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Pregnancy is a known risk factor for amebic enteritis, which develops into potentially fatal fulminant amebic enteritis in some cases. We describe a case of a 27-year-old non-immunosuppressed pregnant woman with fulminant amebic enteritis complicated with cytomegalovirus enteritis. She improved with intensive care and intravenous metronidazole and ganciclovir but eventually required subtotal colectomy for intestinal stenosis. It is difficult to diagnose amebic enteritis, especially in a non-endemic area. Amebic enteritis must be considered as a differential diagnosis for refractory diarrhea with bloody stools in women in the perinatal period, even those without immunosuppression.

Aim To evaluate the association between bromodomain-containing protein 4 (BRD4) expression and clinicopathological factors and prognosis in human breast cancer specimens. Patients and methods We used tissue microarrays constructed from samples of patients (n=183) who underwent surgery. We validated the association between BRD4 expression and prognosis in solid tumours, including breast cancer, using The Cancer Genome Atlas (TCGA) database. Results Immunohistochemical staining showed that BRD4 was widely distributed in breast cancer tissues. BRD4 was strongly expressed in 19.7% of patients but BRD4 staining intensity was not correlated with other clinicopathological factors. Most importantly, patients with a strong BRD4 expression had a significantly longer disease-specific survival than those with a weak BRD4 expression (100.0% vs. 91.3% at 5 years, p=0.027). mRNA expression analysis showed similar results (91.2% vs. 80.2% at 6 years, p=0.047). Conclusion Strong BRD4 expression was associated with a significantly better prognosis in breast cancer tumours.

Background/aim This study aimed to investigate the efficacy of first-line gemcitabine monotherapy for metastatic breast cancer (MBC) and its effect on health-related quality of life (HRQoL) compared with treatment of physician's choice (TPC). Patients and methods We enrolled 96 patients into the first-line gemcitabine group (n=47) or other treatment of physician's choice (TPC) group (n=49) from May 2010 to April 2013. HRQoL was evaluated every 4 weeks. Results There was no significant difference in the median time to treatment failure (5.3 vs. 4.6 months, hazard ratio=0.87, p=0.546) and the incidence rates of grade 3/4 haematological toxicity (10.6% vs. 8.1%, p=0.677) and grade 3/4 non-haematological toxicity (4.2% vs. 8.1%, p=0.429) between the gemcitabine and TPC groups. Changes in HRQoL from baseline to 12 weeks were not significantly different. Conclusion Gemcitabine achieves similar efficacy and HRQoL benefit to other chemotherapy and can be used as first-line treatment for MBC.

A 60-year-old woman was not accompanied by any symptom. She had a gallstone which was identified 20 years prior. Ultrasonography performed by a local doctor revealed that the gallbladder was filled with small stones, and the patient was referred to our department for further examination and treatment for gallbladder stone. Tumor markers are elevated. Contrast- enhanced CT revealed gallbladder stones and thickening in the gallbladder body. PET-CT showed abnormal accumulation of FDG-PET with SUVmax 3.6 in the body of the gallbladder. With a diagnosis of gallbladder cancer, extended cholecystectomy and gallbladder bed resection with regional lymph node dissection were performed. The tumor was diagnosed histologically as small cell type neuroendocrine carcinoma of the gallbladder(pT2a[SS], pN0, pStage ⅡA; Japanese society of hepato-biliary-pancreatic surgery, the 7th edition). The postoperative course was uneventful. This patient has been followed up for 8 years without obvious signs of recurrence. R0 resection and lack of lymph node metastasis can allow long- term survival.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can achieve marked future liver remnant (FLR) hypertrophy but this procedure is associated with a risk of mortality due to liver failure because of an insufficient FLR functional increase, a situation comparable to small-for-size syndrome (SFSS) after living-donor liver transplantation (LDLT). The clinical data, morphologic volume changes, and histopathologic and immunohistochemical findings in hepatocytes and bile ductules were compared between ALPPS (n = 10) and LDLT with a risk for SFSS (n = 12). Although the patient characteristics and short-term outcome differed between the groups, the mean hypertrophy ratios with respect to liver volume for the FLR after performing the first-stage ALPPS procedures resembled those in small-for-size grafts after similar time intervals: 1.702 ± 0.407 in ALPPS vs. 1.948 ± 0.252 in LDLT (P = 0.205). The histologic grades for sinusoidal dilation (P = 0.896), congestion (P = 0.922), vacuolar change (P = 0.964), hepatocanalicular cholestasis (P = 0.969), and ductular reaction (P = 0.728) within the FLR at the second-stage operation during ALPPS or implanted graft were all similar between the groups. The hepatic regenerative process may be similar in ALPPS and LDLT using a small-for-size graft. Reducing the hepatic vascular inflow that may be excessive for the FLR volume during the first stage of ALPPS might enhance the functional recovery since measures with a similar effect appear to lessen the likelihood of SFSS.

Background There is limited information on the oncological outcomes of immediate autologous breast reconstruction in the Asian population. This study aimed to evaluate the oncological outcomes of immediate one-stage autologous breast reconstruction using a free perforator flap for breast cancer patients at a single institution in Japan. Methods We retrospectively reviewed 239 patients who underwent immediate one-stage autologous breast reconstruction using a free perforator flap after skin- or nipple-sparing mastectomy. The whole breast was pathologically analyzed in 5-mm sections. Clinical and pathological data were collected from medical records. Results For tumor stage among the 239 patients, 101 (42.3%) had stage 0, 127 (53.1%) had stage I and II, and 11 (4.6%) had stage III. Twenty-three patients (9.6%) had margin involvement in the surgical specimen. Adjuvant chemotherapy was performed in 75 patients (30%), and endocrine therapy was administered in 153 patients (64%). Radiation therapy was performed in 15 patients (6.3%) because of multiple lymph node metastases or margin involvement. With a median follow-up time of 73 mo, local recurrence was found in 3.3%, distant metastases in 2.5%, and contralateral breast cancer in 3.7%. All patients with local recurrence did not receive radiation therapy as adjuvant treatment. Conclusions Among the patients who underwent immediate one-stage autologous reconstruction after breast surgery, 3.3% had local recurrence. For patients with margin involvement, radiation therapy is a promising option.

