Height, body mass index, physical activity, and risk of colorectal cancer in relation to expression of insulin receptor: The Japan Public Health Center-based Prospective Study.

To ascertain the involvement of insulin receptors (IRs) in colorectal carcinogenesis, we investigated the association of height, body mass index (BMI), and physical activity with colorectal cancer (CRC) and two subtypes of CRC according to the expression level of IR. We utilized data from a large-scale, population-based prospective cohort study of 18,158 middle-aged and elderly subjects in Akita and Okinawa, Japan. In the statistical analysis, we used the Cox proportional hazards model and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CRC and its subtypes as defined by immunohistochemistry of IRß, a transmembrane subunit of IR. In the IRß-defined subtypes, height showed no apparent association with the risk of IRß-positive CRC. In contrast, a multivariable HR of IRß-positive CRC was 1.77 (95% CI = 1.04-3.03) with a BMI of ≥30.0 kg/m2 (i.e., obesity), compared to a BMI of <25.0 kg/m2. Further, an increase in physical activity was significantly associated with decreased risk of IRß-positive CRC (multivariable HR per 5 METs-hour/day = 0.93, 95% CI = 0.88-0.99). Meanwhile, we found no significant association between any exposure and IRß-negative CRC. Likewise, heterogeneity between the two subtypes of CRC was not statistically significant. These findings imply that obesity and physical activity exert promoting and suppressing effects on the development of CRC expressing IRs, respectively.

Dietary vitamin D intake and risk of colorectal cancer according to vitamin D receptor expression in tumors and their surrounding stroma.

BACKGROUND: Colorectal Cancer (CRC) has been molecularly classified into several subtypes according to tumor, stromal, and immune components. Here, we investigated whether the preventive effect of vitamin D on CRC varies with subtypes defined by Vitamin D receptor (VDR) expression in tumors and their surrounding stroma, along with the association of somatic mutations in CRC. METHODS: In a population-based prospective study of 22,743 Japanese participants, VDR expression levels in tumors and their surrounding stroma were defined in 507 cases of newly diagnosed CRC using immunohistochemistry. Hazard ratios of CRC and its subtypes according to dietary vitamin D intake were estimated using multivariable Cox proportional hazards models. RESULTS: Dietary vitamin D intake was not associated with CRC or its subtypes defined by VDR expression in tumors. However, an inverse association was observed for CRC with high VDR expression in the stroma (the highest tertile vs the lowest tertile: 0.46 [0.23-0.94], Ptrend = 0.03), but not for CRC with low VDR expression in the stroma (Pheterogeneity = 0.02). Furthermore, CRC with high VDR expression in the stroma had more somatic TP53 and BRAF mutations and fewer APC mutations than those with low VDR expression in the stroma. CONCLUSIONS: This study provides the first evidence that the preventive effect of vitamin D on CRC depends on VDR expression in the stroma rather than in the tumors. CRC with high VDR expression in the stroma is likely to develop through a part of the serrated polyp pathway, which tends to occur with BRAF but not with APC mutations.

Smoking and risk of colorectal cancer according to KRAS and BRAF mutation status in a Japanese prospective Study.

Although smoking is a major modifiable risk factor for many types of cancer, evidence for colorectal cancer is equivocal in Asian populations. Recent Western studies have proposed that the association between smoking and colorectal cancer is restricted to specific tumor molecular subtypes. However, no studies have evaluated the association according to tumor molecular subtypes in Asian populations. In a Japanese prospective population-based cohort study of 18 773 participants, we collected tumor tissues from incident colorectal cancer cases and evaluated KRAS (Kirsten rat sarcoma viral oncogene homolog) and BRAF (v-raf murine sarcoma viral oncogene homolog B) mutation status using target sequencing. Multivariable-adjusted Cox proportional hazard model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of smoking with the risk of overall colorectal cancer and its subtypes defined by KRAS and BRAF mutation status. Among 339 cases, KRAS and BRAF mutations were identified in 164 (48.4%) and 16 (4.7%) cases, respectively. The multivariable-adjusted HR for ever smoking compared with never smoking was 1.24 [95% CI: 0.93-1.66], 1.75 [1.14-2.68], 0.87 [0.59-1.29], 1.24 [0.93-1.67] and 1.22 [0.38-3.93] for overall, KRAS wild-type, KRAS-mutated, BRAF wild-type and BRAF-mutated colorectal cancer, respectively. The statistically significant heterogeneity was indicated between KRAS mutation status (Pheterogeneity = 0.01) but not between BRAF mutation status. This study is the first to demonstrate that smokers have an approximately 2-fold higher risk of KRAS wild-type colorectal cancer than never smokers in an Asian population. Our findings support that smoking is a risk factor for colorectal cancer, especially for its subtype without KRAS mutations, in Asian populations.

