Use of endoscopic ultrasound-guided fine needle aspiration of the pancreas to diagnose a case of primary linitis plastica of the colon with retroperitoneal dissemination.

A 54-year-old man had previously undergone curative sigmoidectomy for poorly differentiated adenocarcinoma with a signet-ring cell component of the sigmoid colon, which was characterized morphologically by stenosis and inelasticity of the colon (linitis plastica). Six weeks after surgery, the patient developed stenosis of the right ureter. Disseminated sigmoid cancer was suspected, and chemotherapy was started. Nine months after initiation of chemotherapy, obstructive jaundice was observed which was due to stenosis of the distal bile duct (BD). Although computed tomography showed no evident metastatic lesion that could cause the stenosis, swelling of the entire pancreas was evident compared to that of 11 months earlier. Endoscopic ultrasound (EUS) also did not detect any focal masses in the head of the pancreas, although there was a diffuse hypoechoic change in the entire pancreas. Histopathology of the stenotic BD and biopsy specimen from the head of the pancreas showed no malignant cells. Two months after the initial endoscopic bile duct drainage, the patient was admitted again for epigastric pain. A second EUS fine needle aspiration (EUS-FNA) of the head of the pancreas was performed and showed poorly differentiated carcinoma with some signet-ring cells. This finding provided histological confirmation of a disseminated pancreatic lesion of the previously resected linitis plastica of the sigmoid colon. This is a rare case of disseminated pancreatic lesion from primary linitis plastica of the colon diagnosed by EUS-FNA.

Non-negligible rate of needle tract seeding after endoscopic ultrasound-guided fine-needle aspiration for patients undergoing distal pancreatectomy for pancreatic cancer.

BACKGROUND AND AIMS: Needle tract seeding after preoperative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for pancreatic body and tail cancer has been reported. This study aimed to investigate the long-term outcomes, including the needle tract seeding ratio, of patients undergoing distal pancreatectomy for pancreatic body and tail cancer diagnosed preoperatively by EUS-FNA. METHODS: This retrospective, observational cohort study assessed patients from three university hospitals and 11 tertiary referral centers. All patients who underwent distal pancreatectomy for invasive cancer of the pancreatic body and tail between January 2006 and December 2015 were identified and reviewed. Needle tract seeding rate, recurrence-free survival (RFS), and overall survival (OS) were evaluated. RESULTS: Of the 301 total patients analyzed, 176 underwent preoperative EUS-FNA (EUS-FNA group) and 125 did not (non-EUS-FNA group). The median follow-up periods of the EUS-FNA group and non-EUS-FNA group were 32.8 and 30.1 months. Six patients (3.4%) in the EUS-FNA group were diagnosed as having needle tract seeding. The 5-year cumulative needle tract seeding rate estimated using Fine and Gray's method was 3.8% (95% CI 1.6-7.8%). The median RFS or OS was not significantly different between the EUS-FNA group and the non-EUS-FNA group (23.7 vs 16.9 months: P = 0.205; 48.0 vs 43.9 months: P = 0.392). CONCLUSION: Although preoperative EUS-FNA for pancreatic body and tail cancer has no negative effect on RFS or OS, needle tract seeding after EUS-FNA was observed to have a non-negligible rate. (UMIN000030719).

Survey on patients with undiagnosed diseases in Japan: potential patient numbers benefiting from Japan's initiative on rare and undiagnosed diseases (IRUD).

