Granzyme B Expression in the Tumor Microenvironment as a Prognostic Biomarker for Patients with Triple-Negative Breast Cancer.

Tumor-infiltrating lymphocytes in the tumor microenvironment are important in the treatment of triple-negative breast cancer (TNBC). Cytotoxic T cells produce cytokines and cytotoxic factors, such as perforin and granzyme, which induce apoptosis by damaging target cells. To identify biomarkers of these cells, we investigated granzyme B (GZMB) in the tumor microenvironment as a biomarker of treatment response and prognosis in 230 patients with primary TNBC who underwent surgery without preoperative chemotherapy between January 2004 and December 2014. Programmed cell death ligand 1 (PD-L1) positivity was defined as a composite positive score ≥10 based on the PD-L1 immunostaining of tumor cells and immune cells. GZMB-high was defined as positivity in ≥1% of tumor-infiltrating lymphocytes (TILs). Among the 230 TNBC patients, 117 (50.9%) had CD8-positive infiltrating tumors. In the PD-L1-positive group, a Kaplan-Meier analysis showed that GZMB-high TNBC patients had better recurrence-free survival (RFS) and overall survival (OS) than GZMB-low patients and that OS was significantly longer (RFS: p = 0.0220, OS: p = 0.0254). A multivariate analysis also showed significantly better OS in PD-L1- and GZMB-high patients (hazard ratio: 0.25 (95% IC: 0.07-0.88), p = 0.03). Our findings indicate that GZMB is a useful prognostic biomarker in PD-L1-positive TNBC patients.

Atypical clinical presentation of mechanical small bowel obstruction with superior mesenteric vein occlusion caused by a retained free intraperitoneal staple after laparoscopic appendectomy: A case report.

Mechanical small bowel obstruction (SBO) is a common postoperative complication, and most cases are caused by postoperative adhesions. We herein report a case of SBO with superior mesenteric vein occlusion caused by a metal staple after laparoscopic appendectomy. A 35-year-old Japanese woman presented to our department with severe upper abdominal pain and vomiting. She had undergone laparoscopic appendectomy using a linear stapler 7 years before. Abdominal CT showed mild small intestinal dilation with mesenteric edema and volvulus of the small bowel mesentery. Moreover, occlusion of the superior mesenteric vein was observed. Emergency exploratory laparoscopy revealed a strangulated SBO caused by a free unformed staple. The obstruction was released by a laparoscopic technique without bowel resection. The number of laparoscopic surgeries has recently been increasing, and complications specific to laparoscopic surgery have been recognized. All spilled and unformed staples should be removed to the greatest extent possible during laparoscopic operations.

Microsatellite instability in Japanese female patients with triple-negative breast cancer.

BACKGROUND: It is important to identify biomarkers for triple-negative breast cancers (TNBCs). Recently, pembrolizumab, an immune checkpoint inhibitor (ICI) for programmed cell death 1 (PD-1), was approved as a treatment strategy for unresectable or metastatic tumor with high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency, such as malignant melanoma, non-small cell lung cancer, renal cell cancer and urothelial cancer. In addition, results from clinical trials suggested that ICI was a promising treatment for TNBCs with accumulated mutations. However, the frequency of MSI in Japanese TNBCs still remains unclear. We aimed to analyze the presence of MSI-H in TNBCs as a biomarker for ICI therapy. METHODS: In this study, we retrospectively evaluated the MSI of 228 TNBCs using an innovative method, MSI Analysis System Version 1.2 (Promega), consisting of 5 microsatellite markers: BAT-26, NR-21, BAT-25, MONO-27 and NR-24 without a normal tissue control. RESULTS: Among 228 tumors, 222 (97.4%) were microsatellite stable, 4 (1.7%) low-frequency MSI and 2 (0.9%) MSI-H, respectively. Two MSI-H tumors were potentially aggressive pathologically as indicated by nuclear grade 3 and high Ki-67 (> 30%), and were classified as basal-like and non-BRCA-like, but were not consistent regarding tumor-infiltrating lymphocytes, CD8 and PD-L1 expression. CONCLUSIONS: Although we found that MSI-H was uncommon (0.9%) in TNBCs, potential targets for ICIs exist in TNBCs. Therefore, MSI-H breast cancer patients should be picked up using not only conventional methods but also platforms for comprehensive genomic profiling.

T-bet+ lymphocytes infiltration as an independent better prognostic indicator for triple-negative breast cancer.

