Tertiary Lymphoid Tissues Are Microenvironments with Intensive Interactions between Immune Cells and Proinflammatory Parenchymal Cells in Aged Kidneys.

SIGNIFICANCE STATEMENT: Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms underlying TLT expansion and their effect on renal regeneration remain unclear. The authors report that single-nucleus RNA sequencing and validation experiments demonstrate that TLTs potentially amplify inflammation in aged injured kidneys. Lymphocytes within TLTs promote proinflammatory phenotypes of the surrounding proximal tubules and fibroblasts within the TLTs via proinflammatory cytokine production. These proinflammatory parenchymal cells then interact with immune cells by chemokine or cytokine production. Such cell-cell interactions potentially increase inflammation, expand TLTs, and exacerbate kidney injury. These findings help illuminate renal TLT pathology and suggest potential therapeutic targets. BACKGROUND: Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms that expand TLTs and underlie exacerbation of kidney injury remain unclear. METHODS: We performed single-nucleus RNA sequencing (snRNA-seq) on aged mouse kidneys with TLTs after ischemia-reperfusion injury. The results were validated using immunostaining, in situ hybridization of murine and human kidneys, and in vitro experiments. RESULTS: Using snRNA-seq, we identified proinflammatory and profibrotic Vcam1+ injured proximal tubules (PTs) with NF κ B and IFN-inducible transcription factor activation. VCAM1 + PTs were preferentially localized around TLTs and drove inflammation and fibrosis via the production of multiple chemokines or cytokines. Lymphocytes within TLTs expressed Tnf and Ifng at high levels, which synergistically upregulated VCAM1 and chemokine expression in cultured PT cells. In addition, snRNA-seq also identified proinflammatory and profibrotic fibroblasts, which resided within and outside TLTs, respectively. Proinflammatory fibroblasts exhibited STAT1 activation and various chemokine or cytokine production, including CXCL9/CXCL10 and B cell-activating factor, contributing to lymphocyte recruitment and survival. IFN γ upregulated the expression of these molecules in cultured fibroblasts in a STAT1-dependent manner, indicating potential bidirectional interactions between IFN γ -producing CXCR3 + T cells and proinflammatory fibroblasts within TLTs. The cellular and molecular components described in this study were confirmed in human kidneys with TLTs. CONCLUSIONS: These findings suggest that TLTs potentially amplify inflammation by providing a microenvironment that allows intense interactions between renal parenchymal and immune cells. These interactions may serve as novel therapeutic targets in kidney diseases involving TLT formation.

Tertiary lymphoid tissues in kidney diseases: a perspective for the pediatric nephrologist.

Chronic kidney disease (CKD) is a major public health problem worldwide. In the pediatric population, CKD is also an important health issue because it causes several comorbid conditions that can have long-term consequences beyond the pediatric age. Chronic inflammation is a common pathological feature of CKD, irrespective of etiology, and leads to maladaptive repair and kidney dysfunction. Tertiary lymphoid tissues (TLTs) are ectopic lymphoid structures that develop in non-lymphoid organs under chronic inflammation caused by pathological conditions, including infections, autoimmune diseases, and cancers. TLTs in the kidneys have been poorly researched due to the lack of an animal model. We have recently found that, in aged but not young mice, TLTs develop in multiple kidney injury models, and the analysis of age-dependent TLTs has brought about several novel insights into the development and pathogenic impacts of TLTs in the kidney. Age-dependent TLT formation is also observed in human kidneys. In addition to aged kidneys, TLT development is also reported in several human kidney diseases including kidney allografts, lupus nephritis, and IgA nephropathy in both adults and children. In this review, we describe the novel findings on TLTs in the kidney obtained mainly from the analysis of age-dependent TLTs and discuss the clinical relevance of TLTs in kidney diseases.

[A Case of Recurrent Gastric GIST Who Survived for Long after Laparoscopic Resection and Imatinib Therapy].

