BRAF V600E-induced distinct DNA damage response defines the therapeutic potential of p53 activation for TP53 wild-type colorectal cancer.

BRAF V600E, one of the most frequent mutations in the MAPK pathway, confers poor prognosis to colorectal cancers (CRCs), partly because of chemotherapeutic resistance. Oncogene-induced DNA damage responses (DDRs) that primarily activate p53 are important mechanistic barriers to the malignant transformation of cells; however, the mechanism underlying this impairment in cancer remains unknown. Here, we evaluated the responses of BRAFV600E-induced DDRs in two CRC cell lines, SW48 and LIM1215, both of which harbor wild-type TP53, KRAS, and BRAF. BRAFV600E transduction exhibited distinct phenotypes in these cells: SW48 cell proliferation markedly decreased, whereas that of LIM1215 increased. BRAFV600E expression induced the activation of oncogene-induced DDR signaling in SW48 cells, but not in LIM1215 cells, whereas chemotherapeutic agents similarly activated DDRs in both cell lines. Knockdown experiments revealed that these responses in SW48 cells were mediated by p53-p21 pathway activation. Comet assay (both alkaline and neutral) revealed that BRAFV600E increased single-strand breaks to the same extent in both cell lines; however, in case of LIM1215 cells, it only facilitated double-strand breaks. Furthermore, the proliferation of LIM1215 cells, wherein no oncogene-induced DDRs occurred, was synergistically inhibited upon MDM2 inhibitor-mediated p53 activation combined with MEK inhibition. Taken together, these distinct DDR signaling responses highlight the novel characteristics of BRAFV600E-mutated CRC cells and define the therapeutic potential of p53 activation combined with MAPK inhibition against TP53 wild-type CRC harboring a BRAFV600E mutation.

Distal gastrectomy and Roux-en-Y reconstruction for refractory reflux esophagitis after proximal gastrectomy and esophagogastric anastomosis reconstruction.

Refractory gastroesophageal reflux disease can develop after proximal gastrectomy and esophagogastrostomy. We introduce a new method that combines distal gastrectomy and Roux-en-Y reconstruction to treat refractory reflux esophagitis in patients who have undergone proximal gastrectomy and esophagogastric anastomosis reconstruction. This novel method may be useful not only for alleviating the symptoms of gastroesophageal reflux disease but also for preventing future esophageal malignancies arising from long-term reflux esophagitis.

Preoperative diagnosis of tumor depth in gastric cancer using transabdominal ultrasonography compared to using endoscopy and computed tomography.

BACKGROUND: An accurate evaluation method for preoperative diagnosis has not yet been established in patients with gastric cancer (GC), though it is essential for optimal treatment. Current standard modalities are endoscopy and contrast computed tomography (CT). In this study, we investigated the efficacy and limitations of transabdominal ultrasonography (TUS) for the assessment of tumor invasion. METHODS: We enrolled 178 consecutive patients with GC evaluated by TUS, endoscopy, and contrast CT before gastrectomy. For the TUS examination, patients ingested water to fill their stomachs. The clinical staging determined using these modalities was compared to the pathological staging. RESULTS: The overall accuracy of clinical T staging using TUS was 47.8% (pT1a: 5.8% (2/35); pT1b: 58.8% (20/35); pT2: 69.6% (16/23); pT3: 66.7% (22/33); pT4a: 46% (23/50); pT4b: 100% (2/2)). Using endoscopy, contrast CT, and TUS, the overall accuracy was 60.7%. The accuracy of TUS was associated with the tumor region (U region: 50% (14/28); M: 31.8% (14/44); L: 53.7% (57/106); P = 0.048), but not with the cross-sectional parts (P = 0.49). Multivariate analysis identified inaccurate TUS as independently correlating with tumor region (M vs. U/L, odds ratio (OR) = 3.11, 95% confidence interval (CI) 1.41-6.87; P = 0.005) and pT (pT1 vs. pT2-4, OR = 3.00, 95%CI 1.31-6.87; P = 0.009). CONCLUSIONS: The present study demonstrated the importance of TUS in evaluating GC. Thus, TUS may be useful for clinical T staging in certain circumstances, leading to treatment optimization.