Prognostic implication of IgG4 and IgG1-positive cell infiltration in the lung in patients with idiopathic interstitial pneumonia.

Immunoglobulin (Ig) G4-positive cells are rarely observed in the lungs of patients with idiopathic interstitial pneumonias (IIPs). IgG1 may be more pathogenic than IgG4, with IgG4 having both pathogenic and protective roles in IgG4-related disease (IgG4-RD). However, the role of both IgG1 and IgG4 in IIPs remains unclear. We hypothesized that patients with IgG4-positive interstitial pneumonia manifest different clinical characteristics than patients with IgG4-RD. Herein, we identified the correlation of the degree of infiltration of IgG1- and IgG4-positive cells with IIP prognosis, using a Japanese nationwide cloud-based database. We included eighty-eight patients diagnosed with IIPs after multidisciplinary discussion, from April 2009 to March 2014. IgG4-positive cell infiltration was identified in 12/88 patients with IIPs and 8/41 patients with idiopathic pulmonary fibrosis (IPF). Additionally, 31/88 patients with IIPs and 19/41 patients with IPF were diagnosed as having IgG1-positive cell infiltration. IgG4-positive IIPs tended to have a better prognosis. Conversely, overall survival in cases with IgG1-positive IPF was significantly worse. IIPs were prevalent with IgG1- or IgG4-positive cell infiltration. IgG1-positive cell infiltration in IPF significantly correlated with a worse prognosis. Overall, evaluating the degree of IgG1-positive cell infiltration may be prognostically useful in cases of IPF.

Pancreatic Duct Stricture That Rapidly Progressed to Pancreatic Ductal Adenocarcinoma and Formed a Mass within 3 Months: A Case Report.

The natural growth rate of pancreatic carcinoma in situ with pancreatic duct stricture remains unclear. Herein, we present a case with pancreatic duct stricture that rapidly grew to form a mass lesion within 3 months. A 74-year-old woman was referred to us for the investigation of a pancreatic duct dilatation. Initial images did not reveal any clear mass lesions near the pancreatic duct stricture. Pancreatic juice cytology showed suspicious findings. Distal pancreatectomy was recommended; however, the patient refused to undergo surgical treatment at that time. Images taken 3 months later demonstrated a nodular pancreatic body mass which was identified as a moderately to poorly differentiated tubular adenocarcinoma. Previous reports have suggested that pancreatic carcinoma in situ and small pancreatic ductal adenocarcinoma require at least 1-2 years to progress to an advanced mass. This case suggests that pancreatic carcinoma in situ may grow rapidly and indicates a need for close follow-up in patients with pancreatic duct strictures, even if the pathological evidence is not confirmed.

Epidermoid Cyst in an Intrapancreatic Accessory Spleen: Case Report and Literature Review of the Preoperative Imaging Findings.

An epidermoid cyst arising within an intrapancreatic accessory spleen (ECIAS) is rare, and also difficult to correctly diagnose before surgery. It is mostly misdiagnosed as a cystic tumor, such as a mucinous cystic neoplasm or as a solid tumor with cystic degeneration, such as a neuro endocrine tumor. We herein report a case of ECIAS and also perform a literature review of 35 reports of ECIAS. Although the preoperative diagnosis of ECIAS using conventional imaging is relatively difficult to make, careful preoperative examinations of the features on computed tomography and magnetic resonance imaging could lead to a correct preoperative diagnosis of ECIAS which might thereby reduce the number of unnecessary resections.