A man patient in his 70s underwent left nephrectomy and laparoscopic partial gastrectomy for the treatment of a left renal cell carcinoma and gastrointestinal stromal tumor(GIST)arising from the stomach. Histopathologically, both the renal cell carcinoma and GIST were kit-positive, CD34-positive, and S-100 protein-negative, and the Ki-67 index was about 40% as determined by the hot spot method, so that it was diagnosed as an intermediate-group GIST. After surgery, the patient was followed without adjuvant therapy, as he did not wish to receive postoperative chemotherapy. A computed tomography(CT)conducted 3 years after the surgery revealed tumorous shadows in the abdominal wall, inferior periesophageal region, and dorsal aspect of the pancreas. Positron emission tomography(PET)-CT showed fluorodeoxyglucose(FDG) accumulation in these lesions. Therefore, based on a suspicion of recurrent renal cell carcinoma or GIST, we carried out abdominal wall tumor resection for both exploratory and diagnostic purposes, which yielded histopathological diagnosis of GIST, with features similar to those observed at the time of the initial operation. Because the number of tumors remained unchanged during the subsequent follow-up period, the tumorous lesions in the periesophageal region and on the dorsal aspect of the pancreas were resected laparoscopically. Each of the resected tumors showed histological features consistent with GIST. The patient was started on oral imatinib therapy after this operation. To date(5 years after the surgery for the recurrent tumors and 8 years after the initial operation), the patient has remained free of recurrence. The pattern of tumor recurrence noted in the present case(ie, metastasis/dissemination to the skeletal muscles)is relatively rare, and few reports have been published concerning long-term survivors through multidisciplinary treatment (surgical treatment and others). We report this case with a review of the literature.

[A Case of Unresectable Advanced Gastric Cancer Successfully Treated with Conversion Surgery].

A man in his 70s consulted a local clinic with a chief complaint of difficulty eating. Upper gastrointestinal endoscopy revealed a type 4 tumor spreading irregularly from immediately below the esophageal cardia to the lower gastric body. The patient was referred to our hospital with a diagnosis of advanced gastric cancer(human epidermal growth factor receptor 2 [HER2]-positive moderately-differentiated adenocarcinoma)accompanied by lymph node enlargement. We planned an open total gastrectomy after staging laparoscopy to rule out dissemination because peritoneal dissemination could not be ruled out using computed tomography(CT). To perform a total gastrectomy, a celiotomy was done after staging laparoscopy results suggested that dissemination was unlikely. However, the border between the pericardial lymph nodes and the pancreas or peritoneal artery was not visible, forcing us to terminate the staging laparotomy based on a judgment of unresectable locally advanced gastric cancer. Therefore, the patient was administered 6 cycles of combined S-1/CDDP plus trastuzumab as the primary therapy. The response to therapy was favorable, and we scheduled a surgical resection. However, the scheduled surgery was rescheduled because of COVID-19 pneumonia, and R0 resection was finally performed after the 7th cycle of S-1/CDDP plus trastuzumab therapy. Histopathologically, the regional lymph node metastasis had disappeared, the viable tumor remained within the mucosal layer, and scarring was evident from the submucosal layer to the serosa. In recent years, conversion surgery for unresectable gastric cancer has been sporadically reported. However, we are unable to definitively opine on whether this kind of surgery may contribute to improving the prognosis, resection remains indispensable for radical treatment. We report this case along with a review of the literature.

[A Case of Triple Negative Breast Cancer with Successful Control of Recurrent Disease Activity for More than Ten Years].