PURPOSE: T-box transcription factor 21 (T-bet), which is the master regulator of effector T-cell activation, is derived by stimulation of T-cell receptors. In this study, we focused on T-bet and examined the function of activated T cells. METHODS: This study included 242 patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on tumor-infiltrating lymphocytes (TILs) was defined as ≥ 30 per 6.25 × 10-3 mm2. RESULTS: Of the 242 TNBC cases, CD8 was positively expressed in 127 (52.5%) tumors, and T-bet was positively expressed in 67 (27.7%) tumors. T-bet expression was significantly correlated with CD8 expression (p < 0.0001). Patients with T-bet+ tumors had longer overall survival (OS) compared with patients with T-bet- tumors (p = 0.047). The combination of CD8+ and T-bet+ was associated with a better recurrence-free survival (RFS) and OS compared to CD8+/T-bet- tumors (p = 0.037 and p = 0.024, respectively). Adjuvant chemotherapy provided significantly greater benefit to patients with T-bet+ tumors (p = 0.031 for RFS, p = 0.0003 for OS). Multivariate analysis revealed that T-bet expression on TILs was an independent and positive prognostic indicator (HR = 0.36, 95% confidence interval (CI) 0.12-0.94, p = 0.037 for RFS, HR = 0.30, 95% CI 0.07-0.95, p = 0.039 for OS). CONCLUSIONS: OS was significantly improved for patients with high T-bet-expressing TILs in TNBC. Thus, T-bet may be a predictive indicator for survival and various immunotherapy strategies in TNBC.

Laparoscopic high anterior resection for triple colorectal cancers with persistent ascending and descending mesocolons: A case report.

Persistent mesocolon is an embryological anomaly of the colon resulting from failure of the primitive dorsal mesocolon to fuse with the parietal peritoneum. We herein present a case of laparoscopic high anterior resection for triple colorectal cancers with persistent ascending and descending mesocolons and a right-bound inferior mesenteric artery. Preoperative 3-D CT demonstrated that the sigmoid colon had shifted to the right abdomen and was located under the ascending colon. Moreover, the inferior mesenteric artery and vein traveled toward the right abdomen accompanied by the mesentery of the descending colon. Adhesiolysis between the ascending and sigmoid colon was initially performed, and the sigmoid colon was placed in its normal position. The inferior mesenteric artery was then divided with lymph node dissection using a medial approach, and high anterior resection was completed. An understanding of the anatomical characteristics of persistent mesocolon is important to ensure safe laparoscopic surgery.

BRCAness Combined With a Family History of Cancer Is Associated With a Poor Prognosis for Breast Cancer Patients With a High Risk of BRCA Mutations.

BACKGROUND: The inexpensive prediction of the characteristics of BRCA-mutated breast cancer as "BRCAness" using the somatic cells of patients with breast cancer could be useful for developing a therapeutic strategy. Our objective was to correlate BRCAness with the clinicopathologic features, including a family history (FH) of cancer, in breast cancer patients with a high risk of BRCA mutations. PATIENTS AND METHODS: The present study included 124 patients, including 55 with early-onset and 77 with triple-negative breast cancer, who had undergone resection at Kyushu University Hospital from 2005 to 2014. Early-onset breast cancer is defined as an onset in patients aged ≤ 40 years. BRCAness was performed using multiple ligation-dependent probe amplification. The patients' FH of cancer was surveyed from first- to third-degree relatives. RESULTS: Of the 124 patients, the multiple ligation-dependent probe amplification assay results indicated that 59 tumors (47.6%) had BRCAness and 27 patients (21.8%) had a positive FH for cancer. The patients with BRCAness experienced significantly shorter recurrence-free survival (RFS) and overall survival (OS) compared with those without. Patients with FH had shorter RFS and OS compared to those without BRCAness. The patients were divided into those with and without BRCAness and those with and without a positive FH. The BRCAness with FH subgroup experienced significantly shorter RFS and OS. Multivariate analysis revealed that BRCAness and a positive FH were independent negative prognostic factors. CONCLUSION: Our findings suggest that BRCAness tumors with a positive FH of cancer were associated with a poor prognosis in the BRCA-mutation high-risk group. We propose that BRCAness and a positive FH will serve to predict patients' prognosis.

The combination of PD-L1 expression and decreased tumor-infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer.

This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD-L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs-low tumors (P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival (P = 0.0018) and overall survival (P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies.

BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases. METHODS: The BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens. RESULTS: Of the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter recurrence-free survival (RFS) compared with the non-BRCAness group (P = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC. CONCLUSIONS: The 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs.

Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat).

