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Systemic sclerosis (SSc) is characterized by fibrosis of the skin and various internal organs. However, there is limited knowledge concerning small-bowel lesions. We evaluated the clinical state of patients with SSc according to the capsule endoscopy (CE) findings. Sixty-five consecutive patients with SSc (61 females; mean age, 64.3 years) underwent CE at Hiroshima University Hospital between April 2012 and December 2019. SSc was subclassified into diffuse and limited cutaneous SSc. Among the 65 patients, 55 (51 females; mean age, 64.5 years; diffuse cutaneous SSc, 27 patients) were evaluated for the presence of fibrosis in the gastrointestinal tract by biopsy. Small-bowel lesions were detected in 27 (42%) patients with SSc. Type 1b angioectasia (Yano-Yamamoto classification) was more frequent in limited cutaneous SSc patients (p = 0.0071). The average capsule transit time of the esophagus was significantly longer in diffuse cutaneous SSc patients (p = 0.0418). There were more cases of Type 1a angioectasia in SSc patients without fibrosis. The average capsule transit time of the esophagus was significantly longer in SSc patients with fibrosis. Thus, this study revealed that the frequency of small-bowel angioectasia and gastrointestinal motility in patients with SSc differed depending on SSc subclassification and the presence of fibrosis.

Considering the difficulty in detecting primary breast cancers using whole-body positron emission tomography (WBPET) owing to its limited spatial resolution, we aimed to evaluate the detectability of breast cancer by ring-type dedicated breast PET (DbPET) on the World Health Organization (WHO) histological classification in comparison with WBPET.A total of 938 patients with breast cancer underwent WBPET and ring-type DbPET, and 1021 lesions were histologically assessed based on the WHO classification of tumors of the breast. The findings of WBPET and DbPET were retrospectively evaluated and compared.The size-related sensitivity of DbPET was superior to that of WBPET for subcentimetric tumors (81.9% vs. 52.4%, P 0.001). The histological distribution was as follows: 11 lobular carcinoma in situ, 158 ductal carcinoma in situ, 738 infiltrating duct carcinoma not otherwise specified (NOS), 12 lobular carcinoma NOS, 40 mucinous adenocarcinoma, 13 tubular carcinoma, 36 invasive breast carcinoma others, and 13 papillary neoplasms. WBPET had low sensitivity for lobular carcinoma in situ, ductal carcinoma in situ, lobular carcinoma NOS, mucinous adenocarcinoma, and tubular carcinoma. DbPET showed improved sensitivity for all the above except lobular and tubular carcinoma. The maximum standardized uptake values (SUVmax) of DbPET were significantly higher than those of WBPET for histological types, excluding lobular carcinoma in situ. The SUVmax of papillary neoplasms was high regardless of low-grade histology and Ki-67 labeling index.DBPET was found to have high sensitivity and SUVmax values for all histologic types that showed low sensitivity of detection on WBPET, except lobular carcinoma in situ.

The clinicopathological or genetic features related to the prognosis of mucinous adenocarcinoma are unknown because of its rarity. The clinicopathological or targetable features were investigated for better management of patients with mucinous adenocarcinoma of the lung. We comprehensively evaluated the clinicopathological and genetic features of 60 completely resected mucinous lung adenocarcinomas. Targetable genetic variants were explored using nCounter and polymerase chain reaction, PD-L1 and TTF-1 expression were evaluated using immunohistochemistry. We analyzed the prognostic impact using the Kaplan–Meier method and log-rank test. Of the 60 enrolled patients, 13 (21.7%) had adenocarcinoma in situ/minimally invasive adenocarcinoma, and 47 (78.3%) had invasive mucinous adenocarcinoma (IMA). Fifteen patients (25%) showed a pneumonic appearance on computed tomography (CT). CD74-NRG1 fusion, EGFR mutations, and BRAF mutation were detected in three (5%), four (6.7%), and one (1.7%) patient(s), respectively. KRAS mutations were detected in 31 patients (51.7%). Two patients (3.5%) showed immunoreactivity for PD-L1. No in situ or minimally invasive cases recurred. IMA patients with pneumonic appearance had significantly worse recurrence-free survival (RFS) and overall survival (OS) (p

This study aimed to assess the clinical effect of the pathological axillary assessment method in breast cancer without clinical lymph node metastasis. Data of patients with clinically node-negative breast cancer were retrospectively reviewed. The study period was divided into early (January 2000–July 2007) and late (August 2007–December 2014) periods based on the pathological assessment method used (single-sectional and detailed multi-sectional lymph node processing). In the late period, lymph nodes were evaluated at six levels including immunohistochemistry on each 1.5–2 mm interval section. The axillary diagnostic accuracy and role of chemotherapy were assessed. In 1698 patients, 27 isolated tumor cells (ITCs), 39 micrometastases, and 205 macrometastases were noted. The sensitivity for pathological N0 diagnosis was dependent on clinical T stage, Tis (97.8%), T1 (83.0%), T2 (74.2%), T3 (54.5%), and T4 (63.6%). ITCs and micrometastases were detected only in the late period, and 84.7% and 91.6% of cases in the early and late period, respectively, did not have macrometastases. The 5-year disease-free interval (DFI) rates were 95.2% in node-negative cases, 98.4% in ITCs/micrometastases, and 91.4% in macrometastases (P

The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines indicate lymphovascular invasion—evaluated by hematoxylin and eosin (HE) staining—as a surgical requirement after endoscopic submucosal dissection (ESD) in T1 colorectal carcinoma (CRC) patients; however, immunohistochemical evaluation may be superior. This study aimed to clarify the significance of immunohistochemical lymphovascular evaluation as an indicator for additional surgery of T1 CRC after ESD, and assessed the guidelines’ adequacy, even when evaluating through immunostaining. Patients with T1 CRC who underwent ESD were enrolled across three institutions between January 2012 and December 2017. Immunohistochemical lymphovascular evaluation was performed. Clinicopathological features, pathological evaluations, and surgery indications were recorded. Univariate and multivariate logistic regression identified risk factors for lymph node (LN) metastasis of T1 CRC after ESD. Among 370 patients with T1 CRC, recurrence, 5-year overall survival, and 5-year disease specific survival rates were 1.6%, 94.6%, and 99.5%, respectively. Six patients (1.6%) experienced recurrence, five of whom underwent additional surgery. Those with no risk factors did not exhibit recurrence. A total of 215 (58.1%) patients underwent additional surgery after ESD, 21 (9.7%) of whom exhibited LN metastasis. Among 16 patients who underwent additional surgery due to lymphovascular invasion, three (18.8%) had LN metastasis. Multivariate logistic regression analysis identified lymphatic invasion as a significant risk factor for LN metastasis (odds ratio 3.9, 95% confidence interval 1.0–14.6, P = 0.0421). The JSCCR guidelines have clinical validity, and immunohistochemical lymphatic evaluation findings potentially predict LN metastasis for T1 CRC after ESD.

A 65-year-old man presented with a slight headache and transient visual disturbance. Magnetic resonance imaging (MRI) revealed occlusion of the left internal carotid artery (ICA) and acute brain infarctions in both hemispheres, and a blood examination indicated inflammation. Gadolinium enhancement was observed in the walls of the temporal arteries and ICAs. After we diagnosed giant cell arteritis (GCA) by a temporal artery biopsy, aspirin and corticosteroids were administered. The typical symptoms of GCA, such as jaw claudication and temporal artery tenderness, were absent during the entire clinical course, and the findings of contrast-enhanced MRI contributed to the diagnosis.