Efficacy of repeated cytology of pancreatic juice obtained by endoscopic nasopancreatic drainage tube for early diagnosis of pancreatic cancer: a case series including a case of carcinoma in situ.

Repeated cytology of pancreatic juice obtained by endoscopic nasopancreatic drainage (ENPD) tube has been highlighted as an early diagnostic method for small pancreatic cancer, including carcinoma in situ. We report two cases of early-stage pancreatic cancer diagnosed using repeated cytology; both cases underwent curative resection. No significant masses were found on conventional imaging in either case, with only pancreatic duct strictures being observed. ENPD tubes were placed to collect pancreatic juice in both cases. In case 1, two of five pancreatic juice samples showed adenocarcinoma. Therefore, distal pancreatectomy was performed, and a PanIN3 grade neoplasm (carcinoma in situ) was identified at the branch duct near the distal stricture. In case 2, two of seven pancreatic juice samples (collected during the second tube placement) showed adenocarcinoma. Therefore, distal pancreatectomy was performed, and a PanIN3 neoplasm was identified primarily in the pancreatic duct at a narrow section with fibrosis. Partial microinvasion (<1 mm) was observed at the branch duct. Repeated cytology of pancreatic juice obtained by ENPD tube is effective for early diagnosis of pancreatic cancer, especially in cases without mass formation. However, some issues, including the appropriate number of samples, should be addressed in large prospective studies.

Diagnostic utility of endoscopic ultrasound-guided fine-needle aspiration biopsy for glomus tumor of the stomach.

A 52-year-old man was referred for further investigation of a gastric submucosal tumor on the greater curvature of the antrum. Endoscopic ultrasonography demonstrated a hypoechoic solid mass, which was primarily connected to the muscular layer of the stomach. We performed endoscopic ultrasound-guided fine-needle aspiration biopsy. The pathological examination showed proliferation of oval-shaped cells with nest formation, which stained strongly positive for muscle actin, and negative for c-kit, CD34, CD56, desmin, S-100, chromogranin, and neuron-specific enolase. Therefore, we performed laparoscopy and endoscopy cooperative surgery based on the preoperative diagnosis of glomus tumor of the stomach. The final histological diagnosis confirmed the preoperative diagnosis. Although preoperative diagnosis of glomus tumor of the stomach is difficult with conventional images and endoscopic biopsy, endoscopic ultrasound-guided fine-needle aspiration biopsy is an essential tool to gain histological evidence of glomus tumor of the stomach for early diagnosis.

A case of ductal carcinoma with squamous differentiation in malignant phyllodes tumor.

Carcinoma derived from the lining epithelial cells in malignant phyllodes tumor is a rare neoplasm of the breast and belongs to the category of carcinosarcoma. We report a case of ductal carcinoma with squamous differentiation arising in malignant phyllodes tumor. A 54-year-old woman was admitted with a rapidly enlarging left breast mass. A breast tumor with a diameter of 6 cm was located mainly in the left outer area of the breast. Mammography revealed a high-density mass with an irregular margin and ultrasound showed a cystic tumor. A pathological diagnosis of ductal carcinoma with squamous differentiation was made by fine needle aspiration and a core needle biopsy. She underwent neoadjuvant chemotherapy followed by a modified radical mastectomy with a skin flap. Histopathological examination revealed that the invasive ductal carcinoma with squamous differentiation originated from the lining epithelial cells in malignant phyllodes tumor and that there was no transition area between the carcinomatous and the sarcomatous component. She experienced lung and facial bone metastases, microscopic features of which were consistent with the sarcomatous component of the original breast carcinosarcoma. This is an extremely rare case of carcinosarcoma and the histopathological findings and review of the literature are discussed.