Background It is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment. Methods The study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated. Results Of the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively). Conclusion TC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC.

COMPARZ study revealed no marked differences in terms of the progression free survival and overall survival between sunitinib and pazopanib treatment. Regarding the quality of life and early tumor shrinkage, pazopanib showed more favorable results than sunitinib treatment. A 70-year-old man underwent right nephrectomy in 2015. In 2017, iliac bone metastasis was found and consequently lung metastasis was developed. Pazopanib (200 mg × 4 tablets) was introduced. He showed no abnormal liver function markers during pazopanib treatment for more than two years and the size and number of lung metastases decreased. We herein report a case of successful control of metastatic renal cell carcinoma for more than two years using pazopanib treatment.

This study aimed to investigate the efficacy of first-line gemcitabine monotherapy for metastatic breast cancer (MBC) and its effect on health-related quality of life (HRQoL) compared with treatment of physician's choice (TPC).We enrolled 96 patients into the first-line gemcitabine group (n=47) or other treatment of physician's choice (TPC) group (n=49) from May 2010 to April 2013. HRQoL was evaluated every 4 weeks.There was no significant difference in the median time to treatment failure (5.3 vs. 4.6 months, hazard ratio=0.87, p=0.546) and the incidence rates of grade 3/4 haematological toxicity (10.6% vs. 8.1%, p=0.677) and grade 3/4 non-haematological toxicity (4.2% vs. 8.1%, p=0.429) between the gemcitabine and TPC groups. Changes in HRQoL from baseline to 12 weeks were not significantly different.Gemcitabine achieves similar efficacy and HRQoL benefit to other chemotherapy and can be used as first-line treatment for MBC.

Backgrounds: Accurate differential diagnosis regarding histological grades of hepatocellular carcinoma (HCC) is critical for targeted treatment and prognostic evaluation. However, the currently used descriptive diagnosis of histological grading have to observe tedious item of neovascularization, stromal invasion, cellular and structural atypia, which have drawbacks of subjectivity and error-prone. Immunohistochemical (IHC) markers-based diagnosis only needs to determine whether there is staining in the cell membrane, cytoplasm and / or nucleus. Using IHC markers targeted heat shock protein (HSP)70, glypican (GPC)3, glutamine synthetase (GS), and organic anion transport peptide (OATP), we sought to establish an easy method for the diagnosis of the histopathological grades and further explore the best efficacy by their combined or independent application.Methods: We retrospectively conducted a study of 157 patients with 200 histologically confirmed HCCs, which were classified into early (n= 45), well (n=31), moderately (n=68), and poorly (n=56) differentiated (diff.) HCC. The sensitivity, specificity, accuracy of HSP70, GPC3, GS and OATP on each histological grade were examined. Results: HSP70 and GPC3 showed difference in most histological grades of HCC ( P < 0.05). GS distinguished early HCC from three other histological grades (p < 0.01). OATP8 only differentiated early HCC from poorly diff. HCC (P=0.019). When any two of the three indicators (HSP, GPC3, and GS) were negatively expressed, the diagnostic efficacy of early HCC was the highest, with an area under the curve (AUC) of 0.802 and accuracy of 80.5%. The optimal efficacy for poorly diff. HCC detection was obtained when both GPC3 and HSP70 were positively expressed (74.4% accuracy; AUC = 0.703). However, for well and moderately diff. HCC, a relative satisfactory AUC value (>0.60) failed to yield either by the independent or combined diagnosis of any IHC indicators.Conclusion: Using GS, HSP70, and GPC3, early and poorly diff. HCC can be properly diagnosed. IHC markers might be a potential alternative tool for histological differential diagnosis of HCC.

Background/aim Aldehyde dehydrogenase 1 (ALDH1) is known as a breast cancer stem cell (CSC) marker. This study aimed to identify genes associated with ALDH1. Materials and methods ALDH1-positive and -negative breast cancer cells were isolated using laser capture microdissection from five tissue samples of ALDH1-positive breast cancer patients. Messenger RNA expression levels were compared between ALDH1-positive and -negative cells. Results We found 104 differentially expressed genes between ALDH1-positive and -negative cells. Gene ontology and pathway analysis revealed that these genes were correlated with CSC functions and pathways. Network analyses identified 10 genes that were closely associated with ALDH1. We validated these 10 genes utilizing The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium cohort, and found that they were associated with ALDH1 expression and correlated with Wnt pathway signaling. Conclusion The 10 genes we identified could be potential targets for CSC therapy of breast cancer.