Background The programmed death 1/programmed death-ligand 1 (PD-L1) pathway reportedly is as an important factor determining effects of immunotherapy; however, its prognostic impact is controversial, and its association with the surrounding immune microenvironment has not yet been elucidated. Patients and Methods We retrospectively analyzed 126 patients with pathologic stage I non–small-cell lung cancer. Patients with lepidic-dominant adenocarcinoma were excluded. PD-L1 expression was evaluated with immunohistochemistry correlated with clinicopathologic features and surrounding immune microenvironment status, including CD4, CD8, regulatory T cells, and human leukocyte antigen class I. Factors affecting prognosis were assessed by Kaplan-Meier and Cox regression analyses. Results Twenty-three (18.3%) patients were positive for PD-L1 expression. No significant correlation was observed between PD-L1 expression and the surrounding immune microenvironment status. The PD-L1–positive group had a worse prognosis than the PD-L1–negative group (5-year recurrence-free survival rates, 63.4% vs. 81.0%; P = .061). Among surrounding immune cells, intratumoral CD8 status had the strongest impact on prognosis (P = .12). In the intratumoral CD8–high group, PD-L1 expression demonstrated no significant prognostic impact, whereas in the intratumoral CD8–low group, patients positive for PD-L1 demonstrated a significantly worse prognosis than those negative for PD-L1 (5-year recurrence-free survival rates, 41.7% vs. 78.6%; P = .034). Multivariable Cox regression analysis revealed that ‘PD-L1–positive and intratumoral CD8–low’ status was an independent prognostic factor (hazard ratio, 3.80; 95% confidence interval, 1.22-10.5; P = .023). Conclusions The prognostic impact of the PD-1/PD-L1 pathway may be distinct according to concurrent intratumoral CD8 status.

Background and study aims Because superficial non-ampullary duodenal epithelial tumors (SNADETs) are relatively rare, studies evaluating the outcomes of endoscopic resection (ER) for SNADETs are limited. Therefore, this study aimed to evaluate the clinical validity of ER for SNADETs. Patients and methods The study participants included 163 consecutive patients (108 men; mean age, 61.5 ± 11.3 years) with 171 SNADETs, excluding patients with familial adenomatous polyposis resected by ER, at Hiroshima University Hospital between May 2005 and September 2016. Clinicopathological features and the outcomes of ER for 171 cases were retrospectively analyzed. Additionally, the prognosis of 135 patients with more than 12 months’ follow-up was analyzed. Results Mean diameter of SNADETs was 10.7 ± 7.2 mm. Most of the SNADET cases were classified as category 3 (71 %, 121/171), but some were category 5 (2 %, 3/171). En bloc resection rates were 93 % (146/157), 100 % (7/7), and 86 % (6/7) in endoscopic mucosal resection (EMR), polypectomy, and in endoscopic submucosal dissection (ESD) cases, respectively. Complete resection rates were 90 % (141/157), 100 % (7/7), and 71 % (5/7) in EMR, polypectomy, and ESD cases, respectively. Emergency surgery was performed in two patients with intraoperative perforation and in two with delayed perforation without artificial ulcer bed closure after ER. Since endoscopic closure of ulcer by clipping was performed, delayed perforation has not occurred. Local recurrence occurred in 1.2 %, but no metastasis to lymph nodes or other organs occurred after ER. No patient died of primary SNADETs. Conclusion Our data supported the clinical validity of ER for SNADETs. However, delayed perforation should be given much attention.

The molecular mechanisms by which ATP1A1 mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated ATP1A1 L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the ATP1A1 mutation-mediated cell proliferated. We performed transcriptome analysis in APAs with ATP1A1 mutation. ATP1A1 L104R mutation were modulated in human adrenocortical carcinoma (HAC15) cells (ATP1A1-mutant cells), and we evaluated cell proliferation and molecular signaling events. Transcriptome and immunohistochemical analysis showed that Na/K-ATPase (NKA) expressions in ATP1A1 mutated APA were more abundant than those in non-functioning adrenocortical adenoma or KCNJ5 mutated APAs. The significant increase of number of cells, amount of DNA and S-phase population were shown in ATP1A1-mutant cells. Fluo-4 in ATP1A1-mutant cells were significantly increased. Low concentration of ouabain stimulated cell proliferation in ATP1A1-mutant cells. ATP1A1-mutant cells induced Src phosphorylation, and low concentration of ouabain supplementation showed further Src phosphorylation. We demonstrated that NKAs were highly expressed in ATP1A1 mutant APA, and the mutant stimulated cell proliferation and Src phosphorylation in ATP1A1-mutant cells. NKA stimulations would be a risk factor for the progression and development to an ATP1A1 mutant APA.

There are some endoscopic resection (ER) methods for neuroendocrine tumors (NETs), however, which method is most useful remains unclear. This study aimed to compare the outcomes of different ER techniques, such as conventional endoscopic mucosal resection (cEMR), endoscopic submucosal dissection (ESD), and endoscopic submucosal resection with a ligation device (ESMR-L) for rectal NETs.We retrospectively analyzed 96 consecutive patients with 102 rectal NETs of less than 10 mm in diameter who underwent ER between January 2001 and December 2019 at Hiroshima University Hospital. We compared the clinical outcomes of each ER method (cEMR 60 lesions, ESD 21 lesions, and ESMR-L 21 lesions), divided according to the treatment periods, and evaluated the risk factors for vertical margin (VM) positivity in relation to clinicopathological and endoscopic characteristics.As for the mean procedure time, ESD took significantly longer to perform than the other methods. The histological complete resection rate was 80% (48/60) for cEMR, 85.7% (18/21) for ESD, and 100% (21/21) for ESMR-L, and the VM positive rate was 20% (12/60) for cEMR, 14.3% (3/21) for ESD, and 0% (0/21) for ESMR-L, with no significant difference. However, the tumor-front-to-VM distance was significantly longer in the ESMR-L group than in the cEMR and ESD groups. cEMR and ESD were both significant risk factors for VM positivity. No perforation or local recurrence was observed in all methods.ESMR-L is the most useful ER method for small rectal NETs.

Background In Japan, endoscopic submucosal dissection (ESD) is standardized for large colorectal tumors. However, its validity in the elderly population is unclear. We aimed to evaluate the safety and efficacy of ESD for colorectal tumors in elderly patients aged over 80 years. Methods ESD was performed on 178 tumors in 165 consecutive patients aged over 80 years between December 2008 and December 2018. We retrospectively evaluated the clinicopathological characteristics and clinical outcomes of ESD. We also assessed the prognosis of 160 patients followed up for more than 12 months. Results The mean patient age was 83.7 ± 3.1 years. The number of patients with comorbidities was 100 (62.5%). Among all patients, 106 (64.2%) were categorized as class 1 or 2 according to the American Society of Anesthesiologists classification of physical status (ASA-PS), and 59 (35.8%) were classified as class 3. The mean procedure time was 97.7 ± 79.3 min. The rate of histological en bloc resection was 93.8% (167/178). Delayed bleeding in 11 cases (6.2%) and perforation in 7 cases (3.9%) were treated conservatively. The 5-year survival rate was 89.9%. No deaths from primary disease (mean follow-up time: 35.3 ± 27.5 months) were observed. Overall survival rates were significantly lower in the non-curative resection group that did not undergo additional surgery than in the curative resection group (P = 0.0152) and non-curative group that underwent additional surgery (P = 0.0259). Overall survival rates were higher for ASA-PS class 1 or 2 patients than class 3 patients (P = 0.0105). Metachronous tumors (> 5 mm) developed in 9.4% of patients. Conclusions ESD for colorectal tumors in patients aged over 80 years is safe. Colorectal cancer-associated deaths were prevented although comorbidities pose a high risk of poor prognosis.