Aromatase inhibitors (AIs) are important drugs for treating postmenopausal patients with hormone receptor-positive breast cancer. However, acquired resistance to AI therapies is a significant problem. Our study has revealed that the histone deacetylase inhibitor LBH589 treatment abrogated growth of AI-resistant cells in vitro and in vivo, causing cell cycle G2/M arrest and induced apoptosis. LBH589 treatment also reduced the level of NF-κB1 which is overexpressed when AI resistance develops. Analyzing paired tumor specimens from 12 patients, we found that NF-κB1 expression was increased in recurrent AI-resistant tumors as compared to the paired primary tumors before AI treatment. This finding was consistent with up-regulated NF-κB1 expression seen in a collection of well-established AI-resistant cell lines. Furthermore, knockdown of NF-κB1 expression significantly suppressed the proliferation of AI-resistant cells. Treatment of AI-resistant cell lines with LBH589 suppressed NF-κB1 mRNA and protein expression. In addition, LBH589 treatment abrogated growth of AI-resistant tumors in mice, and was associated with significantly decreased levels of NF-κB1 in tumors. In all, our findings strongly support further investigation of LBH589 as a novel therapeutic strategy for patients with AI-resistant breast cancer, in part by suppressing the NF-κB1 pathway.

A poor prognostic case of mucoepidermoid carcinoma of the thyroid: a case report.

Mucoepidermoid carcinoma (MEC) of the thyroid is very rare and low-grade indolent neoplasm. In past reports of the thyroid MEC, only seven cases were described as poor prognosis. A 91-year-old woman presented with a rapidly growing mass of the left upper neck. She was followed thyroid papillary carcinoma (PC) without operation for two years. Fine needle aspiration cytology (FNAC) showed undifferentiated cells. Total thyroidectomy and bilateral neck dissection were performed. In pathological findings, the tumor had two areas of MEC and PC. The boundary of them was mixed. She died of multiple lung metastases only after four months from the operation. We report a rare case of thyroid MEC which had an aggressive behavior and poor prognosis. This case is a precious in that thyroid MEC occurred during observation of PC and suggests a possibility of the transformation from PC to MEC.

Neoadjuvant epirubicin/docetaxel (ET) concomitant chemotherapy for primary breast cancer with tumor diameter >=3.1 cm: results of the Kyushu ET therapy phase II trial.

AIM: Neoadjuvant epirubicin/docetaxel (ET) combination chemotherapy was administered to breast cancer patients in order to investigate their clinical and pathological response. Moreover, the breast-conserving surgery (BCS) rate, disease-free (DFS) and overall survival (OS), safety profile and the correlation of biological markers were investigated. PATIENTS AND METHODS: Out of the 46 enrolled patients, 45 patients were analyzed for clinical response, and 40 patients were examined for pathological response. Estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor type2 (HER2) expression were examined immunohistologically. RESULTS: The median tumor size was 4.5 cm in diameter. Complete (CR) and partial responses were seen in 3 and 30 patients, respectively. A pathological CR was achieved in 4 patients and correlated with ER and PgR negativity. Moreover, BCS was performed on 16 patients. The 5-year cumulative DFS was 60.7% and OS was 91.8%. CONCLUSION: ET therapy is clinically effective with a pathological CR rate of 10% for patients with a large tumor, and should be considered as a neoadjuvant treatment option.

Short-term and low-dose prednisolone administration reduces aromatase inhibitor-induced arthralgia in patients with breast cancer.

Aromatase inhibitors (AIs) are important therapeutic drugs for postmenopausal women with hormone receptor-positive breast cancer. However, adverse effects of AIs such as arthralgia have been extensively reported. We performed a joint prospective, multi-institutional investigation to find out whether a low-dose and short-term prednisolone is effective against AI-induced arthralgia in 27 patients with breast cancer. Patients were administered 5 mg of oral prednisolone once a day in the morning for only one week. Patients were then asked to answer a questionnaire about joint pain symptoms at one week, one month and two months after the beginning of prednisolone use. Joint pain symptoms improved in 67% of patients immediately after prednisolone use, with 63% still reporting analgesic effect at one month, and 52% at two months after beginning internal use of prednisolone. At one week, one month and two months after the use of prednisolone, 30%, 30% and 26% of patients reported improved daily life, respectively. Our results suggest that prednisolone could substitute non-steroidal anti-inflammatory drugs, acetoaminophen or cyclooxygenase-2 inhibitors in patients with AI-induced arthralgia.

Metastatic breast carcinoma simulating linitis plastica of the colon: report of a case.

A 48-year-old woman developed a mobile abdominal mass in the course of treatment for recurrent breast cancer. Imaging studies indicated linitis plastica of the colon. She underwent surgery because of the stenosis of the transverse colon. An examination of the resected specimen revealed a segmental stricture, thickening of the entire wall, and a granular mucosa resembling cobblestones. Microscopic findings of the colon lesion were very similar to those of her primary, invasive lobular carcinoma of the breast. Atypical cells showed immunoreactivity for cytokeratin-7, but not for cytokeratin-20. These findings suggested that the lesion of the colon was a colonic metastasis of breast cancer. Metastatic gastrointestinal diseases originating from breast carcinoma are unusual, and colonic metastases are especially rare. Although colon cancer may occur in patients with a history of breast cancer, metastatic colon cancer should be suspected if linitis plastica is detected.