Background Pathological complete response (pCR) is often achieved by neoadjuvant chemotherapy (NAC), particularly in hormone receptor-negative breast cancer. Contrast-enhanced magnetic resonance imaging (cMRI) is the most reliable imaging modality to evaluate the pathological effect of NAC. Ultrasonography is indispensable to collect representative specimens from the target lesion by core needle biopsy (CNB). This study aimed to evaluate the accuracy of predicting pCR by adding CNB after NAC, in cases with complete clinical response (cCR) diagnosed by cMRI. Methods In this prospective multicentre study, we evaluated patients diagnosed with cCR by cMRI after NAC. Ultrasound-guided CNB (uCNB) using a 14G needle was performed without clip markers under general anaesthesia as planned surgery. Specimens collected by uCNB were compared to those resected surgically and were categorized as (i) no carcinoma (ypT0), (ii) no invasive carcinoma and only residual carcinoma in situ (ypTis) and (iii) residual invasive carcinoma. The concordance of pathological results between the uCNB and surgical specimens was evaluated. Results Of the 83 patients evaluated, 41 (49.4%) and 17 (20.5%) of them had ypT0 and ypTis, respectively. The false negative rates (FNR), sensitivity and specificity for predicting ypT0 by uCNB were 50.0%, 50.0%, 100%, respectively, and those for predicting ypT0+ypTis were 28.0%, 72.0% and 98.3%, respectively. The concordance rates were 74.7% (62/83) for ypT0 and 90.4% (75/83) for ypT0+ypTis. Conclusion In cCR cases diagnosed by cMRI, uCNB was not accurate enough to predict pCR. Additional modalities like clip placements and/or thicker core needles may be required for better prediction.

We attempted to establish an ultrasound (US) imaging-diagnostic system for histopathological grades of differentiation of hepatocellular carcinoma (HCC). We conducted a retrospective study of histopathologically confirmed 200 HCCs, classified as early (45 lesions), well- (31 lesions), moderately (68 lesions) or poorly differentiated (diff.) (56 lesions) HCCs. We performed grayscale US to estimate the presence/absence of halo and mosaic signs, Sonazoid contrast-enhanced US (CEUS) to determine vascularity (hypo/iso/hyper) of lesion in arterial and portal phase (PP), and echogenicity of lesion in post-vascular phase (PVP). All findings were of significance for the diagnosis of some (but not all) histological grades (p < 0.001–0.05). Combined findings with a relatively high diagnostic efficacy for early, poorly and moderately diff. HCC were a combination of absence of halo sign and isoechogenicity in PVP of CEUS (accuracy: 93.0%, AUC: 0.908), hypovascularity in PP (accuracy: 78.0%, area under the curve (AUC): 0.750), and a combination of isovascularity in PP and hypoechogenicity in PVP (accuracy: 75.0%, AUC: 0.739), respectively. On the other hand, neither any individual finding nor any combination of findings yielded an AUC of over 0.657 for the diagnosis of well-diff. HCC. Our study provides encouraging data on Sonazoid CEUS in the histological differential diagnosis of HCC, especially in early HCC, and the effectiveness of this imaging method should be further proved by prospective, large sample, multicenter studies.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can achieve marked future liver remnant (FLR) hypertrophy but this procedure is associated with a risk of mortality due to liver failure because of an insufficient FLR functional increase, a situation comparable to small-for-size syndrome (SFSS) after living-donor liver transplantation (LDLT).The clinical data, morphologic volume changes, and histopathologic and immunohistochemical findings in hepatocytes and bile ductules were compared between ALPPS (n = 10) and LDLT with a risk for SFSS (n = 12).Although the patient characteristics and short-term outcome differed between the groups, the mean hypertrophy ratios with respect to liver volume for the FLR after performing the first-stage ALPPS procedures resembled those in small-for-size grafts after similar time intervals: 1.702 ± 0.407 in ALPPS vs. 1.948 ± 0.252 in LDLT (P = 0.205). The histologic grades for sinusoidal dilation (P = 0.896), congestion (P = 0.922), vacuolar change (P = 0.964), hepatocanalicular cholestasis (P = 0.969), and ductular reaction (P = 0.728) within the FLR at the second-stage operation during ALPPS or implanted graft were all similar between the groups.The hepatic regenerative process may be similar in ALPPS and LDLT using a small-for-size graft. Reducing the hepatic vascular inflow that may be excessive for the FLR volume during the first stage of ALPPS might enhance the functional recovery since measures with a similar effect appear to lessen the likelihood of SFSS.