Purpose To evaluate immune responses paralleling the pathological and therapeutic effects of neoadjuvant chemotherapy (NAC) in the tumor microenvironment of breast cancer. Patients and Methods 38 patients with stages II and III breast cancer received NAC followed by surgery in 2012–2018. Peripheral natural killer (pNK) cell activity, tumor-infiltrating lymphocytes (TILs), and levels of tumor microenvironmental factors were assessed before and after NAC. Results In univariate analysis, grade 2 (G2) and better therapeutic effects were significantly associated with high post-NAC levels of NK cells and interleukin-6, and tended to be associated with higher CD4, CD8 and CTLA-4 transcripts. Disappearance of axillary lymph node metastasis (Ax+) was significantly associated with 1) increased NK and pNK levels, 2) decreased vascular endothelial growth factor (VEGF) transcripts after NAC, 3) the presence of ≥5% TILs, and tended to be associated with higher CTLA-4 levels before NAC. Multivariate analysis showed that G2 and better therapeutic effects were significantly associated with higher NK levels after NAC (OR = 1.07, 95% CI 1.00–1.14; p = 0.0255), and that disappearance of Ax+ was significantly associated with the presence of ≥5% pre-NAC TILs (OR = 19.87, 95% CI 2.24–175.80; p = 0.0072). Conclusions Increased NK cells after NAC, together with increased CD4+ and CD8+ T-cells, and decreased CTLA-4+ T cells and VEGF correlate with beneficial therapeutic effects. Systemic activation of pNK cell activity and the presence of pre-NAC TILs may improve the elimination of Ax + together with decreased immunosuppression by VEGF in tumors.

Introduction: The Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations guidelines recommend surveillance colonoscopy instead of colectomy after the complete removal of “endoscopically resectable” dysplastic lesions in ulcerative colitis (UC). There are no studies on long-term outcomes of endoscopic submucosal dissection (ESD) for UC-associated neoplasia (UCAN). We aimed to evaluate the clinical outcomes of ESD for UC-associated dysplasia (UCAD) during long-term follow-up. Methods: We retrospectively enrolled 17 consecutive UC patients with 22 UCADs, who underwent initial ESD or total proctocolectomy at the Hiroshima University Hospital. The clinicopathological features of the patients and neoplasias and clinical outcomes of ESD were evaluated and compared with those of total proctocolectomy. Results: UCAD in the ESD and total proctocolectomy groups was mostly noted on the left side of the colon, and most lesions were superficial macroscopic lesions. In the ESD group, en bloc resection and histological complete resection rates were 83 and 67%, respectively. One patient died of malignant melanoma; however, none of the patients died of UC-associated carcinoma in both groups. Metachronous neoplasias developed in 5 of the 7 patients in the ESD group. Among the 5 patients with metachronous UCAN, 4 finally underwent total proctocolectomy and 1 underwent additional ESD. Conclusions: ESD for UCAD is a useful method for total excisional biopsy. UC patients with UCAD resected by ESD have a high risk of developing metachronous UCAN during the follow-up period.

Highlights • Liver metastasis of anal squamous cell carcinoma with a presented pseudocyst is very rare. • Some hepatic diseases such as infections, simple biliary cysts, and neoplasms demonstrate a cystic change of the liver. • Metastasis should be suspected when CT findings in patients with a history of gastrointestinal cancer show cystic changes involving the liver., Introduction Liver metastasis of an anal squamous cell carcinoma (SCC) with a pseudocyst is uncommon. There are many diseases which form hepatic cystic lesions and sometimes it is difficult to arrive at an accurate diagnosis. Presentation of case A 69-year-old woman visited our hospital with complaints of bloody stool and difficult defecation. A palpable mass in the anal canal was found on digital examination. The laboratory tests revealed anemia and raised levels of SCC antigen. On endoscopy a type 2 tumor was identified in the anal canal and biopsy revealed SCC. The patient was diagnosed with advanced anal SCC (cT2N1aM0, cStage IIIA) as a result of the examination and underwent chemoradiotherapy (CRT); unfortunately the tumor persisted after CRT. A salvage abdominoperineal resection with D2 and left lateral lymph node dissection was conducted. Histopathologically, the tumor was diagnosed as poorly differentiated SCC. She was readmitted for fever 3 weeks after surgery, and the abdominal CT showed multiple low density areas with enhancement at the edge of the liver, suggesting abscess or metastasis. The metastatic SCC was revealed by cytology of liver drainage and liver biopsy. Discussion Anal cancers are sometimes encountered however; a pseudo cystic presentation of a liver metastasis is very rare which makes it difficult to distinguish from other diseases. Conclusion We present a case of SCC in the anal canal with liver metastasis presenting as a hepatic pseudocyst.

18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) is related to the biological parameters and prognosis of breast cancer. However, whether whole-body PET (WBPET) and dedicated breast PET (DbPET) can reflect the tumor microenvironment is unclear. This study investigated the relationship between stromal tumor-infiltrating lymphocytes (TILs) and maximum standardized uptake value (SUVmax) in WBPET and DbPET. A total of 125 invasive breast cancers underwent WBPET and ring-type DbPET and resected specimens were pathologically assessed. The impact of SUVmax on the tumor biological parameters and TILs was retrospectively evaluated. SUVmax was classified as high and low relative to the median values (WBPET-SUVmax: 2.2 and DbPET-SUVmax: 6.0). SUVmax correlated with tumor size, nuclear grade, Ki-67 labeling index, and TILs in both WBPET and DbPET (all p

In November 2011, a 61-year-old woman was diagnosed with squamous cell carcinoma (SCC) of the cervix in a uterus didelphys with vaginal septum. The patient was diagnosed with Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage IIB because of infiltration to the left parametrium without infiltration to the pelvic wall. The patient was treated with external-beam radiotherapy (EBRT) and brachytherapy (BT), using concomitant chemotherapy with cisplatin. A total of 50 Gy were delivered (2 Gy/fraction/day) to the pelvis, with a central shield after 40 Gy. The patient was treated four times with BT (6 Gy × 4 fractions), with tandem and ovoid applicators inserted once to the left side; tandem to the left side and ovoid bilaterally were inserted twice; and tandem to the right side and ovoid bilaterally were inserted once. Six years and 8 months after the start of treatment, the patient had had no relapse or severe late adverse effects. For accurate diagnosis and optimal treatment of the uterus didelphys, careful interview and pelvic examination at initial diagnosis of a patient are very important.

Background: We investigated whether contrast-enhanced ultrasonography (CEUS) scores can predict lymphocyte-predominant breast cancer (LPBC). Patients and Methods: We evaluated 75 patients who underwent US and CEUS. LPBC was defined as tissues with ≥50% stromal tumour-infiltrating lymphocytes (TILs) preoperatively. Characteristic US images predicting LPBC were evaluated using TIL-US scores via three ultrasonic tissue characteristics: Shape, internal echo level, and posterior echoes. TIL-CEUS was evaluated based on TIL-US plus CEUS. Results: TIL-US and TIL-CEUS cut-offs for predicting LPBC were 4 and 6 (area under the curve=0.93 and 0.96, respectively) points based on receiver operating characteristics curves. Sensitivity, specificity, and accuracy values (95% confidence intervaI) were 0.94 (0.77-0.99), 0.75 (0.70-0.77), and 0.80 (0.72-0.82); and 0.94 (0.78-0.99), 0.86 (0.81-0.87), and 0.88 (0.80-0.90) for TIL-US and TIL-CEUS, respectively. TIL-CEUS score was a significant single predictor for LPBC in multivariate logistic regression (p=0.001). Conclusion: TIL-CEUS can be used for preoperative LPBC prediction and detection.

The current understanding of clinicopathological features and genomic variants of small-bowel cancer is limited, in part due to the rarity of the disease. However, understanding of these factors is necessary for the development of novel therapeutic agents for small-bowel cancer. Thus, we aimed to identify the clinicopathological features and genomic variants associated with its prognosis and recurrence. We retrospectively examined 24 consecutive patients with primary small-bowel cancer surgically treated between May 2005 and August 2018 and collected 29 tumor specimens. The 29 lesions were subjected to mismatch repair status evaluation, using immunohistochemistry (IHC), and targeted genomic sequencing, after which they were analyzed using a panel of 90 cancer-related genes. IHC revealed that 45% (13/29) of the lesions exhibited deficient mismatch repair. The most common genomic variants in small-bowel cancers were in TP53 (48%, 13/27), followed by KRAS (44%, 12/27), ARID1A (33%, 9/27), PIK3CA (26%, 7/27), APC (26%, 7/27), and SMAD4, NOTCH3, CREBBP, PTCH1, and EP300 (22%, 6/27 each). Overall survival and disease-specific survival of patients with tumor mutational burden (TMB) ≥10 mutations/Mb (n = 17) were significantly better than those of patients with TMB SMAD4 had poorer recurrence-free survival than those with wild-type SMAD4. Our results suggested that TMB and SMAD4 mutations were associated with the prognosis of small-bowel cancer patients. Thus, cancer genomic analysis could be useful in the search for biomarkers of prognosis prediction in small-bowel cancers.

Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenging but essential for improving its poor prognosis. We established a multicenter study to clarify the clinicopathological features, and to propose new algorithm for early diagnosis of PDAC. Ninety-six patients with stage 0 and IA PDAC were enrolled from 13 high-volume centers. Overall, 70% of the patients were asymptomatic. The serum pancreatic enzyme levels were abnormal in half of the patients. The sensitivity of endoscopic ultrasonography (EUS) for detecting small PDAC was superior to computed tomography and magnetic resonance imaging (MRI) (82%, 58%, and 38%, respectively). Indirect imaging findings were useful to detect early-stage PDAC, especially, main pancreatic duct stenosis on MRI had the highest positive rate of 86% in stage 0 patients. For preoperative pathological diagnosis, the sensitivity of endoscopic retrograde cholangiopancreatography (ERCP)-associated pancreatic juice cytology was 84%. Among the stage IA patients, EUS-guided fine-needle aspiration revealed adenocarcinoma in 93% patients. For early diagnosis of PDAC, it is essential to identify asymptomatic patients and ensure close examinations of indirect imaging findings and standardization of preoperative pathological diagnosis. Therefore, a new diagnostic algorithm based on tumor size and imaging findings should be developed.

Submucosal deep invasion of gastric cancer (T1b2; depth of submucosal invasion ≥ 500 μm) is a risk factor for lymph node metastasis and, thus, is one of the criteria for curative treatment. Our aim was to evaluate the specific influence of endoscopic submucosal dissection (ESD) on the prognosis of patients with T1b2 gastric cancer. This was a retrospective analysis of 248 consecutive patients, with 252 pT1b2 gastric cancer lesions, who underwent ESD prior to additional surgery (Group A, n = 101) or surgery only (Group B, n = 147). After propensity score-matching (for sex, age, tumor diameter and gross type), we compared pathological characteristics between the 2 groups and the prognosis over a follow-up period ≥ 60 months. Compared to Group B, patients in Group A were older, with a higher proportion of men. The proportion of depressed and undifferentiated type tumors was greater in Group B than A, with larger tumor size and depth of submucosal invasion as well. There was no incidence of local recurrence, but distant metastasis was identified in 5% of cases in Group A and 3% in Group B. After propensity score-matching, there were no difference in the 5-year overall survival rate between Group A and B (87.5% vs. 91.2%, respectively), nor in the 5-year disease-specific survival rate (96.3% vs. 96.4%, respectively). ESD prior to surgery for T1b2 gastric cancer did not adversely affect clinical outcomes after additional surgery.

Highlights • The immune factors that determine the pathological and therapeutic effects of preoperative chemotherapy in patients with breast cancer are associated with local and systemic immune responses in the presence of tumor-infiltrating lymphocytes, in collaboration with downregulation of immunosuppressive factors mediated by vascular endothelial growth factor (VEGF) and cytotoxic T lymphocyte antigen 4 (CTLA-4) in regulatory T cells (Tregs) in the tumor microenvironment. • Multivariate analysis showed that grade 2 and better therapeutic effects tended to be associated with higher natural killer cell levels after preoperative chemotherapy (odds ratio = 1.02; 95% confidence interval, 0.99–1.05; p = 0.07). • Therapy targeting VEGF and CTLA-4 in Tregs to overcome tumor-derived immunosuppression may enhance the pathological and therapeutic responses to preoperative chemotherapy in patients with breast cancer., Immune activation plays an important role in achieving the pathological and therapeutic effects of preoperative chemotherapy in patients with breast cancer. We evaluated how the immune response contributes to various therapeutic effects. This study was conducted on 43 patients with stages II–IV breast cancer who received preoperative chemotherapy followed by surgery. Peripheral natural killer (pNK) cell activity and the neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, and platelet-lymphocyte ratio (PLR) were assessed before and after chemotherapy. Tumor-infiltrating lymphocytes (TILs) and levels of 14 tumor microenvironmental factors, analyzed by next-generation sequencing, were assessed in formalin-fixed, paraffin-embedded sections of preoperative biopsy samples and surgical specimens. Univariate analysis showed that grade 2 (G2) and better therapeutic effects were significantly associated with human epidermal growth factor receptor 2 (HER-2)-positive cancer, lower PLRs, and higher NK cell and interleukin-6 levels after chemotherapy. The disappearance of axillary lymph-node metastasis was significantly associated with HER-2-positive cancer; increased pNK cell activity and lower PLRs and vascular endothelial growth factor (VEGF) levels after chemotherapy; and increased cytotoxic T lymphocyte antigen 4 (CTLA-4) levels in regulatory T cells (Tregs) and ≥5% TILs before chemotherapy. Multivariate analysis showed that G2 and better therapeutic effects tended to be associated with higher NK cell levels after chemotherapy (odds ratio = 1.02; 95% confidence interval, 0.99–1.05; P = 0.07). The activation of local and systemic immune responses by downregulation of immunosuppressive factors, such as VEGF and CTLA-4 in Tregs, had variable pathological and therapeutic effects after preoperative chemotherapy in patients with breast cancer.

Hypoxia is a common pathway to the progression of end-stage kidney disease. Retinoic acid-inducible gene I (RIG-I) encodes an RNA helicase that recognizes viruses including SARS-CoV2, which is responsible for the production of interferon (IFN)-α/β to prevent the spread of viral infection. Recently, RIG-I activation was found under hypoxic conditions, and klotho deficiency was shown to intensify the activation of RIG-I in mouse brains. However, the roles of these functions in renal inflammation remain elusive. Here, for in vitro study, the expression of RIG-I and IFN-α/β was examined in normal rat kidney (NRK)-52E cells incubated under hypoxic conditions (1% O2). Next, siRNA targeting RIG-I or scramble siRNA was transfected into NRK52E cells to examine the expression of RIG-I and IFN-α/β under hypoxic conditions. We also investigated the expression levels of RIG-I and IFN-α/β in 33 human kidney biopsy samples diagnosed with IgA nephropathy. For in vivo study, we induced renal hypoxia by clamping the renal artery for 10 min in wild-type mice (WT mice) and Klotho-knockout mice (Kl−/− mice). Incubation under hypoxic conditions increased the expression of RIG-I and IFN-α/β in NRK52E cells. Their upregulation was inhibited in NRK52E cells transfected with siRNA targeting RIG-I. In patients with IgA nephropathy, immunohistochemical staining of renal biopsy samples revealed that the expression of RIG-I was correlated with that of IFN-α/β (r = 0.57, PP−/− mice. These findings suggest that hypoxia induces the expression of IFN-α/β through the upregulation of RIG-I, and that klotho deficiency intensifies this hypoxia-induced expression in kidneys.

Signet ring cell carcinoma (SRCC) of the stomach is a rare type of cancer with a slowly rising incidence. It tends to be more difficult to detect by pathologists mainly due to its cellular morphology and diffuse invasion manner, and it has poor prognosis when detected at an advanced stage. Computational pathology tools that can assist pathologists in detecting SRCC would be of a massive benefit. In this paper, we trained deep learning models using transfer learning, fully-supervised learning, and weakly-supervised learning to predict SRCC in Whole Slide Images (WSIs) using a training set of 1,765 WSIs. We evaluated the models on four different test sets of about 500 images each. The best model achieved a Receiver Operator Curve (ROC) area under the curve (AUC) of at least 0.99 on all four test sets, setting a top baseline performance for SRCC WSI classification.