Pseudo-Meigs' syndrome associated with breast cancer metastasis to both ovaries: Report of a case.

A 50-year-old woman was admitted because of abdominal fullness due to bilateral ovarian tumors, pleural effusion, and ascites associated with breast cancer. Although chemotherapy and the removal of ascites were performed periodically, the ascites did not disappear. The cytology of the ascites did not indicate malignancy. Pseudo-Meigs' syndrome caused by metastasis to both ovarian tumors was suspected. The patient underwent a bilateral salpingo-oophorectomy, and the pathological diagnosis was bilateral metastatic ovarian tumors from breast cancer. The ascites and pleural effusion resolved after the surgery, with the consequent improvement of the patient's quality of life; however, she unfortunately died 4 months later due to hepatic failure caused by multiple metastases.

Unusual multiple gastric carcinoids with hypergastrinemia: report of a case.

We report the case of a patient demonstrating multiple gastric carcinoids with hypergastrinemia. A 50-year-old Japanese woman was admitted to our hospital for the further examination of multiple carcinoids of the stomach with hypergastrinemia, although she was asymptomatic. However, based on our clinical examination, this case seemed to be neither type I nor II carcinoid. We performed a total gastrectomy with D1 lymph node dissection. A pathological examination showed numerous endocrine micronests, hyperplasia of the parietal cells extending to the foveolar neck region, and numerous dilated oxyntic glands filled with eosinophilic secretions. Many parietal cells exhibited vacuolated cytoplasms and apical snouts. Furthermore, the dilated glands at the base of the mucosa had hyperchromatic nuclei and ciliated surfaces. The postoperative serum gastrin level was soon normalized to 47 pg/ml. This is only the third reported case of multiple gastric carcinoids with hypergastrinemia due to an intrinsic abnormality in the acid secretion of the parietal cells.

The impact of visceral fat accumulation on laparoscopy-assisted distal gastrectomy for early gastric cancer.

BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) has been widely accepted for the treatment for early gastric cancer. Obesity is a rapidly growing epidemic, and the number of obese patients with gastric cancer is increasing, but the impact of visceral fat (VF) accumulation on laparoscopic gastric surgery remains unknown. The aim of the present study was to determine the impact of VF accumulation on LADG. MATERIALS AND METHODS: The medical charts of 30 patients who underwent LADG for early gastric cancer in our hospital between November 2000 and November 2006 were analyzed retrospectively. The patients were divided into two groups on the basis of VF accumulation measured on cross-sectional computed tomography at the level of the umbilicus. Twelve patients had high VF accumulation (> or =100 cm2) and 18 had low VF accumulation (<100 cm2). RESULTS: Although subcutaneous fat accumulation was not correlated with operation time or operative blood loss, VF accumulation was strongly, and significantly, correlated with both operation time and operative blood loss. The high-VF-accumulation group had a significantly longer operation time and significantly more operative blood loss than the low-VF-accumulation group. There was no significant difference in the rate of postoperative complications or conversion to open laparotomy between the two groups. There were no operative deaths or requirements for blood transfusion in either group. CONCLUSIONS: VF accumulation was significantly correlated with operative difficulties during LADG. Although LADG was as safe for patients with high VF accumulation as for patients with low VF accumulation, a longer operative time and more operative blood loss were observed in patients with high VF accumulation. VF accumulation appears to be a possible risk factor in LADG and should be considered when making a decision about treating early gastric cancer with LADG.

Endoscopic neck surgery: current status for thyroid and parathyroid diseases.

During the last 3 years, 59 patients underwent endoscopic neck surgery. We started the video-assisted neck surgery with the gasless skin-lifting method for benign thyroid and parathyroid diseases to avoid complications of carbon dioxide (CO2) insufflation. Hemithyroidectomy was performed for benign thyroid tumors and subtotal thyroidectomy was selected for Graves' disease. Parathyroid adenomas were extirpated for primary hyperparathyroidism with precise preoperative localization by imaging modalities. In order to obtain a better visual field and to improve the cosmetic results, we have adopted the complete endoscopic method via breast approach with low CO2 insufflation pressure since August 2001. An intraoperative parathormone assay was introduced recently to confirm the complete removal of parathyroid adenomas. Both gasless and insufflation methods are feasible for endoscopic neck surgery with excellent cosmetic results.