Purpose: This study aimed to evaluate response to neoadjuvant chemotherapy (NAC) for patients with hormone receptor-negative (HR-negative) breast cancer (BC) to identify subtypes that require anthracycline treatment. Methods: In total, 103 patients with operable HR-negative BC were registered. They were randomely assigned to administration of 6 cycles of docetaxel (75mg/m2) and cyclophosphamide (600 mg/m2) (TC6) or 3 cycles of 5-fluorouracil (500 mg/m2), epirubicin (100mg/m2), and cyclophosphamide (500mg/m2) followed by 3 cycles of docetaxel (100mg/m2) (FEC-D). Cytokeratin (CK) 5/6 and EGFR expression were used to identify basal and non-basal triple-negative (TN) BC. The primary endpoint was pathological complete response (pCR); secondary endpoints were safety, breast-conserving surgery, disease-free survival, and overall survival. Predictive factors of pCR for each regimen were also evaluated. Results: The pCR rate was 36% for FEC-D and 25.5% for TC6, which did not differ significantly (P=0.265). When TN BC was subdivided into basal and non-basal subtypes, the pCR rate in the basal subtype was significantly lower for TC6 (13.6%) than for FEC-D (42.9%) (P=0.033), but did not significantly differ in the non-basal (TC6, 36.4%; FEC-D, 25.0%) and HER2-positive (TC6, 41.7%; FEC-D, 35.7%) cases. The relative dose intensities of epirubicin and docetaxel in FEC-D and docetaxel in TC6 were 96.3±13.0%, 93.5±14.6%, and 93.9±16.3% (mean±SD), respectively. Occurrence of grade ≥2 adverse events was significant in FEC-D-treated patients. Poor appetite (P The rates of breast-conserving surgery were 68.0 and 72.3% for FEC-D and TC6, respectively (P=0.641). Patients achieved pCR had better DFS (log rank test, P = 0.287) and OS (log rank test, P = 0.069), though not significant. Patients treated with FEC-D had better DFS (log rank test, P = 0.107) and OS (log rank test, P = 0.159), though not significant. Among patients with TN BC, those treated with FEC-D had significantly better DFS (log rank test, P = 0.016) and OS (log rank test, P = 0.034) than treated with TC6. Low ALDH1 expression and high topo IIα protein expression were strongly correlated with pCR in FEC-D, with odds ratios (ORs) of 4.33 [95% CI, 1.02–18.38] and 4.08 [0.97–17.2], respectively. ALDH1 was also associated with pCR in TC, OR=3.50 [0.84–14.6]. Other factors, including age, tumor size, nodal status, tumor grade, Ki67, p53, and TOP 2A status were not associated with pCR in either regimen. Conclusions:We found that TC6 was less effective than FEC-D for treating HR-negative BC because it was insufficient for TNBC, particularly for basal BC. This suggests that anthracycline is more important than taxane for basal BC. Additionally, ALDH1 could be a marker for resistance to conventional chemotherapy. Citation Format: Narui K, Ishikawa T, Shimizu D, Tanabe M, Sasaki T, Oba MS, Morita S, Nawata S, Kida K, Mogaki M, Doi T, Tsugawa K, Ogata H, Ota T, Kosaka Y, Sengoku N, Kuranami M, Saito Y, Suzuki Y, Suto A, Arioka H, Chishima T, Ichikawa Y, Endo I, Tokuda Y. A randomized phase II neoadjuvant study comparing docetaxel and cyclophosphamide (TC) with 5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel (FEC-D) for hormone receptor-negative breast cancer: The Kanagawa breast oncology group (KBOG) 1101 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-04.

We describe a case of bowel strangulation caused by massive peritoneal adhesion as a result of effective chemotherapy. A 71-year-old man, who had obstructive descending colon cancer with massive peritoneal metastases and, therefore, received palliative surgery consisting of diverting colostomy and sampling of peritoneal nodules, developed bowel strangulation on day 4 of the 2nd course of chemotherapy, including irinotecan, l-leucovorin, and 5-fluorouracil. Emergent celiotomy showed a massive intraperitoneal adhesion formed around several intestinal loops, which were not observed at the prior surgery. One loop was strangled, but recovered by adhesiotomy alone. Intestinal loops were formed around aggregates of peritoneal nodules as the centers, several of which were then sampled. We closed the abdomen after all intestinal loops were eradicated by total enterolysis. Fortunately, the patient has been doing well and received chemotherapy without recurrent bowel obstruction 10 months after the present episode. Histological findings of the aggregates causing intestinal loops demonstrated extensive necrosis of cancerous tissue surrounded by fibrosis with abundant lymphocyte infiltration. These findings were not observed in the specimen sampled before chemotherapy, suggesting that intestinal loops were caused by inflammatory adhesion occurring around the peritoneal metastases as a result of effectiveness of chemotherapy.

Aldehyde dehydrogenase 1 (ALDH1) has been identified as a breast cancer stem cell marker, but its value as a predictor of prognosis and chemoresistance is controversial. This study investigated the effect of ALDH1 on prognosis and chemoresponse by breast cancer subtype. We immunohistochemically analyzed 653 invasive breast cancer specimens and evaluated correlations among clinicopathological factors, survival status, response to neoadjuvant chemotherapy, and ALDH1 expression. Of 653 specimens, 139 (21.3 %) expressed ALDH1 in tumor cells. ALDH1 expression was correlated significantly with larger tumor size, node metastasis, higher nuclear grade, and with HER2(+) and progesterone/estrogen receptor (HR)(-) subtypes. ALDH1 expression was significantly observed in HER2 type and triple-negative breast cancer (TNBC). Patients with ALDH1(+) cancers had significantly shorter disease-free survival (P 0001) and overall survival (P = 0.044). ALDH1 expression significantly affected prognosis of luminal types, but not TNBC and HER2-enriched types. For the 234 patients treated with neoadjuvant chemotherapy, pathological complete response (pCR) rate was significantly lower in ALDH1(+) cases (13.5 vs. 30.3 %, P = 0.003). pCR and ALDH1 expression were significantly correlated in TNBC patients (P = 0.003). ALDH1(+) breast cancers tended to be aggressive, with poor prognoses. Although ALDH1(+) TNBC showed higher chemoresistance, ALDH1 had significant impact on prognosis in the luminal type but not in TNBC.

Recently, a new entity "myoepithelioma-like tumor of the vulvar region (MELTVR)" was proposed as a rare mesenchymal neoplasm arising in vulvar regions of adult women. While MELTVRs morphologically resemble soft tissue myoepitheliomas and extraskeletal myxoid chondrosarcomas, they have a unique immunohistochemical profile (positive for epithelial membrane antigen and estrogen receptor, negative for S100 protein and glial fibrillary acidic protein, and loss of INI1/SMARCB1 expression), and lack EWSR1 and NR4A3 gene rearrangement, as seen by fluorescence in situ hybridization. MELTVRs are usually well-demarcated tumors, with no reports of extensive infiltrative growth. In the current report, we present an unusual case of MELTVR showing infiltrative growth and harboring only a few estrogen receptor-positive cells, which might indicate a variation in this rare tumor.