[A Case of Long-Term Survival with Multidisciplinary Treatment for Postoperative Local Recurrence of Intrahepatic Cholangiocarcinoma].

We report a case of local recurrence of intrahepatic bile duct cancer that was successfully treated using chemotherapy and radiation therapy. A man in his 80s underwent hepatic resection for intrahepatic cholangiocarcinoma, and abdominal CT 11 months after surgery revealed local recurrence around the dissected surface. He was diagnosed with a local recurrence of intrahepatic cholangiocarcinoma and started systemic chemotherapy(GEM plus CDDP plus S-1). After 11 courses of chemotherapy, stereotactic body radiation therapy(SBRT)was administered to the same site at 50 Gy/10 Fr, as the local recurrence area had increased, although no distant metastases were detected on imaging. The patient was then started on chemotherapy( GEM plus S-1), but after 2 courses, 8 courses of GEM alone were administered at the patient's request. No increase in tumor markers was observed, but an increase in the low-absorption area was observed on imaging. Thereafter, the regimen was changed to S-1. Three months later, the same area was reduced in size and obscured on imaging evaluation. The patient is still taking it 12 months later. No recurrence has been observed since 2 years and 7 months after the start of treatment for local recurrence. This case suggested that multidisciplinary therapy might be useful for local recurrence of intrahepatic cholangiocarcinoma.

[A Case of Radical Resection after Neoadjuvant Chemotherapy for Rectal Cancer with Pelvic Abscess].

A 66-year-old man with a history of frequent diarrhea was diagnosed with rectal cancer with obstruction and a pelvic abscess. Following a transverse colostomy, he was referred to our hospital. The initial diagnosis was rectal cancer(cT4a N1bM0, cStage Ⅲb)and a pelvic abscess due to tumor perforation. To address this condition, we performed neoadjuvant chemotherapy using a combination of 5-fluorouracil, Leucovorin, oxaliplatin, and irinotecan(FOLFOXIRI). Following 6 courses of FOLFOXIRI, the abscess disappeared and no signs of tumor progression and distant metastases were detected. Subsequently, we performed radical resection with D3LD2 lymph node dissection, leading to a pathological diagnosis of ypT3N1aM0, ypStage Ⅲb. The patient then underwent adjuvant chemotherapy with capecitabine and oxaliplatin(CAPOX). No recurrence was observed after 9 months of follow-up.

[A Case of Conversion Surgery after Chemotherapy for Unresectable Liver Metastasis of Rectal Cancer].

A 50s female was diagnosed as rectal cancer with multiple liver metastases after fecal occult blood scrutiny. Liver metastases were multiple in both lobes and involved the right Glisson's capsule. We determined that the liver metastases were unresectable and initiated FOLFOXIRI plus panitumumab treatment. After 6 courses of chemotherapy, rectal cancer resection was performed. After 12 courses of chemotherapy, the liver metastases which had extensively involved the right Glisson on imaging, shrank until the P7 root was visible. If S7 Glisson could be preserved, the radical resection was planned. If not, associated liver partition and portal vein ligation for staged hepatectomy(ALPPS)was planned. Intraoperatively, it was determined that preservation of S7 Glisson was possible and blood flow preservation in the S7 region was feasible, and an anterior segment hepatic resection(S5-6-8)and lateral segment hepatic partial resection(S2/3)were performed. She was discharged on the 18th day and has been under outpatient observation 12 months after hepatectomy.

[A Case of Recurrent Gastric Cancer with Long-Term Control via Two Resections and Multidisciplinary Treatment Including Nivolumab].