Background The use of general anesthesia (GA) with inhalational anesthetics for breast cancer surgery may be associated with breast cancer recurrence and increased mortality due to the immunosuppressive effects of these drugs. Less-immunosuppressive anesthetic techniques may reduce breast cancer recurrence. We evaluated the feasibility, safety, and efficacy of outpatient breast-conserving surgery (BCS) for breast cancer in a breast clinic in terms of the anesthetic technique used, complications occurring, recurrence, and survival. Methods: The sample comprised 456 consecutive patients with stage 0–III breast cancer who underwent BCS/axillary lymph node (ALN) management using local and intravenous anesthesia and/or sedation between May 2008 and January 2020. Most patients received adjuvant chemotherapy and/or endocrine therapy and radiotherapy after surgery. Patient outcomes were evaluated retrospectively. Results: All patients recovered and were discharged after resting for 3–4 h postoperatively. No procedure-related severe complication or death occurred. Sixty-four complications (14.0%) were observed: 14 wound infections, 17 hematomas, and 33 axillary lymphoceles. The median follow-up period was 2259 days (range, 9–4190 days), during which disease recurrence was observed in 25 (5.4%) patients. The overall survival and breast cancer–specific survival rates were 92.3% and 94.7%, respectively. Conclusions: Outpatient surgery for breast cancer involving BCS and ALN management under local and intravenous anesthesia and/or sedation can be performed safely, without serious complication or death. Less-immunosuppressive anesthetic techniques with spontaneous breathing may reduce the recurrence of breast cancer and improve survival relative to GA., Highlights • Outpatient surgery for breast cancer involving breast-conserving surgery (BCS) and axillary lymph node (ALN) management under local and intravenous anesthesia and/or sedation can be performed safely. • Less-immunosuppressive anesthetic techniques with spontaneous breathing may reduce the recurrence of breast cancer and improve survival compared with general anesthesia.

Backgrounds Colorectal neoplasias (CRN)s developing from the ulcerative colitis (UC) mucosa include both colitic and sporadic neoplasias. Although several genomic analyses of advanced colitis-associated cancer are available, such studies do not distinguish between colitic and sporadic cases, and the early-stage genomic alterations involved in the onset of colitic cancer remain unclear. To address this, we performed a genomic analysis of early-stage CRN developing from the UC mucosa (CRNUC). Methods We extracted DNA from 36 early-stage CRNUCs (T1 cancer, 10; dysplasia, 26) from 32 UC patients and performed targeted sequencing of 43 genes commonly associated with colitis-associated cancer and compared the results with sequencing data from the Japanese invasive colitis-associated cancer. Results The most frequently mutated gene in the CRNUC cohort was APC (mutated in 47.2% of the cases), followed by TP53 (44.4%), KRAS (27.8%), and PRKDC (27.8%). None of the TP53 mutations occurred at any of the hotspot codons. Although the TP53 mutations in The Cancer Genome Atlas of Colorectal Cancer were dispersed throughout the gene, those detected here in CRNUC cases were concentrated in the amino terminal part of the DNA-binding domain. Interestingly, the mutations in KRAS and TP53 were mutually exclusive in CRNUC, and CRNUCs with KRAS mutations had histologically serrated lesions in the gland duct. Mayo endoscopic subscore was higher in TP53-mutated CRNUCs and lower in KRAS-mutated CRNUCs. Conclusions Our findings suggest that early-stage CRNUC can be classified into 2 groups: those developing through the carcinogenic pathway via TP53 mutations and those developing through the carcinogenic pathway via KRAS mutations.

Tumor-infiltrating lymphocytes are an important prognostic factor after neoadjuvant chemotherapy (NAC) in patients with breast cancer. Natural killer (NK) cells play critical roles in antitumor immune surveillance. Here, we assessed the relationship between peripheral natural killer (pNK) cell activity, tumor microenvironmental factors (TMEFs), and the therapeutic efficacy of preoperative chemotherapy in patients with breast cancer. In a cohort of 39 patients diagnosed with stage II-IV breast cancer who received NAC, we measured pNK cell activity by chromium release assay and assessed TMEF levels by next-generation sequencing. Following NAC, pNK cell activity was increased in 24/39 patients but decreased in 15/39 patients. Increased pNK cell activity following preoperative chemotherapy was associated significantly with the disappearance of axillary lymph node metastasis (Ax+; p = 0.0235). Increased pNK cell activity remained significantly associated with the disappearance of Ax+ in multivariate logistic regression analysis (OR 5.41, 95% CI 1.19-24.52, p = 0.0283). A Grade 2 or higher effect of NAC was associated with high pre-NAC cytotoxic T lymphocyte-associated protein 4 (CTLA-4) levels (p = 0.0281) and elevated post-NAC NK (p = 0.0005) cells and transforming growth factor-beta (TGF-β; p = 0.0350) levels. The disappearance of Ax+ was associated with high pre-NAC CTLA-4 levels (p = 0.0278) and elevated CD4 levels after NAC (p = 0.0250). The systemic activation of pNK cells after NAC may improve metastatic tumor elimination in patients with breast cancer owing to a release from local immunosuppression, and immune activation in the tumor microenvironment.

Long-term prognosis of T1 laterally spreading tumors (LSTs) after treatment have not been clarified. This study compared clinicopathological characteristics and long-term prognosis of T1 LSTs. We retrospectively assessed 169 patients with 169 T1 LSTs between January 1992 and December 2008 by ten hospitals. Patients who did not meet the Japanese Society for Cancer of the Colon and Rectum (JSCCR) 2016 guidelines for the treatment of colorectal carcinoma (CRC) criteria were defined as non-endoscopically curable. The number of non-endoscopically curable patients with LST-granular/ nodular mixed (LST-G-M) was 61, that with LST-non-granular/ flat elevated (LST-NG-FE) was 23, and that with LST-non-granular/ pseudo depressed (LST-NG-PD) was 23. Clinicopathological variables and long-term prognosis were analyzed. For overall patients, tumor size, number of non-endoscopically curable cases, and rate of submucosal invasion depth ≥ 1000 μm for the LST-G-M group were significantly higher than those in the other groups. For non-endoscopically curable patients, the tumor size for those with LST-G-M was significantly larger than those in the other groups. The rate of submucosal invasion width ≥ 4000 μm and type B/C muscularis mucosae with LST-G-M was higher than that with LST-NG-FE. All recurrences occurred in non-endoscopically curable patients with LST-G-M. Five-year overall and disease-free survivals for non-endoscopically curable patients with LST-G-M were significantly shorter than those for patients with non-endoscopically curable LST-NG-FE and PD. Our data supported adequacy of the JSCCR guidelines for the treatment of CRC criteria for endoscopically curable patients after T1 LSTs treatment. Patients with T1 LST-G-M should be followed up more carefully.

Background Because immunosuppression is necessary for kidney transplant recipients, malignant tumorigenesis of recipient organs is a concern; however, few studies have discussed the malignant alteration of transplanted grafts that have been functional for a long time. In addition, a urothelial carcinoma (UC) in transplanted kidney graft is a rare disease. Case report A 62-year-old man had end-stage renal failure 31 years ago and received a kidney transplant from his father. Acute renal failure due to obstruction of the transplanted ureter was diagnosed. Ultrasound, ureterogram, and non-enhanced computed tomography scans revealed no obvious evidence of any neoplastic lesion. We treated the obstruction and hydronephrosis with transplant ureter stenting. However, the regional lymph nodes enlarged, and it became necessary to change the ureteral stent frequently because of stent stenosis; therefore, he underwent lower transplant ureteral resection and reconstruction. Histopathology confirmed a UC with a flat and infiltrative growth pattern. The patient then underwent graftectomy including right external iliac vein resection and reconstruction; however, because of numerous metastatic nodules, radical surgery could not be performed. The patient subsequently died because of septic shock after the second surgery. Conclusion We report a case of an invasive UC with a flat and infiltrative growth pattern derived from a transplant kidney graft that occurred 31 years after a living-donor transplant that could not be treated immediately and was difficult to diagnose.