BACKGROUND: There is now an international partnership to establish global programs for patients with rare and undiagnosed diseases, involving interdisciplinary expert panels and phenotype-driven genetic analyses utilizing next-generation sequencing and analytics. Whereas it is crucial to have data such as the actual number of undiagnosed patients, to help inform the implementation plan with such programs, there have been no systematic studies to quantitate the numbers of patients principally because of the inherent difficulty in most health systems to identify patients whose condition has not yet been diagnosed and coded. Our national experience with a rare disease program, Nan-Byo which was established in 1972, and the more recently expanded Initiative on Rare and Undiagnosed Diseases (IRUD), provided a unique opportunity to design a cross-sectional study to ascertain the undiagnosed patients in Japan based on the IRUD referral criteria. RESULTS: Two rounds of online surveys were performed: one survey targeting physicians affiliated with general hospitals (GH) and family clinics (FC) (the response rate: 30.6% (242/792)) and one nationwide survey targeting university hospitals (UH) in Japan (47.1% (839/1781)). A high percentage of doctors needing IRUD was seen in pediatrics at GH, FC, while there was a clear demand for IRUD in most departments at UH. We calculated the number of undiagnosed patients in Japan, as the "percentage of doctors needing IRUD" × "number of patients who would be referred to IRUD per doctor needing IRUD (cases/person)" × "total number of doctors in the relevant facilities in Japan (persons)", resulting in 3681 cases in pediatrics/pediatric surgery and 33,703 cases in other departments, for a total of 37,384 cases. CONCLUSIONS: Our study revealed the extant demand for IRUD in most departments and 37,000+ potential patients with undiagnosed diseases in the Japanese health system. These data inform the establishment of an equitable, sustainable, efficient and effective outpatient-based IRUD. These findings would serve as a valuable reference for undiagnosed diseases programs in different international jurisdictions and for countries and regions who also share vision(s) for societal implementation that help to advance international efforts to support patients with rare diseases who are direly waiting for diagnosis, subsequent treatment and care.

Case of lamotrigine-induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug-induced hypersensitivity syndrome.

The pathological mechanisms and immunological kinetics of drug-induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)-6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti-IL-6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL-6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.

A Rupture of a Lung Metastatic Lesion of Colon Cancer, Leading to Pneumothorax Caused by Bevacizumab.

The patient was a 57-year-old man who was diagnosed with multiple lung metastases of sigmoid colon cancer. The patient developed progressive disease after 8 courses of bevacizumab + capecitabine and oxaliplatin therapy, therefore, bevacizumab + irinotecan, leucovorin, and 5-fluorouracil therapy was started. During the fifth course, he experienced pain on the left side of his chest. On computed tomography, bleeding from the pulmonary metastatic lesions was suspected. Two days later, a pneumothorax was detected. Although several cases of pneumothorax induced by bevacizumab have been reported, this case is the first documentation that bevacizumab caused a rupture of the lung metastatic lesion, leading to a pneumothorax.

Rare type of pancreatitis as the first presentation of anti-neutrophil cytoplasmic antibody-related vasculitis.

A pancreatic tumor was suspected on the abdominal ultrasound of a 72-year-old man. Abdominal computed tomography showed pancreatic enlargement as well as a diffuse, poorly enhanced area in the pancreas; endoscopic ultrasound-guided fine needle aspiration biopsy and endoscopic retrograde cholangiopancreatography failed to provide a definitive diagnosis. Based on the trend of improvement of the pancreatic enlargement, the treatment plan involved follow-up examinations. Later, he was hospitalized with an alveolar hemorrhage and rapidly progressive glomerulonephritis; he tested positive for myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA) and was diagnosed with ANCA-related vasculitis, specifically microscopic polyangiitis. It appears that factors such as thrombus formation caused by the vasculitis in the early stages of ANCA-related vasculitis cause abnormal distribution of the pancreatic blood flow, resulting in non-uniform pancreatitis. Pancreatic lesions in ANCA-related vasculitis are very rare. Only a few cases have been reported previously. Therefore, we report our case and a review of the literature.

Serum HER2 as an adjunct to assess HER2 status for advanced gastric cancer: A prospective multicenter trial (SHERLOCK).

BACKGROUND: Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity of gastric cancer can be an obstacle to accurate HER2 assessment. Serum HER2, concentrations of the HER2 extracellular domain shed into the bloodstream, has a potential to compensate HER2 immunohistochemistry (IHC) but has not been scrutinized in gastric cancer. This study sought to explore the clinical utility of serum HER2 in gastric cancer. METHODS: We performed a prospective multicenter trial (SHERLOCK trial) involving patients with all-stage gastric or gastro-esophageal junction cancer. Serum HER2 was measured using direct chemiluminescence while tissue HER2 status was determined using IHC and fluorescent in situ hybridization. For stage IV cases, concordance between local and central laboratories in tissue HER2 assessment was also evaluated. RESULTS: Of 224 patients enrolled, both tissue HER2 status and serum HER2 levels were successfully determined in 212 patients and 21% (45/212) were tissue HER2-positive. Serum HER2 levels, ranged from 4.5 to 148.0 ng/ml (median 10.3), correlated with tissue HER2 status (p = 0.003). At a cut-off level of 28.0 ng/ml determined by receiver operating characteristics analysis, sensitivity, specificity, positive and negative predictive values of serum HER2 were 22.6%, 100%, 100% and 82.3%, respectively. All nine cases with elevated serum HER2 were tissue HER2-positive stage IV cases. Among 61 stage IV cases, the agreement rate for IHC scoring between the local and the central laboratories was 82% and tissue HER2 judgment was conflicting in five (8.2%) cases. Of these five cases, four were confirmed as false-negative and two of these four patients demonstrated elevated serum HER2. CONCLUSIONS: Serum HER2 levels correlated with tissue HER2 status in gastric cancer. Although the low sensitivity is a drawback, serum HER2 might be a useful adjunct tool to detect tissue HER2 false-negative gastric cancer.

Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma.

The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis through chemokine production. We demonstrate that CD4(+) and CD8(+) skin-resident memory T cells (TRM cells), which are responsible for long-term skin immunity, reside predominantly within the hair follicle epithelium of the unperturbed epidermis. TRM cell tropism for the epidermis and follicles is herein termed epidermotropism. Hair follicle expression of IL-15 was required for CD8(+) TRM cells, and IL-7 for CD8(+) and CD4(+) TRM cells, to exert epidermotropism. A lack of either cytokine in the skin led to impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4(+) TRM lymphoma cell localization depended on the presence of hair follicle-derived IL-7. These findings implicate hair follicle-derived cytokines as regulators of malignant and non-malignant TRM cell tissue residence, and they suggest that the cytokines may be targeted therapeutically in inflammatory skin diseases and lymphoma.

Loss of HER2 Positivity after Trastuzumab in HER2-Positive Gastric Cancer: Is Change in HER2 Status Significantly Frequent?

Trastuzumab has recently been introduced as a treatment for HER2-positive metastatic and/or unresectable gastric cancer (MUGC); however, compared with breast cancer, some issues concerning HER2 and trastuzumab therapy for gastric cancer remain unclear. A 74-year-old woman received trastuzumab-containing chemotherapy for HER2-positive MUGC. She had a marked response to 8 months of chemotherapy, and gastrectomy and hepatic metastasectomy with curative intent were performed. The resected specimen showed complete loss of HER2 positivity in the residual tumor. For MUGC, a change in HER2 status during the course of the disease with or without chemotherapy has rarely been reported. However, in breast cancer, a significant frequency of change in HER2 status during the course of disease has been reported, and reevaluation of HER2 positivity in metastatic/recurrent sites is recommended. The choice of trastuzumab for MUGC is currently based on the HER2 status of the primary tumor at the time of initial diagnosis, without reassessment of HER2 status during the course of disease and/or in metastatic/recurrent sites, on the assumption that HER2 status is stable. However, our case casts doubt on the stability of HER2 in gastric cancer.

[Perioperative primary thrombosis prophylaxis for colorectal cancer in an asymptomatic antiphospholipid antibody carrier -a case report and literature review-].

An 82-year-old woman presented with hematochezia and was diagnosed with resectable colon cancer. Laboratory analysis revealed prolonged activated partial thromboplastin time and false-positive reactions in serological tests for syphilis; results that were subsequently found to be caused by the presence of antiphospholipid antibody. Because she had no history of thrombotic events or pregnancy morbidity, she was considered to be an asymptomatic antiphospholipid antibody carrier (aaPL carrier). Throughout the perioperative period, anticoagulation was performed without complications, including thrombosis. aaPL carriers are not uncommon in clinical practice, and the attending gastroenterologist should assess the risk of future thrombotic events and the most effective means of preventing thrombosis. However, there are few evidence-based recommendations for primary thrombosis prevention in aaPL carriers over the long-term and in high-risk periods, such as the perioperative period. Here, we discuss aaPL carrier management with a focus on the perioperative period together with a review of the literature.

Development of hypertension within 2 weeks of initiation of sorafenib for advanced hepatocellular carcinoma is a predictor of efficacy.