Introduction: Retroperitoneal tumor is often seen in urology clinical practice. To diagnose the tumor, tumor specimens must be obtained. However, in some cases, the tumor is penetrated by vessels around the ureter, and it may be difficult to detect the optimal spot for obtaining a specimen, even when performing open surgery. Case Presentation: A 53-year-old male patient was referred to our hospital for further examination of left back pain due to hydronephrosis. Enhanced computed tomography demonstrated ureter stenosis in front of the ilium, which was surrounded by a retroperitoneal tumor. The tumor was penetrated by blood vessels; therefore, we performed an open surgical biopsy on the suspicion of a retroperitoneal tumor using ureteroscopic assistance. The diagnosis of idiopathic retroperitoneal fibrosis was made according to the biopsy. Conclusion: We herein report the first case of a ureteroscopy-assisted biopsy for the pathological diagnosis of a retroperitoneal tumor.

[Background]Aldehyde dehydrogenase 1 (ALDH1) has been identified as a breast cancer stem cell marker. The clinical significance of ALDH1 as a chemo-resistant and prognostic indicator has been reported recently. However, the analysis according to each intrinsic subtype was not reported. [Aims] To investigate the impact of ALDH1 on chemo-resistance and prognosis according to intrinsic subtypes in invasive breast cancers. [Methods] 1) Patients and tumor specimens; A total of 653 primary breast cancer patients were enrolled in this study from 2004 to 2013 at the Yokohama City University Medical Center in Japan. We performed immunohistochemical analyses using paraffin-embedded core needle biopsy sections prior to the treatment. 2) Correlation of ALDH1 with clinicopathological factors; Analyses were performed to investigate association of ALDH1 expression with other biomarkers and clinicopathological factors in breast cancers. Age, histologic type, tumor size, nodal status, ER/PgR/HER2 status, nuclear grade, Ki67, Topo2, p53, CK5/6 and EGFR were observed. 3) Neoadjuvant patient cohort study 234 breast cancer patients receiving neoadjuvant chemotherapy were enrolled. The correlation between ALDH1 and pathological complete response (pCR) rate was investigated in each intrinsic subtype. 4) Prognostic cohort study We performed a Cox analysis of disease free survival and overall survival of all 653 cases according to each subtype, taking account of clinicopathological factors. [Results] ALDH1 expression in tumor cells was seen in 139 of 653 cases (21.3%). The ALDH1 expression correlated significantly with tumor size, clinical node metastasis, clinical staging, nuclear grade and HER2 status positively, ER and PgR status negatively. ALDH1 expression was significantly seen in HER2-positive cancers and triple negative type. In neoadjuvant study, we analyzed 234 patients treated with neoadjuvant chemotherapy including 63 luminal type, 20 luminal-HER2 type, 45 HER2-enriched type and 106 triple negative type. The pCR rate was significantly lower in patients with ALDH1-positive cases (13.5%vs.30.3%,p=0.003). In multivariate analysis, ALDH1 and ER are correlated with pCR rate significantly. According to the intrinsic subtypes, the correlation between pCR and ALDH1 expression was extremely significant in triple negative type (p=0.003). In HER2 positive type, ALDH1 expression had tendency with low pCR, but with no significance. In luminal type, two patients achieved pCR and both had no ALDH1 expression. In prognostic analysis, patients with ALDH1 expression had significantly poor disease free survival (DFS; p [Conclusions] Breast cancers with ALDH1 expression posse biologically aggressive phenotypes that tend to have a poor prognosis. Chemoresistance was significantly seen in ALDH1-positive triple negative type, on the other hand, impact on prognosis was seen in luminal type more highly than triple negative type. Citation Format: Kumiko Kida, Takashi Ishikawa, Akimitsu Yamada, Kazutaka Narui, Sadataka Sugae, Mikiko Tanabe, Yasushi Ichikawa, Itaru Endo. The impact of ALDH1 on chemo-resistance and prognosis according to intrinsic subtype in breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-06-16.

BACKGROUND: Triple negative breast cancer (TNBC) is heterogeneous and consists of tumors associated with basal like, BRCA related and cancer stem cell (CSC) phenotypes. Although anti-cancer agents are substantial for treating TNBC, existing ones do not work in some subpopulation in TNBC at all. However, it has not been reported that subdivision of TNBC is useful for choosing ant-cancer agents. AIM: To examine whether subdividing TNBC is beneficial for tailored chemotherapy and to identify predictive factors for existing anti-cancer agents in TNBC. METHODS: Sixty-six TNBC cases from a randomized phase II trial comparing TCx6 (TC6) with FEC followed by docetaxel (FEC-D) as neoadjuvant chemotherapy for hormone receptor-negative breast cancer (Kanagawa Breast Oncology Group 1101 Study). TNBC was subdivided by 1) IHC of CK 5/6 and EGFR into basal- and non-basal subtypes, and 2) MLPA of BRCA1 into BRCA1 and non-BRCA1 subtypes. The pCR rates were examined according to each regimen and subtype. 3) The association of grade 3 pCR was examined with Ki-67, p53, aldehyde dehydrogenase (ALDH) 1 and topoisomerase 2A (topoIIα) by IHC and TOP2A by FISH for each regimen. RESULTS: 1) In basal subtype, the pCR rate was significantly higher for FEC-D (42.9%) compared with TC6 (13.6%) (p=0.033), but it was equivalent in non-basal subtype (FEC-D vs TC: 25.0% vs 36.4%, p=0.554). 2) In BRCA1 subtype, it was more significant (FEC-D vs TC: 53.8 % vs 13.3%, p=0.022). 3) An association between pCR and low ALDH1 expression was found in both FEC-D and TC6 (OR: 3.75 and 2.73). High topo IIα protein expression was associated with pCR in FEC-D (OR: 3.5). DISCUSSION: TC6 was less effective than FEC-D in basal subtype and BRCA1 subtype, showing that taxanes cannot exert their anticancer role in tumors with BRCA1 dysfunction. Although basal subtype may contain more BRCA1-defective tumors than non-basal subtype, MLPA of BRCA1 was better to identify subtype resistant to taxanes than CK5/6 and EGFR. ALDH1 predicted treatment efficacy, and could therefore represent a marker of resistance to conventional chemotherapy. Citation Format: Takashi Ishikawa, Kazutaka Narui, Kazuhiro Shimada, Kumiko Kida, Mari S Oba, Mikiko Tanabe, Yasushi Ichikawa, Sadatoshi Sugae, Itaru Endo. BRCAness is important to identify TNBC subtype resistant to taxanes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-27.