AIM To investigate whether tumor-infiltrating lymphocyte (TIL) scoring based on 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) can predict the pathological response to neoadjuvant chemotherapy. PATIENTS AND METHODS A total of 261 patients with breast cancer underwent complete resection after neoadjuvant chemotherapy. PET-TIL score was calculated using tumor size, Ki-67 labeling index, and maximum standardized uptake value (SUVmax) on FDG PET/CT. The efficacy of the PET-TIL score in predicting the pathological complete response (pCR) was retrospectively evaluated. RESULTS pCR rates were 11.4%, 58.6%, and 38.8% in luminal, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative breast cancer, respectively. The corresponding median PET-TIL scores were 28, 37, and 45. pCR rates were 20.0% and 44.2% in the low and high PET-TIL score groups, respectively (p

Background: The tumor microenvironment can be classified into immunologically active “inflamed” tumors and inactive “non-inflamed” tumors based on the infiltration of cytotoxic immune cells. Previous studies on liver cancer have reported a superior prognosis for inflamed tumors compared to non-inflamed tumors. However, liver cancer is highly heterogeneous immunologically and genetically, and a finer classification of the liver cancer microenvironment may improve our understanding of its immunological diversity and response to immune therapy. Methods: We characterized the immune gene signatures of 234 primary liver cancers, mainly virus-related, from a Japanese population using RNA-Seq of tumors and matched non-tumorous hepatitis livers. We then compared them with the somatic alterations detected using the whole-genome sequencing. Findings: Liver cancers expressed lower levels of immune marker genes than non-tumorous hepatitis livers, indicating immunosuppression in the tumor microenvironment. Several immunosuppression mechanisms functioned actively and mutually exclusively, resulting in four immune subclasses of liver cancer: tumor-associated macrophage (TAM), CTNNB1, cytolytic activity (CYT), and regulatory T cell (Treg). The CYT and Treg subclasses represented inflamed tumors, while the TAM and CTNNB1 subclasses represented non-inflamed tumors. The TAM subclass, which comprised 31% of liver cancers, showed a poor survival, expressed elevated levels of extracellular matrix genes, and was associated with somatic mutations of chromatin regulator ARID2. The results of cell line experiments suggested a functional link between ARID2 and chemokine production by liver cancer cells. Interpretation: Primary liver cancer was classified into four subclasses based on mutually exclusive mechanisms for immunosuppression. This classification indicate the importance of immunosuppression mechanisms, such as TAM and Treg, as therapeutic targets for liver cancer. Funding: The Japan Agency for Medical Research and Development (AMED). Keywords: Liver cancer, Tumor microenvironment, Tumor-associated macrophage, Regulatory T cell

Aim We investigated the chemotherapy effect of resectable colorectal cancer with liver metastasis (CRLM) on the function of intrahepatic immune cells. Methods We classified patients into adjuvant chemotherapy (bevacizumab+CapeOX) after hepatectomy group (group A) and neoadjuvant chemotherapy followed by hepatectomy group (group B), and collected peripheral blood mononuclear cells (PBMC) and liver mononuclear cells (LMNC) to ascertain phenotypic and functional differences. Results There were no significant differences in lymphocyte fractions of either PBMC or LMNC between groups, except for the significantly lower percentage of natural killer (NK) cells in LMNC in group B than in group A. Significantly higher percentage of natural-killer group 2, member D (NKG2D)- positive NK cells in PBMC and percentage of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-, NKp30-, and signal regulatory protein β (SIRPβ)-positive NK cells in LMNC were found in group B. Furthermore, significantly higher expressions of NKG2D and SIRPβ in peripheral blood NK cells and of NKp46 and CD122 in liver NK cells were found in group B. When LMNC were incubated with interleukin (IL)-2 in vitro, no difference was observed in the expression of these molecules in NK cells between groups. Consistently, there was no difference in the cytotoxic activity of those LMNC against a colon adenocarcinoma cell line between groups. Conclusion Colorectal cancer with liver metastasis patients treated with neoadjuvant chemotherapy showed enhanced expression of activation markers on peripheral blood and liver NK cells in comparison with patients who did not receive therapy; however, the difference in those function remains unclear. These results suggest that neoadjuvant chemotherapy does not have a negative impact on intrahepatic immune cells in resectable CRLM patients.

Dedicated breast positron emission tomography (DbPET) provides detailed high-resolution images and can detect intratumoral heterogeneity using 18F-fluorodeoxyglucose (FDG). We aimed to evaluate the correlation between FDG uptake on DbPET and the clinicopathological features of breast cancer, particularly those with an intratumoral heterogeneous distribution of FDG on DbPET. We evaluated 195 consecutive patients with invasive breast cancer who underwent preoperative whole-body PET (WBPET) and DbPET concurrently between January 2016 and March 2017. The relationships between clinicopathological factors and the maximum standard uptake values (SUVmax) of DbPET and WBPET, including clinical stage, nuclear grade, Ki67 proliferation index, estrogen receptor (ER) and human epidermal growth factor receptor type 2 (HER2) statuses, and the intratumoral heterogeneous distribution of FDG on DbPET, were evaluated. The SUVmax of DbPET was significantly correlated with clinical T stage, N stage, nuclear grade, and Ki67 proliferation index (all p

AimsThe aim of our study was to analyse correlations between KRAS mutation status, chromosomal changes that affect KRAS status in cells from pancreatic tumours.MethodsWe collected 69 cases of surgically resected pancreatic ductal adenocarcinoma (PDA) and seven cases of chronic pancreatitis (CP). Chromosomal abnormalities of KRAS and CEP12 were detected using fluorescence in situ hybridisation (FISH).ResultsThe number of CEP12 signals per cell ranged from 1.78 to 2.04 and 1.46 to 4.88 in CP and PDA samples, respectively, while the number of KRAS signals per cell ranged from 1.94 to 2.06 and 1.88 to 8.18 in CP and PDA samples, respectively. The ‘chromosomal instability index’, which was defined as the percentage of cells with any chromosomal abnormality, was over 5.7 times greater in PDA than in CP. We performed KRAS mutation analysis by direct sequencing and found that tumours with KRAS mutations have a significantly higher mean KRAS signal per cell from PDA samples compared with tumours with wild-type KRAS. KRAS amplification was noted in 10% of cases. Although we found that lymph node metastasis and distal metastasis of PDA were more frequent in cases with KRAS amplification, this was not correlated with overall survival. Using a threshold of 40%, we found that the chromosomal instability index robustly discriminated PDA cells from CP cells.ConclusionsBased on these findings, we concluded that FISH testing of KRAS using cytology samples may represent an accurate approach for the diagnosis of PDA.

Background: Chronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function. This study aims to investigate the genetic backgrounds of IIP through gene expression profiling and pathway analysis, and to identify potential biomarkers that can aid in diagnosis and serve as novel therapeutic targets. Methods:RNA extracted from lung specimens of 12 patients with chronic fibrosing IIP was profiled using Illumina Human WG-6 v3 BeadChips, and Ingenuity Pathway Analysis was performed to identify altered functional and canonical signaling pathways. For validating the results from gene expression analysis, immunohistochemical staining of 10 patients with chronic fibrosing IIP was performed. Results: Ninety-eight genes were upregulated in IIP patients relative to control subjects. Some of the upregulated genes, namely desmoglein 3 (DSG3), protocadherin gamma-A9 (PCDHGA9) and discoidin domain-containing receptor 1 (DDR1) are implicated in cell-cell interaction and/or adhesion; some, namely collagen type VII, alpha 1 (COL7A1), contactin-associated protein-like 3B (CNTNAP3B) and mucin-1 (MUC1) are encoding the extracellular matrix molecule or the molecules involved in cell-matrix interactions; and the others, namely CDC25C and growth factor independent protein 1B (GFI1B) are known to affect cell proliferation by affecting the progression of cell cycle or regulating transcription. According to pathway analysis, alternated pathways in IIP were related to cell death and survival and cellular growth and proliferation, which are more similar to cancer than to inflammatory response and immunological diseases. Using immunohistochemistry, we further validate that DSG3, the most highly upregulated gene, shows higher expression in chronic fibrosing IIP lung as compared to control lung. Conclusion: We identified several genes upregulated in chronic fibrosing IIP patients as compared to control, and found genes and pathways implicated in cancer, rather than in inflammatory or immunological disease to play important roles in the pathogenesis of IIPs. Moreover, DSG3 is a novel potential biomarker for chronic fibrosing IIP with its significantly high expression in IIP lung., This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

