corresponding metastatic lymph nodes (LMNs) might affect its potential as a prognostic indicator in treatments including anti-HER2 agents. METHODS: The analysis was conducted in 102 patients who underwent surgical resection for primary gastric cancers (PGCs; adenocarcinoma, intestinal type) with synchronous LNMs. HER2 gene status and protein expression were investigated by immunohistochemistry (IHC) in all patients; fluorescence in situ hybridization (FISH) was performed in 22 patients. The correlation between HER2 gene status in PGCs and their LNMs was evaluated. RESULTS: Positive HER2 expression as detected by IHC + FISH was observed in 27/102 PGC samples (26.5%) and 29/102 LNM samples (28.4%). HER2 amplification status in 102 paired PGC and LNM samples as evaluated by FISH + IHC was concordant in 92 patients (90.2%), 69 (67.6%) were unamplified and 23/102 (22.5%) were amplified at both sites, and discordant in 10 patients (9.8%), 4 (3.9%) were positive for PGC and negative for LNM, while 6 (5.9%) were positive for LNM and negative for PGC. The results of FISH + IHC showed very strong concordance in HER2 status between the PGC and LNM groups (k = 0.754). CONCLUSION: The high concordance between HER2 results for PGCs and their LNMs indicates that assessment of HER2 status in the primary cancer alone is a reliable basis for deciding treatment with anti-HER2 agents in patients with LNMs from gastric adenocarcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9365749431029643.

Pharmacokinetics of docetaxel in gastric cancer patients with malignant ascites.

PURPOSE: The purpose of this study was to investigate whether intravenous (i.v.) administration allowed docetaxel to penetrate ascites in gastric cancer patients with peritoneal dissemination. PATIENTS AND METHODS: Twelve patients with disseminated gastric carcinoma were enrolled in the study. All patients received docetaxel-containing drug regimens: i.v. administration of 40 mg/m(2) docetaxel in 6 patients, and 60 mg/m(2) in the remainder. Docetaxel concentrations in the plasma and ascites were measured. RESULTS: Docetaxel was detected in the ascites of 4 patients in the 40 mg/m(2) group and 5 patients in the 60 mg/m(2) group. The highest concentration of docetaxel in plasma was detected at immediately after administration (median: 1,660 ng/mL, 501-2,560 ng/mL), after which it gradually decreased. The highest concentration of docetaxel in ascites was observed at ~7 h after administration and varied among cases (median: 18 ng/mL, 11-52 ng/mL). CONCLUSION: Intravenous administration allows to penetrate ascites in gastric cancer patients with peritoneal dissemination.