Background We compared clinical outcomes of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) against those of classical 2-stage hepatectomy in treating metastatic liver disease. Methods Short-term outcomes, serial changes in volume of the future liver remnant (FLR), functional FLR volume, and tumor growth activity during the treatment period, were compared between our first 11 consecutive patients treated with ALPPS and 54 patients treated with classical 2-stage hepatectomy. Results Mortality in the ALPPS group (9%) tended to be higher than in the classical 2-stage group (2%, P = 0.341). The FLR hypertrophy ratio (FLR volume after vs. before the procedure) 1 week after the first operation in the ALPPS group (1.54 ± 0.18) exceeded that in the classical 2-stage group (1.19 ± 0.29, P = 0.005), being similar to the ratio at 3 weeks after the first procedure in the classical 2-stage group (1.40 ± 0.43). However, functional volume of the FLR in the ALPPS group 1 week after the first procedure (52.1%) tended to be smaller than that in the classical group 3 weeks after the first procedure (59.2%). Conclusions ALPPS should be used with extreme caution, giving special attention to postoperative complications and grade of functional liver regeneration.

Background Although sentinel lymph node biopsy (SLNB) is a standard staging method for assessing nodal status of breast cancer patients, SLNB after neoadjuvant chemotherapy (NAC) remains controversial. The aim of this study was to validate the practicality and accuracy of SLNB by our modified Indigocarmine blue dye methods following NAC. Methods One hundred consecutive cases with breast cancers treated by NAC were enrolled in this study. After NAC, all patients underwent SLNB performed by our modified Indigocarmine blue dye methods without radioisotope, followed by back-up axillary lymph node dissection (ALND). Results Sentinel nodes (SNs) were identified in 94 cases (identification rate, 94%); the accuracy was 94.7% (89/94 cases); and the false negative rate (FNR) 13.5% (5/37 cases). For cases with vs. without clinically evident metastatic nodes before NAC, the identification rate was 92.4% (61/66 cases) vs. 97.1% (33/34 cases); the accuracy 91.8% (56/61 cases) vs. 97.0% (32/33 cases) and the FNR 16.1% (5/31 cases) vs. 0% (0/6 case), respectively. There were six patients without identified SNs, three of them had metastatic nodes. False negatives occurred in five cases; in four, fewer than two sentinel nodes had been removed. Conclusion Following NAC, the accuracy of SLNB by modified Indigocarmine blue dye methods is adequate compared with other tracers. In patients in whom no SNs have been identified, lymphatic metastasis is likely and therefore ALND is recommended. For patients with cN0 prior to NAC, SLNB by modified Indigocarmine blue dye methods is clinically feasible, though controversial for patients with positive nodes.

Background: Taxane-based regimens have been developed and used widely to treat breast cancer. It has therefore become important to identify subgroups of patients in which anthracyclines are indispensable. Pathological response to neoadjuvant chemotherapy (NAC) predicts prognosis in hormone-negative subtypes. We therefore initiated a randomized phase II NAC study to compare a taxane with and without an anthracycline in these breast-cancer subtypes. Aim: To determine the safety and activity of six cycles of docetaxel and cyclophosphamide (TC6) compared with 5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel (FEC-D), and to examine the predictive factors for each regimen. Methods: Eligibility criteria were operable hormone-receptor-negative breast cancer, age younger than 75 years and ECOG PS0-1. According to HER2 status, patients were randomly assigned to TC (75/600 mg/m2) every 3 weeks X 6 or FEC (500/100/500 mg/m2) every 3 weeks X 3 followed by D (100 mg/m2) every 3 weeks X 3. The primary endpoint was the rate of pathological complete response (pCR; grade 3). Triple-negative (TN) breast cancer was subdivided by cytokeratin 5/6 and epidermal growth factor receptor into basal- and non-basal subtypes. Secondary endpoints were safety, breast-conserving surgery, disease-free survival, overall survival, and predictive factors: Ki-67, p53, aldehyde dehydrogenase (ALDH) 1 and topoisomerase 2A by both immunohistochemistry and fluorescence in situ hybridization for each regimen. Results: Ninety-seven of 103 patients were analyzed successfully (50 for FEC-D and 47 for TC6). Significantly more severe adverse events (grade 2) were observed in FEC-D-treated patients (poor appetite, nausea and vomiting: p = 0.001; febrile neutropenia: p = 0.016). The pCR rate tended to be higher in FEC-D-treated patients compared with TC6-treated patients (pCR: 36.0 vs. 25.5%, n.s.). FEC-D treatment was significantly more effective than TC6 in basal-type (p = 0.033) but not in non-basal and HER2 subtypes. ALDH1 was associated with resistance to both regimens (FEC-D: p = 0.047, TC6: p = 0.085) Conclusions: TC6 was safer, but not more effective than FEC-D. TC6 was significantly less active than FEC-D in basal subtype, and equivalent to FEC-D in HER2 and non-basal subtypes. Concurrent use of trastuzumab with TC could thus represent a reasonable option for NAC in HER2-subtype patients. ALDH1 could provide a marker for novel strategies such as stem cell-based therapies for breast cancer. Analyses on pathological factors in surgical specimens after NAC will be presented at the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-08.

Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors and pulmonary cysts with repeated pneumothorax. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is known to be involved in the signaling of mammalian target of rapamycin (mTOR). We investigated the lung of a BHD patient who presented with a unique mutation. A 33-year-old woman visited our hospital due to repeated pneumothorax. Histopathologic study of the resected lung demonstrated multiple epithelial cysts. An increase of blood vessels was observed in the vicinity of subpleural cysts. Genomic DNA analysis revealed heterozygous mutation at the 3' end of intron 5 of the FLCN gene. Total mRNA and protein were extracted from the resected lung tissue. RT-PCR and sequence analysis demonstrated the production of exon 6-skipped FLCN mRNA. In Western blotting, the band intensities of phospho-mTOR, phospho-S6, phospho-Akt, hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were increased in the BHD lung compared with normal lungs. Histopathologic analysis demonstrated strong immunostainings of mTOR signaling molecules in cyst-lining cells. Collective data indicates that dysregulation of mTOR signaling facilitates S6-mediated protein synthesis and HIF-1α-mediated angiogenesis, which may contribute to the development of pulmonary cysts in this disorder.

Breast cancer is not a single entity. This study therefore aimed to identify differences in the impacts of anticancer agents and predictive factors between different breast cancer subtypes. A total of 234 patients with luminal (n = 109), luminal-HER2 (L-H, n = 29), HER-2 (n = 35), or triple negative (TN, n = 61) breast cancer subtypes were treated with standard neoadjuvant chemotherapy consisting of an anthracycline and/or taxane. Pathological response and prognosis were examined in each subtype. Expression levels of estrogen and progesterone receptors, HER-2, nuclear grade, MIB-1, p53, topoisomerase IIalpha (topoIIalpha), cytokeratin (CK) 5/6, and epidermal growth factor receptor (EGFR) were examined in association with quasipathological complete response (QpCR). QpCR rates were 9.1% (10/109) in luminal, 45% (13/29) in L-H, 37% (13/35) in HER2, and 54.1% (33/61) in TN. Non-QpCR patients showed significantly poorer 3-year disease-free survival than QpCR patients in TN, but not in patients with other subtypes. No factors were associated with QpCR in luminal patients. Patients with higher nuclear grade were more likely to achieve QpCR in L-H. The proliferative markers MIB-1 and topoIlalpha had opposite impacts on pathological response in HER-2 and TN. The QpCR rate was significantly higher in TN lacking CK5/6 and/or EGFR expression, defined as nonbasal subtype, compared with basal subtype (p = 0.049). Cytotoxic anticancer agents were associated with different responses in different breast cancer subtypes. Identifying basal-type cancer and further subdivision of nonbasal types is important for treating TN patients.

Background Human epidermal growth factor receptor (HER2)-negative breast cancers are more heterogeneous than HER2−positive cancers, and tailored treatment is therefore required for luminal A and triple-negative breast cancer subtypes (LABC and TNBC). We therefore examined predictive factors for the efficacy of standard chemotherapy in LABC and TNBC subtypes. Methods A total of 109 LABC and 61 TNBC patients were treated with standard neoadjuvant chemotherapy (NAC) consisting of an anthracycline and/or taxane. The pathological treatment response and prognosis were examined for each subtype. Expression levels of the following factors were examined in association with quasi-pathological complete response (QpCR): estrogen- and progesterone-receptor (ER and PgR) status, HER2, nuclear grade, MIB-1, p53, topoisomerase IIα (topoIIα), cytokeratin (CK) 5/6 and epidermal growth factor (EGFR). Results QpCR rates in LABC and TNBC were 9.1% (10/109) and 54.1% (33/61), respectively. In LABC, the expression of PgR tended to be inversely associated with pathological response (p=0.087), while in TNBC, increased expression of topoIIa (p=0.006) and MIB-1 (p=0.018) were identified as predictors of QpCR. TopoIIα expression was also significantly associated with pathological response in multivariate analysis (p=0.014). The QpCR rate was higher in TNBC lacking CK5/6 and/or EGFR expression, defined as non-basal subtype (p=0.053). Conclusions Low expression of PgR may be a possible predictor of the efficacy of chemotherapy in LABC, while a high level of proliferative activity, indicated by topoIIa and MIB-1, is associated with chemosensitivity in TNBC. Further subclassification into basaland non basal-subtypes may also be helpful for the development of individualized treatments. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-23.