A 78-year-old woman underwent total gastrectomy with distal pancreatectomy and splenectomy for type 3 gastric cancer and a cystic tumor of the pancreas. Her pathological diagnosis was pT4aN3bM0, pStage ⅢC, and HER2-negative. Capecitabine and oxaliplatin was started as an adjuvant therapy, and capecitabine was administered until 1 year postoperatively. Thirteen months after surgery, she had a recurrence in S3 of the liver and underwent liver resection due to solitary metastasis. The postoperative diagnosis was peritoneal dissemination of gastric cancer with invasion of the falciform ligament. S-1 was started postoperatively. Ten months after surgery, she had a recurrence in S3 of the liver and underwent repeated resection. It invaded into the diaphragm and pericardium, and the final diagnosis was recurrent peritoneal dissemination of gastric cancer. After 5 courses of paclitaxel and ramucirumab, nivolumab was started as a fourth-line therapy for the recurrence of the right supraclavicular lymph nodes, bone, and liver. She had some immune-related adverse events(irAE), including hypothyroidism and hypoadrenocorticism, which required management, but she maintained PR more than 2 years after the initiation of the treatment. Multimodality therapies, including repeated resection and nivolumab, were considered to help her long-term survival.

[A Case of Pancreatic Metastasis from Renal Cell Carcinoma 16 Years after Left Nephrectomy].

A 73-year-old woman underwent left nephrectomy for renal cell carcinoma(RCC). The computed tomography(CT)and magnetic resonance imaging(MRI)revealed a 20-mm tumor in the pancreatic tale showing early enhancement in the arterial phase 16 years after surgery. Fluorodeoxyglucose positron emission tomography(FDG-PET)showed slightly uptake (maximum standard uptake value: SUVmax 2.3)and EUS-FNA showed a hyper-vascularized tumor in the pancreatic tail. A single pancreatic metastasis from RCC was diagnosed, and we performed distal pancreatectomy. The histopathological diagnosis was a metastatic pancreatic tumor from RCC. The postoperative course was uneventful and 1 month after surgery, she is alive with no recurrence.

[The Use of Platinum-Based Chemotherapy for Esophageal Cancer Patients with Impaired Renal Function].

INTRODUCTION: The key drugs of first-line chemotherapy for metastatic esophageal cancer are 5-FU and cisplatin(CF). However, the treatment strategy for unfit patients of CF regimen remains controversial. METHODS: Fifty patients who received first-line chemotherapy including platinum-containing drug for metastatic esophageal cancer between 2018-2022 at Osaka National Hospital were analyzed. They were divided into 4 groups according to estimated creatinine clearance(Ccr) at the beginning of the treatment; Group A(over 60 mL/min)31 patients, Group B(50-59 mL/min)12 patients, Group C(30-49 mL/min)5 patients, and Group D(under 30 mL/min)2 patients. The background and treatment outcome data of each group were retrieved retrospectively and compared. RESULTS: Group B, C, D had more elderly patients than Group A. Each Group B, C, D included 1 patient who received FOLFOX regimen. More than half patients in Group B, C, D reduced the dose of CDDP and the initial dose of CDDP was adequately reduced according to Ccr. Group B, C, D had more patients with decreased renal function over Grade 1 than Group A. The clinical response rate was Group A 65%, Group B 42%, Group C 60%, Group D 50%, respectively. There were no patients who ceased the treatment due to adverse events. CONCLUSION: Adequate dose reduction of CF regimen would become more important in the era that only CF regimen can be a partner of immune-checkpoint inhibitor.

[A Case of Peritoneal Lymphomatosis Diagnosed by Single-Port Laparoscopic Biopsy].