A woman in her 70s underwent mastectomy plus axillary lymph node excision(Bt plus Ax)in December 2011 for left breast cancer classified as pT2N1M0, pStage ⅡB. The tumor was identified as an invasive ductal carcinoma(IDC), neural/ glial antigen 2(NG2), pT2(35 mm), INF γ, ly2, v0, g+, f+, s+, extensive intraductal component(EIC)-negative, ICT- positive, NCAT-positive, n(4/18), estrogen receptor(ER)-negative, progesterone receptor(PgR)-negative, human epidermal growth factor receptor 2(HER2)-negative, Ki-67 30-40%. Postoperative adjuvant fluorouracil plus epirubicin HCl plus cyclophosphamide(FEC)plus paclitaxel(PTX)therapy was administered. The patient refused to undergo postoperative radiation therapy. Two years after the surgery, she was diagnosed as having a lung metastasis and local disease recurrence. Biopsy of the local recurrent lesion revealed the same histopathological diagnosis as before. Capecitabine was selected for treatment of the recurrent lesion. After 2 years of capecitabine treatment, the response was rated as progressive disease (PD). At this time, eribulin mesylate was selected, along with intensity-modulated radiation therapy(IMRT). This resulted in disappearance of the tumor on imaging. However, considering that the histological findings did not suggest complete response(CR)and that the tumor was triple-negative(TN), we adopted a strategy of continuing the drug therapy at reduced dose level. With this strategy, the disease activity could be successfully controlled for 6.5 years. Subsequently, liver metastasis was detected, and the drug was switched to vinorelbine ditartrate(a drug with less non-hematological toxicity). Meanwhile, a breast cancer susceptibility gene(BRCA)analysis was performed in January 2021, which was negative. Subsequently, in September 2021, we obtained a positive result for PDL1-SP142 and negative result for 22C3. About half a year later, ie, in October 2021(11 years after the surgery), we detected an increase in the size of the liver metastasis and selected atezolizumab and nab-PTX for treatment. Applicable regimens of drug therapy are still available at present and drug therapy has been continued based on a discussion and mutual understanding of the adverse reactions, etc. with the patient. Few reports have been published concerning long-term survivors among TN breast cancer cases.

[Laparoscopic Abdominoperineal Resection of the Rectum in a Case with Pagetoid Spread of Anal Canal Carcinoma].

The patient, a man in his 60s, first noticed an elevated lesion around the anus 3 years ago. The lesion failed to subside with the topical drug preparations prescribed at a local clinic, and the patient was referred to the Department of Dermatology of our hospital for further workup and treatment. The findings of biopsy from the lesion suggested skin infiltration of anal canal carcinoma, and the patient was referred to the Department of Surgery. Examination here revealed only induration of the anal canal, with no abnormality of the rectal mucosa even when the endoscope was reversed to visualize the rectum. Examination by various imaging modalities failed to reveal any metastases to the lymph nodes or distant organs, and the primary lesion remained unidentified. Laparoscopic abdominoperineal excision of the rectum was performed, beginning with anal manipulation. First, a 15-mm margin was set on the skin from the tumor edge, and the skin stump was divided into 4 equal portions. After confirming by rapid intraoperative frozen-section examination that the margin was negative along the full circumference, anal manipulation was performed, leaving a distance in the vertical direction immediately below the tumor. Upon completion of the anal manipulation, intraperitoneal manipulation was performed in a routine manner. The anal skin was relaxed subcutaneously, as done during mastectomy, and the subsequent suture closure could be done smoothly. The tumor was classified as pT1bN0M0, pStage Ⅰ. The experience with this case indicates that biopsy should be proactively employed for the diagnosis in such cases, and that proactive skin biopsy is useful when dealing with intractable anal skin lesions.

[Brain Metastasis Following Conversion Surgery for Sigmoid Colon Cancer-A Case Report].

A 64-year-old man was diagnosed with KRAS-mutant type sigmoid colon cancer with metastasis in the lung, liver, left adrenal gland, and para-aortic lymph node(T3N1M1b, Stage ⅣB[Union for International Cancer Control 8th edition]). Laparoscopic transverse colostomy was performed to treat colonic obstruction. Subsequently, a combination regimen of capecitabine plus oxaliplatin plus bevacizumab was administered. After 5 courses of chemotherapy, the S8 liver tumor disappeared completely. Sigmoidectomy, para-aortic lymph node dissection, and left adrenal gland resection were performed. After 3 months, right S3 segmental pneumonectomy and right S8 and S10 partial pneumonectomy were performed. R0 resection for the primary lesion and metastatic lesions of the chest and abdomen was achieved. Following the conversion surgery, he was administered the adjuvant chemotherapy regimen of uracil-tegafur plus Leucovorin. After 2 courses of chemotherapy, he presented to our hospital complaining of vomiting and dizziness. Contrast-enhanced magnetic resonance imaging revealed multiple brain metastases. Thus, we should be mindful of the possibility of brain metastasis in cases of unresectable colon cancer showing satisfactory response to chemotherapy with an indication of conversion surgery.