The risk factors in the progression of nonalcoholic fatty liver disease (NAFLD) have not been fully clarified. Porphyromonas gingivalis (P.g) has been considered to be a confounding risk factor for systemic diseases. We aimed to evaluate the effect of P.g infection on risk of progression to NASH. (1) Serum IgG antibody titers against P.g fimbriae (fimA) in 200 biopsy-proven NAFLD patients were measured by ELISA and compared with histological findings. (2) C57BL/6J mice were fed a control diet (CD) or high-fat diet (HFD) with or without P.g-odontogenic infection and analyzed histologically. Mouse livers were analyzed using CE–TOFMS and LC–TOFMS. (1) A significant correlation between fibrosis progression and antibody titers against P.g possessing fimA type 4 was identified (P = 0.0081). Multivariate analysis identified older age and type 4 P.g-positivity as risk factors for advanced fibrosis. (2) Fibrosis and steatosis were more severe in HFD P.g(+) mice compared with HFD P.g(−) mice. In metabolome analysis, fatty acid metabolism was significantly disrupted with HFD in P.g-infected mouse livers. Monounsaturated/saturated fatty acid ratios were significantly higher in the HFD P.g(+) group than in the HFD P.g(−) group (P

Spinal nerve sheath tumors are well known to typically originate from dorsal sensory nerve roots. However, it is difficult to anatomically identify the origin in the case of cauda equina tumors. In this study, we aimed to ascertain whether a cauda equina nerve root removed with a nerve sheath tumor was a motor nerve using acetylcholinesterase (AchE) staining. Nerve rootlet sections removed with tumors were stained for AchE using the AchE Rapid Staining Kit. Additionally, we performed intraoperative motor-evoked potential (MEP) monitoring following either transcranial electrical stimulation (TES) or electrical stimulation of nerve rootlets. The muscular strength of the lower extremities was assessed bilaterally before and after surgery using manual muscle testing. An AchE-positive motor nerve rootlet that was the origin of a cauda equina tumor was observed in one of the 12 patients. In this patient, a MEP in the right quadriceps evoked by electrical stimulation of this rootlet was detected. TES-MEP showed a 30% decrease in the amplitude in the right quadriceps evoked after tumor resection with this nerve rootlet. However, the motor strength in both lower extremities did not change after surgery. AchE staining and intraoperative MEP monitoring could detect the motor nerve rootlet that was the origin of a cauda equina tumor. Nerve sheath tumors originating from the motor nerve might be rare even in cauda equina.

An atomic bomb (A-bomb) was dropped on Hiroshima on 6th August 1945. Although numerous studies have investigated cancer incidence and mortality among A-bomb survivors, only a small number have addressed urological cancer in these survivors. The aim of the present study was to investigate the clinicopathological features of prostate cancer (PCa) in A-bomb survivors. The clinicopathological features and prognosis of PCa were retrospectively reviewed in 212 survivors and 595 control patients between November 1996 and December 2010. The histopathological and clinical outcomes of surgical treatment of PCa were also evaluated in 69 survivors and 162 control patients. Despite the higher age at diagnosis compared with the control group (P=0.0031), survivors were more likely to have been diagnosed with PCa from a health check compared with the control group (P

Background and Aims Endoscopic submucosal dissection (ESD) is an effective procedure for en bloc resection of superficial colorectal tumors regardless of tumor size or location. However, there are few reports on long-term outcomes for patients with superficial colorectal tumors after ESD. We therefore aimed to evaluate the long-term outcomes after ESD for superficial colorectal tumors. Methods ESD was performed on 257 colorectal tumors in 255 consecutive patients at Hiroshima University Hospital between June 2003 and July 2010. We investigated the following variables: patient characteristics, the American Society of Anesthesiologists score, tumor location, tumor size, growth type, histology, en bloc resection rate, achievement of curative resection, procedure time, and adverse events. The 5-year overall survival (OS), 5-year disease-specific survival (DSS), local recurrence, and metachronous tumor occurrence were also analyzed. Results We identified 224 tumors in 222 patients who were confirmed dead or had follow-up data for more than 5 years. After a median follow-up of 79 months, 5-year OS and DSS rates were 94.6% and 100%, respectively. The local recurrence rate (1.5%) was significantly higher in patients undergoing piecemeal resection (9.1%) compared with en bloc resection (0.6%), in cases of histologic incomplete resection compared with complete resection, and in cases of non-R0 resection compared with R0 resection. The rates of total number of tumors (≥6 mm) and carcinoma metachronous tumors after ESD without additional surgical resection were 18.9% (38/201) and 4.0% (8/201), respectively. Conclusions Long-term outcomes after ESD for superficial colorectal tumors are favorable. Patients should be surveyed for both local recurrence and metachronous tumors after ESD.

We aimed to clarify the long-term outcomes of patients with T1 colorectal carcinoma (CRC) after endoscopic resection (ER) and surgical resection. We examined T1 CRC patients treated during 1992–2008 and who had ≥5 years of follow-up. Patients who did not meet the curative criteria after ER according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines were defined as “non-endoscopically curable” and classified into three groups: ER alone (Group A: 121 patients), additional surgery after ER (Group B: 238 patients), and surgical resection alone (Group C: 342 patients). Long-term outcomes and predictors of recurrence were analyzed. Of the 882 patients with T1 CRC, 701 were non-endoscopically curable. Among these patients, recurrence and 5-year overall survival (OS) rates were 0.6 and 91.1%, respectively. In Groups A, B, and C, recurrence rates were 5.0, 5.5, and 3.8%, OS rates were 79.3, 92.4, and 91.5% (p

Background & Aims Patients with hepatocellular carcinoma (HCC) have a high-risk of multi-centric (MC) tumor occurrence due to a strong carcinogenic background in the liver. In addition, they have a high risk of intrahepatic metastasis (IM). Liver tumors withIM or MC are profoundly different in their development and clinical outcome. However, clinically or pathologically discriminating between IM and MC can be challenging. This study investigated whether IM or MC could be diagnosed at the molecular level. Methods We performed whole genome and RNA sequencing analyses of 49 tumors including two extra-hepatic metastases, and one nodule-in-nodule tumor from 23 HCC patients. Results Sequencing-based molecular diagnosis using somatic single nucleotide variation information showed higher sensitivity compared to previous techniques due to the inclusion of a larger number of mutation events. This proved useful in cases, which showed inconsistent clinical diagnoses. In addition, whole genome sequencing offered advantages in profiling of other genetic alterations, such as structural variations, copy number alterations, and variant allele frequencies, and helped to confirm the IM/MCdiagnosis. Divergent alterations between IM tumors with sorafenib treatment, long time-intervals, or tumor-in-tumor nodules indicated high intra-tumor heterogeneity, evolution, and clonal switching of liver cancers. Conclusions It is important to analyze the differences between IM tumors, in addition to IM/MC diagnosis, before selecting a therapeutic strategy for multiple tumors in the liver. Lay summary Whole genome sequencing of multiple liver tumors enabled the accuratediagnosis ofmulti-centric occurrence and intrahepatic metastasis using somatic single nucleotide variation information. In addition, genetic discrepancies between tumors help us to understand the physical changes during recurrence and cancer spread.

Histopathological classification of gastric and colonic epithelial tumours is one of the routine pathological diagnosis tasks for pathologists. Computational pathology techniques based on Artificial intelligence (AI) would be of high benefit in easing the ever increasing workloads on pathologists, especially in regions that have shortages in access to pathological diagnosis services. In this study, we trained convolutional neural networks (CNNs) and recurrent neural networks (RNNs) on biopsy histopathology whole-slide images (WSIs) of stomach and colon. The models were trained to classify WSI into adenocarcinoma, adenoma, and non-neoplastic. We evaluated our models on three independent test sets each, achieving area under the curves (AUCs) up to 0.97 and 0.99 for gastric adenocarcinoma and adenoma, respectively, and 0.96 and 0.99 for colonic adenocarcinoma and adenoma respectively. The results demonstrate the generalisation ability of our models and the high promising potential of deployment in a practical histopathological diagnostic workflow system.