Peritoneal lymphomatosis is an extremely rare presentation of non-Hodgkin lymphoma. We report a case of peritoneal lymphomatosis diagnosed by single-port laparoscopic biopsy. A 70-year-old woman presented to our hospital with a 2-day history of increasing abdominal distension. Abdominal CT and positron emission tomography/CT(PET-CT)demonstrated extensive disseminated disease with marked thickening of the peritoneal surfaces, and a large omental cake with large volume ascites. Under the diagnosis of peritoneal carcinoma, single-port laparoscopic biopsy was performed. Pathological and immunohistochemical examination revealed diffuse large B-cell lymphoma presenting as peritoneal lymphomatosis. She was treated with a combination chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, and prednisolone(R- CHOP), and no recurrence was reported for 1 year and 6 months. Single-port laparoscopic biopsy was minimally invasive, and helpful for an urgent and accurate diagnosis and treatment of the disseminated peritoneal disease.

Biosynthesis of the Fairy Chemicals, 2-Azahypoxanthine and Imidazole-4-carboxamide, in the Fairy Ring-Forming Fungus Lepista sordida.

Fairy rings resulting from a fungus-plant interaction appear worldwide. 2-Azahypoxanthine (AHX) and imidazole-4-carboxamide (ICA) were first isolated from the culture broth of one of the fairy ring-forming fungi, Lepista sordida. Afterward, a common metabolite of AHX in plants, 2-aza-8-oxohypoxanthine (AOH), was found in AHX-treated rice. The biosynthetic pathway of the three compounds that are named as fairy chemicals (FCs) in plants has been partially elucidated; however, that in mushrooms remains unknown. In this study, it was revealed that the carbon skeletons of AHX and ICA were constructed from Gly in L. sordida mycelia and the fungus metabolized 5-aminoimidazole-4-carboxamide (AICA) to both of the compounds. These results indicated that FCs were biosynthesized by a diversion of the purine metabolic pathway in L. sordida mycelia, similar to that in plants. Furthermore, we showed that recombinant adenine phosphoribosyltransferase (APRT) catalyzed reversible interconversion not only between 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranosyl 5'-monophosphate (AICAR) and AICA but also between ICA-ribotide (ICAR) and ICA. Furthermore, the presence of ICAR in L. sordida mycelia was proven for the first time by LC-MS/MS detection, and this study provided the first report that there was a novel metabolic pathway of ICA in which its ribotide was an intermediate in the fungus.

[A Case of Hyperammonemia Induced by Chemotherapy with 5-Fluorouracil for Metastatic Colon Cancer].

Systemic chemotherapy based on 5-fluorouracil(5-FU)is a standard treatment for unresectable or recurrent colon cancers. Here, we report a case of hyperammonemia induced by chemotherapy using 5-FU for metastatic colon cancer. An 84-yearold male patient with past histories of liver cirrhosis related to hepatitis C virus and renal dysfunction underwent an operation for the rectosigmoid colon cancer 8 years ago. Three years after that operation, a local recurrence of the colon cancer was diagnosed, and chemotherapy using sLV5FU2 was initiated. The recurrence lesion reduced markedly by this chemotherapy, which was ceased 2 years ago. Two years after the cessation the recurrent tumor had been enlarged, and the chemotherapy using the same drugs at the same dose was performed. On the treatment day 3, he was emergently transported to our hospital due to the disturbance of consciousness. Since laboratory tests showed the high concentration of plasma ammonia and the progressed renal dysfunction with no other definite cause of obnubilation, he was diagnosed as the hyperammonemia induced by 5-FU. He was treated by administrating the branched-chain amino acids solutions combined with fluid therapy, which quickly recovered him from the encephalopathy. He is followed up without any chemotherapy because of his high age. When a patient treated with the chemotherapy using 5-FU is sent with the disturbance of consciousness, we should take hyperammonemia into consideration, especially when he or she has the hepatic or renal dysfunction.

[A Case of Primary Duodenal Cancer with Duodenocolic Fistula Treated with Pancreatoduodenectomy and Right Hemicolectomy].