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury.

Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

[Rectal Neuroendocrine Tumor G2 of Measuring Less Than 1 cm in Diameter with Lymph Node Metastases-A Case Report].

A 40-year-old man visited our hospital with rectal submucosal tumors measuring 5 mm and the 7 mm as detected by colonoscopy, following which an endoscopic submucosal resection was performed. Pathological examination revealed that the tumors was neuroendocrine tumor(NET); the tumor measuring 5 mm was NET G1 without lymphatic and venous invasion, while the 7 mm size was NET G2 with venous invasion but without lymphatic invasion. Lymph node and distant metastasis were not observed by computed tomography. Informed consent was obtained and he agreed to undergo additional rectal resection. Laparoscopic low anterior resection was performed and pathological examination enabled a diagnosis of rectal neuroendocrine tumor with regional lymph node metastases(T1a, N1, M0, Stage ⅢB[Union for International Cancer Control 8th edition]). Post-surgery, he was followed up for 3 years, without recurrence. This report suggests that the determination of treatment plan for rectal neuroendocrine tumor measuring less than 1 cm in diameter should be done carefully.

Cholelithiasis in infants with congenital nephrotic syndrome of the Finnish type.

BACKGROUND: Congenital nephrotic syndrome of the Finnish type (CNF) caused by NPHS1 mutations is a rare disease. Infants with CNF can develop many complications, but hepatobiliary complications are uncommon. CNF is not reported as a risk factor of cholelithiasis, which is also a rare disease in the pediatric population. We herein present the cases of three infants with CNF diagnosed with gallstones among a total of seven children with CNF who were treated between 2010 and 2020 in our hospital. CASE-DIAGNOSIS/TREATMENT: The gestational ages, birth weights, and ages at CNF diagnosis of cases 1, 2, and 3 were 38, 37, and 38 weeks; 2450, 2374, and 3120 g; and 25, 3, and 31 days of age, respectively. Imaging studies at the time of CNF diagnosis revealed asymptomatic gallstones in each of them. Case 1 patient developed incarcerated choledocholithiasis and presented with vomiting, white stool, and critically prolonged coagulation at 7 months of age. The gallstones disappeared at 3 months of age in case 2, although they remained in cases 1 and 3 at the last observation. CONCLUSIONS: Infants with CNF can develop cholelithiasis and should undergo hepatobiliary ultrasonography at the time of diagnosis. Patients with gallstones should be evaluated for signs of potential gallstone incarceration because of the risk of hemorrhagic complications due to cholestasis with subsequent vitamin K deficiency and treatment with anticoagulation agents.

[R0 Resection following Chemotherapy for Colon Cancer Liver Metastasis Close to the Inferior Vena Cava and Hepatic Vein Confluence-A Case Report].

A 78-year-old man was diagnosed with sigmoid colon cancer, and laparoscopic sigmoidectomy was performed. On pathological examination, he was diagnosed with RAS-wild type sigmoid colon cancer with regional lymph node metastasis (T3, N1, M0, Stage ⅢB[Union for International Cancer Control 8th edition]). Computed tomography revealed S8 and S7 liver metastasis, 3 months after the initial surgery. The location of the S8 tumor was close to the inferior vena cava(IVC), right hepatic vein(RHV)and segment Ⅷ hepatic vein(V8). He was administered cetuximab plus modified FOLFOX6. After 6 courses of chemotherapy, the S8 and S7 liver tumor shrank. S8 plus 4 plus 1 and S7 partial hepatectomy was performed and R0 resection was achieved. The RHV and V8 were resected, while right superficial and middle hepatic veins were preserved. An IVC invasion was not observed. He was administered 12 courses of adjuvant modified FOLFOX6. After the partial hepatectomy, he has been followed up for 1.5 years with no recurrence.

[A Case of Adenocarcinoma Arising from an Ectopic Pancreas of the Stomach Presenting as Pyloric Stenosis].