Objective: We investigated the pathological effects of neoadjuvant chemotherapy based on the human epidermal growth factor receptor 2 in operable breast cancer. Methods: This prospective clinical study was a pilot involving 63 female patients. Before surgery, patients with tumors overexpressing human epidermal growth factor receptor 2 received four cycles of 60 mg/m 2 anthracycline and 600 mg/m 2 cyclophosphamide every 3 weeks, whereas those whose tumors did not overexpress human epidermal growth factor receptor 2 received four cycles of 75 mg/m 2 docetaxel and 600 mg/m 2 cyclophosphamide every 3 weeks. A quasi-pathological complete response (i.e. absence of invasive tumor or only focal residual tumor cells) was the primary endpoint, with compliance and predictors for each regimen as secondary endpoints. If a quasi-pathological complete response was not achieved, then crossover to the alternative treatment was recommended. Results: The quasi-pathological complete response rate was 36.5% (23 of 63) overall, 27.8% (5 of 18) for the anthracycline and cyclophosphamide regimen and 40.0% (18 of 45) for the docetaxel and cyclophosphamide regimen. Docetaxel and cyclophosphamide treatment induced a quasi-pathological complete response in most patients with triple-negative tumors (15 of 19). The relative dose intensity was 97.3% for the anthracycline and cyclophosphamide regimen and 96.6% for the docetaxel and cyclophosphamide regimen. Quasi-pathological complete response to the docetaxel and cyclophosphamide regimen was associated with low estrogen receptor and progesterone receptor expression and high MIB-1 and topoisomerase IIa expression, in univariate analyses, but only with low estrogen receptor expression in multivariate analysis. Conclusions: Selecting neoadjuvant chemotherapy regimens on the basis of individual human epidermal growth factor receptor 2 status improved efficacy, with docetaxel and cyclophosphamide treatment showing particular promise in tumors with the potential to be highly malignant.

Lambert–Eaton myasthenic syndrome (LEMS) is a paraneoplastic syndrome and only 3% of small cell lung carcinoma (SCLC) patients have LEMS. Moreover, the recurrence of SCLC after a disease-free survival (DFS) of more than 10 years is rare. We report a patient who had a recurrence of both SCLC and LEMS after a 13-year DFS period. A 69-year-old man was diagnosed with LEMS and SCLC (cT0N2M0, stage IIIA) 13 years ago. Chemoradiotherapy was performed and a complete response was achieved. With anticancer treatment, the LEMS symptoms was alleviated. At the age of 82 years, gait disturbance appeared followed by left supraclavicular lymphadenopathy and further examination revealed the recurrence of SCLC. Careful screening for the recurrence of SCLC might be needed when the patient has recurrent or secondary paraneoplastic neurological syndrome even after a long DFS period.

We aimed to clarify which breast cancer subtypes respond best to docetaxel/cyclophosphamide chemotherapy (TC) as neoadjuvant chemotherapy (NAC).We analyzed pathological responses, clinicopathological characteristics and biological markers (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2), Ki-67, p53, topoisomerase IIα, class III β tubulin, cytokeratin 5/6, epidermal growth factor receptor (EGFR)) in specimens from 79 patients who received NAC-TC.Out of 79 patients, 33 (41.8%) achieved quasipathological complete responses (QpCR). Univariate analysis associated negative ER (p0.001), negative PR (p=0.007), triple-negative subtype (TNBC; p=0.001), high Ki-67 (p=0.022) and low class III β tubulin (p=0.032) with QpCR. Multivariate analyses associated only negative ER (p=0.050) and low class III β tubulin (p=0.028) and only non-basal subtype in TNBC with QpCR.NAC-TC may be especially effective in ER-breast cancer with low class III β tubulin or non-basal TNBC.

HER2-positive breast cancer sensitivity to anthracyclines is enhanced when topoisomerase IIα (TOP2A) is co-amplified under both adjuvant and metastatic settings. However, the relationship between anthracycline sensitivity and TOP2A amplification in HER2-positive breast cancers in neoadjuvant settings is not known.The TOP2A gene status was examined by FISH in biopsies from 18 patients who received anthracycline and cyclophosphamide before surgery.The TOP2A gene was amplified in 6/17 patients and was significantly associated with pathological response to the chemotherapy regimen.TOP2A amplification could predict anthracycline-sensitivity. Thus, the HER2/TOP2A co-amplified subtype may be effectively treated by anthracycline-containing regimens alone.

Primary Hepatic Epithelioid Hemangioendothelioma (HEH) is a rare, low-grade, malignant hepatic neoplasm. Here we present the typical CT and MRI features of HEH in a 35 year old young woman, which were confirmed by needle biopsy. The most significant CT and MRI imaging findings were capsular retraction and peripheral location with slow progression. In addition, there were multiple hypermetabolic liver tumors seen on FDG-PET/CT and hepatic arterial penetration of the tumor on Dynamic CT (DCT), which may be useful in the diagnosis of HEH.

The aim of this study was to assess the prognostic impact of the number of lymph node metastases. The medical records of 33 patients with node-positive gallbladder cancer (GBC) treated at our institution from January 1985 through December 2002 were reviewed. There were 10 cases with a single node metastasis. The sites were as follows: the cystic duct node, the pericholedochal node, the retroportal node, the hilar node, the lymph node around the common hepatic artery, and the paraaortic node. According to the International Union Against Cancer (UICC) 5th edition, 5-year survival rates for the patients with pN1, pN2, and greater than pN2 were 19.2%, 10%, and 0%, respectively (not significant). Patients with a single node metastasis had a higher 5-year survival rate (33%) than patients with two or more lymph node metastases (0%; P < 0.05). There were no lymph node recurrences in patients with a single node metastasis. Number of positive nodes and liver metastasis were factors predictive of significantly worse survival. Rather than using the topographic classification, or even simply classifying whether nodal involvement is positive or negative, classification according to the number of positive nodes will contribute to establishing a more practically useful staging system.