A patient was 59-year-old female. She presented our hospital with weight loss, anorexia and lower abdominal bloating. Abdominal computed tomography(CT), gastrointestinal endoscopy, colonoscopy and duodenal fistulagram showed duodenal cancer or colon cancer with duodenocolic fistula and ovary metastasis. She underwent subtotal stomach preserving pancreatoduodenectomy and right hemicolectomy. In these pathological findings, tumor was diagnosed as a duodenal cancer with duodenocolic fistula. She was surviving 12 months after the last surgery. In cases of cancer with duodenocolic fistula, pancreatoduodenectomy with right hemicolectomy would be necessary for nutrition improvement and cancer treatment.

Polycladomyces subterraneus sp. nov., isolated from soil in Thailand.

A thermophilic poly(L-lactide)-degrading Gram-stain-positive filamentous bacterial strain that develops single spores on the aerial mycelium was isolated from forest soil at Srinagarind Dam, Kanchanaburi Province, Thailand. The results of a polyphasic taxonomic study showed that our isolate had characteristics typical of members of the genus Polycladomyces. The isolate grew aerobically at an optimum temperature of 50-55 °C and optimal pH 6-7. Meso-diaminopimelic acid was present as the diagnostic diamino acid in the peptidoglycan but no characteristic sugars are detected. The predominant menaquinone was MK-7. The diagnostic phospholipids were phosphatidylethanolamine, phosphatidylmethylethanolamine diphosphatidylglycerol, phosphatidylglycerol and phosphatidylserine. The predominant cellular fatty acid was iso-C15 : 0. The DNA G+C content of strain KSR 13T was 53.4 mol%. The 16S rRNA gene sequence analysis also indicated that strain KSR 13T belonged to the genus Polycladomyces, being most closely related to Polycladomyces abyssicola JIR-001T (99.2 %). The DNA-DNA relatedness values that distinguished KSR 13T from P. abyssicola JIR-001T were 17.8-32.1 %, which were significantly below the 70 % cutoff value recommended for species delineation. Following an evaluation of phenotypic, chemotaxonomic and genotypic studies, the new isolate is proposed as a novel species and named Polycladomyces subterraneus sp. nov. The type strain is KSR 13T (=BCC 50740T=NBRC 109332T).

Bioconversion of AHX to AOH by resting cells of Burkholderia contaminans CH-1.

Fairy rings are zones of stimulated grass growth owing to the interaction between a fungus and a plant. We previously reported the discovery of two novel plant-growth regulating compounds related to forming fairy rings, 2-azahypoxanthine (AHX) and 2-aza-8-oxohypoxanthine (AOH). In this study, a bacterial strain CH-1 was isolated from an airborne-contaminated nutrient medium containing AHX. The strain converted AHX to AOH and identified as Burkholderia contaminans based on the gene sequence of its 16S rDNA. The quantitative production of AOH by resting cells of the strain was achieved. Among seven Burkholderia species, two bacteria and two yeasts tested, B. contaminans CH-1 showed the highest rate of conversion of AHX to AOH. By batch system, up to 10.6 mmol AHX was converted to AOH using the resting cells. The yield of this process reached at 91%.

[A Case of a Single Incisional Laparoscopic Assisted Partial Jejunectomy Performed to Treat a Primary Small Intestine Cancer in a Young Woman].

A 35-year-old woman was followed by epilepsy therapy. She was admitted to our hospital because of a 15 kg decrease in weight, bilious vomit, and frequent epileptic seizures because she could not take oral antiepileptic drugs. A primary small intestinal cancer was suspected in the jejunum about 100 cm from the incisor by single-balloon enteroscopy. A single incisional laparoscopic assisted partial jejunectomy that was minimally invasive was performed to improve the symptoms of intestinal obstruction. The histopathological diagnosis was moderately differentiated adenocarcinoma, ly0, v1, pT4(SE), pN0, pM0, pStage II B. A primary small intestinal cancer is a relatively rare disease, accounting for 0.3-1.0%ofall cancers ofthe digestive tract. The primary method oftreatment is surgery, and understanding the positional relationship ofthe tumor is important when performing surgery because most primary small intestinal cancers are located in the vicinity ofthe ligaments ofTreitz. We present a case in which safe and minimally invasive surgery was performed to treat a primary small intestinal cancer in a young woman with intractable epilepsy and a significant decrease in ADL for intestinal obstruction, along with a review of the literature.