The patient was a 37-year-old man who visited a neighborhood clinic complaining of nausea and upper abdominal pain. Since examination revealed abdominal distention, he was referred to our hospital. Abdominal computed tomography at our hospital revealed retention of gastric contents and contrast-enhancing wall thickening localized to the pyloric region. Upper gastrointestinal endoscopy showed stenosis involving the entire circumference of the pylorus. However, multiple biopsies failed to reveal any evidence of malignancy. Four dilatations were performed, with no improvement. Therefore, the patient was referred to the Department of Surgery. Since malignant disease could not be ruled out, laparoscopic distal gastrectomy with D2 lymph node dissection was performed. Histopathological examination of the resected specimen revealed the presence of ectopic pancreatic tissue in the proper muscle layer of the pylorus. Adenocarcinoma invading and proliferating into the surrounding ectopic mucosal lesion was observed. Therefore, the patient was diagnosed with adenocarcinoma arising from ectopic pancreas. The possibility of ectopic pancreatic cancer may need to be considered in patients with pyloric stenosis caused by a submucosal tumor-like lesion.

Influenza virus vaccination in children with nephrotic syndrome: insignificant risk of relapse.

BACKGROUND: Immunization with various vaccines is considered desirable for children with idiopathic nephrotic syndrome (NS) because of their high risk of severe infections. Vaccinations may precipitate relapses of NS, but there is no available data regarding inactivated influenza (flu) virus vaccines. METHODS: We retrospectively reviewed the medical records of children with NS who had received flu vaccines between 2002 and 2015. The day of flu vaccination was defined as day 0, and the period between the pre-vaccination and the post-vaccination days was defined as - X to + Y. The risk ratios and their 95% confidence intervals for NS relapse rate were estimated by generalized estimating equation (GEE) Poisson regression. RESULTS: A total of 104 pediatric patients received 208 flu vaccines. The mean age at onset of NS was at 4.85 ± 3.87 years old. There were 261 NS relapses between days - 180 and + 180. Compared with the relapse rate in the - 180 to 0 interval (1.19 times/person-year), those in 0 to + 30 (1.23), + 31 to + 60 (1.58), + 61 to + 90 (1.41), + 91 to + 120 (1.41), and + 121 to + 180 (1.32) days groups were slightly increased, but without significance. Multivariate analysis using GEE Poisson regression also showed no significant increase in relapse rate in each day group compared with days - 180 to 0. Risk ratios for NS relapse were significantly higher in children who were treated with steroids at the first vaccination. CONCLUSIONS: Our results suggest that flu vaccines should not be avoided in children with NS based on the potential for NS relapses.

A simple, refined approach to diagnosing renovascular hypertension in children: A 10-year study.

BACKGROUND: Despite advances in non-invasive vascular imaging, detection of renal artery stenosis via catheter angiography is the criterion standard for the diagnosis of renovascular hypertension (RVH). However, because of lack of evidence, the utility of various blood tests and imaging modalities remains unclear. METHODS: We retrospectively analyzed the utility of blood tests (plasma renin activity [PRA], aldosterone, and renal vein renin [RVR] values) and imaging studies (computed tomography angiography [CTA], kidney ultrasonography [US]) by comparing them with catheter angiography. Ten pediatric patients with RVH at two institutions from January 2008 to December 2017 were recruited. The sensitivities for diagnosing RVH via imaging and blood tests (kidney [US], PRA, and aldosterone) were derived by examining patient records. Furthermore, the sensitivity and specificity of CT angiography were calculated by considering both the affected and non-affected renal arteries of the patients. RESULTS: A high sensitivity for diagnosing RVH via kidney US (89%) and PRA (80%) was observed. The sensitivity and specificity of CTA were 100%, each. RVR sampling did not aid in the diagnosis of RVH; only two of six patients with unilateral RVH showed significant laterality of RVR boundary ratios. Renal scintigraphy facilitated detection of a non-functional kidney (split renal function <5%). CONCLUSIONS: RVH in children could be diagnosed utilizing non-invasive blood and imaging tests, without catheter angiography. We recommend kidney length measurement along with measurement of PRA level, as a simple and highly useful screening test, followed by CTA as a diagnostic test.