BACKGROUND: Sorafenib is an agent that inhibits vascular endothelial growth factor and is associated with onset or worsening of hypertension in some patients. We conducted a retrospective analysis of whether the development of hypertension during sorafenib treatment of advanced hepatocellular carcinoma could be a predictor of anti-cancer efficacy. METHODS: The study included 38 patients with advanced hepatocellular carcinoma who had received sorafenib for at least 1 month between January 2010 and December 2012. A retrospective analysis of the efficacy of sorafenib was conducted by dividing the patients into two groups-a hypertension group, presenting with grade 2 or higher hypertension according to the Common Terminology Criteria for Adverse Events (CTCTE) version 4.0; and a non-hypertension group, which included all other patients. This study evaluated the occurrence of hypertension within 2 weeks of initiation of therapy in order to avoid any treatment duration bias. Images were evaluated using the modified Response Evaluation Criteria in Solid Tumors. The response rate, time to progression, and overall survival were assessed. RESULTS: Twenty-two patients (58 %) developed grade 2 or higher hypertension within 2 weeks of initiation of therapy. The response rate was significantly higher in the hypertension group. Median time to progression was 153 days in the hypertension group versus 50.5 days in the non-hypertension group, which was significantly longer in the hypertension group. Moreover, median overall survival was 1,329 days in the hypertension group versus 302 days in the non-hypertension group, which was significantly longer in the hypertension group. CONCLUSIONS: Hypertension within 2 weeks of initiation of therapy may be a predictor of the anti-cancer efficacy of sorafenib when used for the treatment of advanced hepatocellular carcinoma.

[Colorectal carcinoma with hemiparesis due to isolated brain metastases as an initial symptom - a case report].

We present a rare case of colorectal carcinoma in which hemiparesis was the initial symptom. A 75-year-old woman presented with incomplete left-sided hemiparesis. Brain magnetic resonance imaging(MRI)revealed a 13-mm mass in the right frontal lobe; the mass was resected via craniotomy. Pathological findings, which included the results of immunohistochemical analysis, indicated brain metastasis from colorectal cancer. Colonoscopy revealed advanced colon cancer in the ascending colon, and computed tomography(CT)did not reveal any extracranial metastases. Left-sided hemicolectomy was performed. Whole-brain radiotherapy was scheduled, but before initiation of the therapy, metastases were detected in the neck lymph node and right arm skin, and the brain metastases relapsed. The relapsed brain metastatic lesions were resected, and radiotherapy was administered to the whole brain and the severely painful site of skin metastasis. However, the patient died 201 days after presentation. Historically, systemic chemotherapy was considered ineffective for metastatic brain tumor, and the standard treatments for brain metastasis were surgery and radiotherapy. Although recent advances in systemic chemotherapy for colorectal cancer have resulted in improved patient survival, patients with brain metastases from colorectal cancer still have a poor prognosis. Modern chemotherapeutic agents, including molecularly targeted agents such as bevacizumab, should be validated for the management of brain metastases.

[Gallbladder cancer with elevated serum α-fetoprotein, α-fetoprotein-L3, and human chorionic gonadotropin levels].

A 61-year-old woman presented with fever and was diagnosed with choledocholithiasis, which was removed endoscopically. Incidentally, a markedly elevated serum α-fetoprotein(AFP)level was detected(1,951 ng/mL), but computed tomography( CT)showed only diffuse gallbladder wall thickening. Subsequently, markedly elevated serum AFP-L3 and human chorionic gonadotropin(HCG)levels were detected(99.6%and 2,867mIU/mL, respectively). Fluorodeoxyglucose(FDG)- positron emission tomography/CT demonstrated high FDG uptake only in the gallbladder. Gallbladder cancer was suspected and the patient was scheduled for a cholecystectomy. However, CT just prior to surgery revealed multiple liver metastases. Percutaneous gallbladder biopsy revealed a moderately differentiated adenocarcinoma positive for AFP but not HCG. The patient underwent chemotherapy consisting of gemcitabine and cisplatin. A CT scan obtained 12 weeks later showed disease progression and AFP and HCG levels were found to have increased to 4,021 ng/mL and 66,000mIU/mL, respectively. Although immunohistochemistry of biopsy specimen did not demonstrate HCG production, increased serum HCG level on disease progression definitely suggested HCG production of gallbladder cancer. We believe the biopsy specimen was very small and therefore did not prove HCG production. Gallbladder cancer with simultaneous production of AFP and HCG is rare, and we therefore report this case together with a review of the literature.