[A Patient with Colon Cancer Local Site Recurrence Who Experienced Difficulty Tolerating Intensive Chemotherapy Was Treated Effectively with sLV5FU2 Therapy].

An 82-year-old man underwent anterior resection for rectal cancer in 2006. Local recurrence was diagnosed 5 years and 4 months after the operation. He could not undergo intensive chemotherapy because of his age and health status(a history of tubercular and pancytopenia due to chronic hepatitis C). sLV5FU2 chemotherapy was initiated. The CEA level decreased immediately after chemotherapy, and a complete response was observed on CT. After 18 courses, chemotherapy was discontinued. A complete response was detected for 1 year after the chemotherapy holiday began. For patients who experience difficulty tolerating intensive chemotherapy, good outcomes have been achieved even if relatively light regimens are used. For elderly patients or those with several complications, we suggest selecting a regimen based on the QOL.

[A Case of Long-Term Survival of Resected Pancreatic Metastasis from Colon Cancer].

Pancreatic metastasis of colorectal cancer is uncommon and is often identified in later stages of cancer, thereby making resection more uncommon. We report a case oflong -term survival after resection of metachronous metastasis to the pancreas from primary sigmoid colon cancer. A 50-year-old female patient underwent a sigmoid colon resection and bilateral salpingo-oophorectomy for sigmoid colon cancer and metastatic ovarian cancer in 2007. She underwent partial lung resection for metastatic lung cancer twice. Four years and 11 months after the first operation, an isolated mass was identified in the pancreatic tail, and a distal pancreatectomy, splenectomy, left adrenal gland removal, and regional lymph node dissection were performed. The tumor stained negatively for cytokeratin 7 and positively for cytokeratin 20, resulting in a diagnosis of pancreatic metastatic cancer from sigmoid colon cancer. The patient is alive 3 years and 4 months after distal pancreatectomy. This suggests that curative resection is effective for metastasis of colorectal cancer to the pancreas, similarly to metastases to the liver and lung.

[Laparoscopic Resection in a Case of Local Recurrence of Rectal Cancer].

A 65-year-old man had undergone high anterior resection for rectal cancer. Seven years after the surgery, a liver metastasis was identified, and the metastasis was surgically resected. A year after the liver surgery, blood testing showed high carcinoembryonic antigen(CEA). A fluorodeoxyglucose(FDG) / -positron emission tomography(PET)/CT examination showed a high FDG accumulation at the rectal anastomosis site, and we diagnosed local recurrence of rectal cancer and prostate invasion. Because there were no distant metastases, he underwent laparoscopic lower anterior resection, radical prostatectomy, and ileostomy. Histopathological examination of the tumor revealed adenocarcinoma and invasion to the right seminal vesicle, suggesting local recurrence of the primary rectal adenocarcinoma. The surgical margin was free of cancer. Operations for local recurrence of rectal cancer are difficult because of tumor invasion and tissue adhesions. In spite of the extended operation, the patient showed good postoperative recovery. Laparoscopic resection for local recurrence of rectal cancer is less invasive than open abdominal operations, and it may be the treatment of choice for local recurrences of rectal cancer.

Erinaceolactones A to C, from the culture broth of Hericium erinaceus.

Three novel compounds, erinaceolactones A to C (1-3), and a known compound (4) were isolated from the culture broth of Hericium erinaceus. The planar structures of 1-3 were determined by the interpretation of spectroscopic data. The absolute configuration of 3 was determined by X-ray crystallography. Although compound 4 had been synthesized, it was isolated from a natural source for the first time. In the bioassay examining plant-growth regulatory activity of these compounds (1-4) and other components of the fungus (5-8), compounds 1, 2, and 4-8 suppressed the growth of lettuce.