[Long-Term Disease Control with Capecitabine plus Bevacizumab Therapy for an Elderly Patient with Unresectable Colon Cancer-A Case Report].

An 83-year-old man visited our hospital with liver tumors detected by abdominal ultrasonography. On investigation, he was diagnosed with sigmoid colon cancer with metastasis in the supraclavicular lymph node, liver, and para-aortic lymph node(T3N1M1b, Stage ⅣB[Union for International Cancer Control 8th edition]). He was administered combination therapy with capecitabine and bevacizumab owing to the increased age and Eastern Cooperative Oncology Group performance status score of 1. After 8 courses of chemotherapy, the primary tumor and liver metastases shrank. As he developed Grade 2 hand-foot syndrome, the dose of capecitabine was decreased to 75%(1,500 mg/m2)from the 11th course and to 50% (1,000 mg/m2)from the 31st course. Until 2 years after initiation of the chemotherapy, the patient showed progression-free survival. Heparinoid-containing moisturizer and steroid ointment were administered for treatment of hand-foot syndrome. This report suggests that capecitabine plus bevacizumab therapy can maintain the quality of life and is safe with dose reduction and treatment of adverse reactions for elderly patients with colon cancer.

[A Case of Small Bowel Perforation Caused by Malignant Lymphoma after Methotrexate Therapy for Rheumatoid Arthritis].

A 73-year-old woman had a history of medication, including methotrexate for rheumatoid arthritis, for 5 years. She had chronic epigastralgia for 2 weeks and found to have multiple submucosal tumors on upper gastrointestinal endoscopy in another hospital. She had a strong abdominal pain thereafter and diagnosed as having gastrointestinal perforation on the basis of CT scans. Abdominal examination revealed disseminated peritonitis, and emergency laparoscopic surgery was performed on the day of admission. A 1 cm perforation of the ileum was identified, and a 5 cm mass of the mesentery near the perforation was also identified. Small bowel partial resection, including both lesions, was performed. From the intraoperative findings, methotrexate-associated lymphoproliferative disorders(MTX-LPD)was suspected, and methotrexate was discontinued after the surgery. At a later date, the pathological result from both the surgical specimen and upper gastrointestinal endoscopy was diffuse large B cell lymphoma(DLBCL). CT scan, PET-CT scan, and upper gastrointestinal endoscopy were performed 1-2 months after surgery, and no tumor was identified. Currently, 6 months after the surgery, the patient is still alive without any progression of the lymphoma.

[Trastuzumab Combination Chemotherapy Followed by R0 Resection for Locally Advanced Human Epidermal Growth Factor Receptor 2-Positive Gastric Cancer-A Case Report].

A man in the 60s visited our hospital with the complaints of epigastralgia and weight loss. Following an investigation, he was diagnosed with human epidermal growth factor receptor 2(HER2)-positive gastric cancer with invasion to the pancreas (T4b[pancreas], N2, M0, Stage ⅣA[Union for International Cancer Control 8th edition]). Preoperatively, he was administered a chemotherapeutic regimen of S-1 and cisplatin plus trastuzumab. After 2 courses of chemotherapy, computed tomography revealed invasion to the abdominal wall and pyloric stenosis; however, invasion to the pancreas was obscured, and the lymph node metastases had shrunk. He underwent laparoscopic gastro-jejunostomy. After 4 courses of chemotherapy, his condition was considered stable. A laparoscopic distal gastrectomy was performed together with resection of the abdominal wall invasion. The pathological stage was pT4b(abdominal wall), pN0, M0, Stage ⅢA, and R0 resection was achieved. The patient was administered 4 courses of adjuvant capecitabine plus oxaliplatin therapy and 4 courses of capecitabine monotherapy. He has been followed-up for 1.5 years since the curative resection and has not developed recurrences. This case suggests the usefulness of multimodal therapy for locally advanced gastric cancer.

[A Case of Extrahepatic Bile Duct Carcinoid Tumor Involving Diagnostic Difficulties].