Highlights • EES involving the ulnar nerve is uncommon and extremely rare. • EES in the ulnar nerve may mimic benign soft tissue tumor. • Despite its rarity, high index of suspicion is advisable due to malignant nature. • Wide excision and reconstruction is needed for EES involving ulnar nerve., Introduction Extraskeletal Ewing sarcoma (EES) of the extremity is uncommon, and only a small number of reported cases have been devoted to the upper-extremity. Presentation of case A 65-year-old woman presented with a recurrent EES, a highly malignant tumor, involving the ulnar nerve at the right elbow region which was initially suspected as a benign soft tissue tumor, schwannoma, thus marginal excision had been performed. Due to its malignant behaviour, we treated the recurrent lesion with wide excision and reconstruction combined with chemotherapy. Histological evaluation revealed a monotonous small round cells appearance. Discussion EES of the extremity involving the ulnar nerve is fairly uncommon. The tumor was often smaller in the adult than in the child population which was consistent with the present case, thus may mimic a benign tumor. Because of the overlapping histopathological features of EES with other tumors, other investigations such as immunohistochemistry and cytogenetic studies must be performed to allow definitive diagnosis. The result of our study was negative for the EWSR1-FLI-1 and CIC-DUX4 fusion gene, however, other less frequent translocations could be found in this case which does not exclude the diagnosis of Ewing sarcoma family. Conclusion Few cases of EES involving the ulnar nerve have been previously reported. The correct diagnosis of EES involving the ulnar nerve has become particularly important in order to enable the initiation of comprehensive management that have the potential to reduce disease progression and the avoidance of improper and potentially harmful surgical therapy.

Background and study aims: Colitis-associated cancer/dysplasia (CC/D) can affect the life expectancy of patients with ulcerative colitis (UC). Although the utility of magnifying chromocolonoscopy has been shown, the use of optical magnification with narrow band imaging (NBI) for distinguishing CC/D from non-neoplastic lesions in patients with UC has not been reported. We evaluated whether endoscopic findings are distinguishing and thus assessed the clinical usefulness of NBI magnification for differentiating UC-associated lesions. Patients and methods: The study involved 27 patients diagnosed and treated at Hiroshima University Hospital between September 2005 and March 2015: a neoplasia group (16 lesions) and a non-neoplasia group (17 lesions). The neoplasias comprised 9 dysplastic lesions, 5 intramucosal carcinomas, and 2 submucosal carcinomas, and 17 non-neoplastic lesions. Targeted biopsy samples of suspicious lesions detected by conventional colonoscopy were classified pathologically as neoplastic or non-neoplastic, and NBI magnifying colonoscopy findings (i. e., the surface [unclear/regular/irregular/amorphous] and vascular [same as the background mucosa/regular/irregular/avascular] patterns) of the 2 lesion types were compared. Results: Irregular/amorphous surface patterns were significantly more common in neoplastic lesions than in non-neoplastic lesions (81 % [13/16] vs. 18 % [3/17], respectively, P

Background & Aims FibroScan® is a tool for the noninvasive diagnosis of hepatic fibrosis. Previous studies have compared liver stiffness to percutaneous liver biopsy findings, but there were no studies which compared liver stiffness to liver resection specimen findings. The aim of this study was to compare FibroScan® measurements to resected liver specimen findings. Methods From April 2011 to November 2015, a total of 114 patients with liver tumor and hepatitis C were enrolled. We divided them into two groups (training set and validation set). The first 66 patients who had liver resection from April 2011 to June 2014 were considered the training set, and the other 48 patients from August 2014 to November 2015 formed the validation set. Liver stiffness was measured by FibroScan® before surgery, and specimens obtained by liver resection were evaluated according to the METAVIR system. Results Using Spearman rank correlation analysis, a positive correlation between liver stiffness measurement and liver fibrosis stage was observed (r = 0.786, p

The long-term outcomes of whole-breast and boost irradiation after breast-conserving surgery (BCS) for patients with breast cancer were retrospectively analyzed. Patients who received whole-breast and boost irradiation after BCS from 1990 to 2002 were included. Boost irradiation was administered to each tumor bed, regardless of the surgical margin status. The median doses of whole-breast and boost irradiation were 45 Gy in 25 fractions (range 36–45 Gy), and 14 Gy in 7 fractions (range 0–14 Gy), respectively. Data for 306 patients were analyzed. With a median follow-up time of 144 months, the 10-year overall survival, disease-free survival, ipsilateral breast tumor recurrence (IBTR), and metachronous contralateral breast cancer (MCBC) occurrence rates were 93.0, 84.1, 2.1, and 4.1 %, respectively. In the multivariate analysis, pT2 was a significant risk factor for IBTR (p = 0.041), while age ≤ 50 years and pT2 were significant risk factors for MCBC occurrence (p = 0.003 and 0.043, respectively). One patient (0.3 %) developed angiosarcoma in the irradiated region 120 months after the completion of radiation therapy. The 12-year outcome of breast-conserving therapy using whole-breast and boost irradiation with doses of 45 and 14 Gy, respectively, was favorable.

We present a rare case of colorectal T1 carcinoma with metastasis of previous lung carcinoma found at the deepest invasive portion. A 61-year-old man presented with cervical lymphadenopathy 18 years after undergoing surgery for right lung carcinoma [poorly differentiated adenocarcinoma stage IIb (T3N0M0)]. Contrast-enhanced computed tomography showed enlarged lymph nodes (LNs) in the neck and mediastinal regions. Combined hybrid-F-fluorodeoxyglucose positron emission-computerized tomography showed increased radionuclide uptake in multiple cervical LNs and mediastinal LNs. LN biopsy revealed a poorly differentiated adenocarcinoma, suspected to be a metastatic tumor of the lung. Subsequent colonoscopy revealed a pedunculated-type lesion with a depressed area in the ascending colon. We performed polypectomy as total excisional biopsy; this tumor was composed mainly of moderately differentiated adenocarcinoma, partially mixed with mucinous adenocarcinoma. The pathological findings of the invasive front of the colorectal carcinoma showed poorly differentiated adenocarcinoma with a morphological pattern similar to that of the previous lung carcinoma. Furthermore, immunohistochemical results for the histological type of the deepest invasive portion of the tissue specimen were positive for thyroid transcription factor-1 but negative for Caudal-type homeobox 2. From these morphological and immunohistochemical findings, the final diagnosis was moderately differentiated lung carcinoma, pTX N3 M1b (LN, colon) Stage IV.

The prognosis of patients with colorectal liver metastases (CRLM) remains low despite advances in chemotherapy and surgery. The expression of h-prune (human homolog of Drosophila prune protein; HGNC13420), an exopolyphosphatase, is correlated with progression and aggressiveness in several cancers and promotes migration and invasion. We investigated the role of h-prune in CRLM. To investigate the role of h-prune, immunohistochemical analysis for h-prune was performed in 87 surgically resected specimens of CRLM obtained between 2001 and 2009 at the Hiroshima University Hospital. Immunohistochemical analysis revealed positive staining for h-prune in 24 (28%) cases. The overall survival rate was significantly lower in h-prune-positive cases than in h-prune-negative cases (p = 0.003). Multivariate analysis showed that h-prune positivity was the only independent factor related to poor overall survival of patients after curative hepatectomy of CRLM. In vitro and in vivo, h-prune-knocked-down and h-prune-overexpressing cells were analyzed. In vitro, h-prune was associated with increased cell motility and upregulation of epithelial-mesenchymal transition (EMT) markers. In a mouse model, h-prune was associated with invasion of the tumor and distant metastases. In summary, h-prune expression is a useful marker to identify high-risk patients for resectable colorectal liver metastasis. h-Prune expression is necessary for cancer cell motility and EMT and is associated with liver and lung metastasis in colorectal cancer cells. h-Prune could be a new prognostic marker and molecular target for CRLM.