A patient in his 60s had undergone laparoscopic anterior resection for the treatment of carcinoma of the rectum in February 2016. Histopathologic examination revealed the lesion as a pT2(MP)n(-)M0, fStage Ⅰrectal cancer. One year post-surgery, contrast-enhanced computed tomography(CT)revealed enhancement of parts of the intrapancreatic distal bile ducts. Magnetic resonance cholangiopancreatography(MRCP)showed filling defects at the same site. Magnetic resonance imaging( MRI)with an endorectal coil(ERC)was then performed to identify reproducible bile duct filling defects. Neither cytology nor biopsy yielded any findings that definitely indicated malignancy. Intraductal ultrasonography(IDUS)led to the suspicion of a nonepithelial tumor or an enlarged lymph node. Repeated biopsies via ERC were performed based on the absence of evidence of malignancy and revealed the presence of some atypical cells within the lesions. Although no definitive diagnosis could be made, the patient was scheduled for surgery in June 2017 after obtaining his consent. Upon taping of the common bile duct during surgery, a tumor was palpable on the dorsal aspect of the pancreas. The bile duct tumor was completely excised and submitted for intraoperative diagnosis; the pancreatic dorsal aspect appeared to be totally split. There was no evidence of atypia in the neoplasm, which was therefore considered to be benign; however, malignancy could not be completely ruled out because the patient had presented with elevated serum levels of carbohydrate antigen(CA)19-9 once before the operation. After intraoperative consultation with the patient's family members, who were reluctant to provide consent for pancreaticoduodenectomy, we completed the operation with resection of the bile duct tumor, followed by choledochojejunostomy. The tumor was found to be chromogranin A(+), cluster of differentiation(CD)56(+/-), CA19-9(+, solely ductal structure), carcinoembryonic antigen(CEA)(+, solely ductal structure), and intranuclear p53(-), with an MIB- 1 index of<2%. With regard to neuroendocrine markers, a region that could potentially have been a carcinoid tumor, based on the findings on hematoxylin and eosin(HE)staining, and a lumenized superficial region showed positivity in toto. Therefore, the lesion as a whole was diagnosed as a G1 carcinoid neuroendocrine tumor(NET). However, the superficial lumenized layer was positive for both CA19-9 and CEA; therefore, the tumor was thought to concurrently have epithelial characteristics. The lateral stumpwas negative, while the status of the ablated region remained unclear. After discussing the histopathologic examination results with the patient and his family members, the patient's follow-upwas decided to consist of periodic checkups without any further surgical intervention. The patient has since remained free of recurrence. Carcinoid tumor of the bile duct is extremely rare but should be considered in cases involving bile duct tumors that show enhancement on imaging prior to surgery and for which no definitive diagnosis can be established despite repeated biopsy explorations.

[Pathological Complete Response Following Chemotherapy for Sigmoid Colon Cancer with Para-Aortic Lymph Node Metastasis-A Case Report].

A man in his 50s visitedour hospital with complaints of frequent urination, painful micturition, macrohematuria, and weight loss. On examination, he was diagnosed with RAS-wild-type sigmoid colon cancer invading the urinary bladder, ureter, andexternal iliac artery, with para-aortic lymph node metastasis(T4b, NX, M1a, Stage ⅣA according to the Union for International Cancer Control 8th edition guidelines)andsigmoid -vesical fistula. Thus, sigmoidcolostomy was performed. Postoperatively, S-1 plus oxaliplatin was administered. After 3 courses of chemotherapy, the primary tumor and para-aortic lymph node metastases shrunk. Moreover, after 8 courses of chemotherapy, further shrinkage of the primary tumor and paraaortic lymph node metastases was confirmed; however, tumor markers in the blood increased. Therefore, the patient received 3 additional courses of S-1 plus oxaliplatin plus cetuximab, which resultedin complete response. Sigmoidectomy, partial cystectomy, ureterectomy, resection of the external iliac artery, andreconstruction using a prosthetic vascular graft were performed. Subsequent pathological examination revealed no viable cancer cells(pathological response), achieving R0 resection. The patient has been followedup for 2.5 years after the curative resection, with no recurrence.