Current status of the surgical training system in Japan: results of a nationwide questionnaire survey of graduating surgical trainees.

PURPOSE: To identify the problems trainees face during surgical training in Japan. METHODS: A nationwide online questionnaire survey was conducted targeting newly certified surgical trainees. RESULTS: The response rate was 53.8% (758/1410). Among those respondents, 25.6% were women, 71.4% were either married or had a partner, 41.3% had children, 72.7% had performed over 200 surgeries under general anesthesia, and 54.1% had chosen, before graduating from medical school, to become a surgeon. While 88.8% were interested in learning surgical techniques, 63.8% were hesitant to become a surgeon for fear of a compromised quality of private life (QOL). Conversely, only 1.4% chose their surgical training programs based on QOL. Overall, 84.6% of the trainees were satisfied with their training and this correlated with the number of surgeries performed. Only 29.9% received non-technical skill training. The average number of night shifts per month was 5.6, and 10.6% worked over 80 h per week. Harassment was reported by 41.5% of the respondents. Moreover, 33.0% had considered dropping out at some time, primarily because of their QOL (51.1%) or the harassment they had encountered (50.4%). CONCLUSION: This survey revealed that while trainees were satisfied with the overall training system, issues such as long working hours and harassment are prevalent. Working to improve these issues could make surgery more attractive for young trainees.

2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting.

PURPOSE: This review is an update of the MASCC/ESMO 2015 recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting. METHODS: A systematic literature search was conducted using PubMed from June 1, 2015, through February 1, 2023. RESULTS: We identified 56 references (16 were duplications or invalid), leaving 40 manuscripts for this search. The panel classified level I evidence (three manuscripts) and level II evidence (14 manuscripts). High-dose chemotherapy and stem cell transplant were discussed in four of these manuscripts, and multiple-day chemotherapy treatment in 15. Some manuscripts covered both topics. Additionally, a search for breakthrough nausea and vomiting resulted in 12 "hits." No new relevant studies were identified. CONCLUSIONS: The recommendations for patients receiving high-dose chemotherapy with stem cell transplants and patients undergoing multiple-day cisplatin were updated. For patients receiving high-dose chemotherapy for stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and aprepitant is recommended. Olanzapine could be considered part of the antiemetic regimen. Patients receiving multiple-day cisplatin should receive a 5-HT3 receptor antagonist plus dexamethasone plus aprepitant plus olanzapine. For patients experiencing breakthrough nausea and vomiting, the available evidence suggests using a single dose of olanzapine daily for 3 days.

The degree of satisfaction and level of learning in male and female surgical residents: a nationwide questionnaire survey of graduating residents in Japan.

PURPOSE: Since 2002, the Japan Surgical Society has established a board certification system for surgeons to be certified for a specialty. Surgery remains a male-dominated field in Japan. This study aimed to clarify if the Japanese surgical residency training system is equally suitable for female and male residents. METHODS: The Japan Surgical Society conducted the first questionnaire survey regarding the system of surgical training for the residents in 2016. The questionnaire included the degree of satisfaction with 7 aspects of the training system, including the number and variety of cases experienced and duration and quality of instruction, and the learning level for 31 procedures. The degree of satisfaction and level of learning were compared between female and male residents. RESULTS: The degree of satisfaction was similar for all items between female and male residents. Female residents chose breast surgery as their subspecialty more frequently than male residents and were more confident in breast surgery procedures than male residents. Conversely, fewer female residents chose gastrointestinal surgery and were less confident in gastrointestinal surgery procedures than male residents. CONCLUSION: Female residents were as satisfied with the current surgical training system as male residents. However, there may be room for improvement in the surgical system, considering that fewer applications for gastrointestinal surgery come from female residents than from males.

High platelet-to-lymphocyte ratios in triple-negative breast cancer associates with immunosuppressive status of TILs.

BACKGROUND: Rating lymphocytes (TILs) are a prognostic marker in breast cancer and high TIL infiltration correlates with better patient outcomes. Meanwhile, parameters involving immune cells in peripheral blood have also been established as prognostic markers. High platelet-to-lymphocyte ratios (PLRs) and neutrophil-to-lymphocyte ratios (NLRs) are related to poor outcomes in breast cancer, but their mechanisms remain unknown. To date, TILs and these parameters have been examined separately. METHODS: We investigated the relationship between TILs and the peripheral blood markers, PLR and NLR, in the same patients, using surgical specimens from 502 patients with invasive breast carcinoma without preoperative chemotherapy. For analysis of triple-negative breast cancer (TNBC) patient outcomes, 59 patients who received preoperative chemotherapy were also examined. For immune cell profiling, multiplexed fluorescent immunohistochemistry (mfIHC) of CD3, CD4, CD8, FOXP3 and T-bet, was conducted. RESULTS: A positive correlation between PLR and TIL was observed in TNBC (P = 0.013). On mfIHC, tumors in patients with high PLR and NLR contained more CD3+CD4+FOXP3+ T-cells (P = 0.049 and 0.019, respectively), while no trend was observed in CD8+ T-cells. TNBC patients had different patterns of outcomes according to TIL and PLR, with the TIL-high/PLR-low group having the lowest rate of disease relapse and death, and the longest distant metastasis-free and overall survivals, while the TIL-low/PLR-high group had the shortest survivals. CONCLUSIONS: Our data suggest that the combination of PLR with TIL assessment may enable more accurate prediction of patient outcomes with TNBC.

Involvement of kallikrein-PAR2-proinflammatory pathway in severe trastuzumab-induced cardiotoxicity.

Trastuzumab-induced cardiotoxicity interferes with continued treatment in approximately 10% of patients with ErbB2-positive breast cancer, but its mechanism has not been fully elucidated. In this study, we recruited trastuzumab-treated patients with ≥30% reduction in left ventricular ejection fraction (SP) and noncardiotoxic patients (NP). From each of these patients, we established three cases of induced pluripotent stem cell-derived cardiomyocytes (pt-iPSC-CMs). Reduced contraction and relaxation velocities following trastuzumab treatment were more evident in SP pt-iPSC-CMs than NP pt-iPSC-CMs, indicating the cardiotoxicity phenotype could be replicated. Differences in ATP production, reactive oxygen species, and autophagy activity were observed between the two groups. Analysis of transcripts revealed enhanced kallikrein5 expression and pro-inflammatory signaling pathways, such as interleukin-1ß, in SP pt-iPSC-CMs after trastuzumab treatment. The kallilkrein5-protease-activated receptor 2 (PAR2)-MAPK signaling pathway was more activated in SP pt-iPSC-CMs, and treatment with a PAR2-antagonist suppressed interleukin-1ß expression. Our data indicate enhanced pro-inflammatory responses through kallikrein5-PAR2 signaling and vulnerability to external stresses appear to be the cause of trastuzumab-induced cardiotoxicity in SP.

Brca1L63X /+ rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer.

Women who are heterozygous for deleterious BRCA1 germline mutations harbor a high risk of hereditary breast cancer. Previous Brca1-heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary-specific homozygous Brca1 loss or addition of Trp53 deficiency. Herein, we report the creation and characterization of a novel Brca1 mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR-Cas9-based genome editing. Homozygotes (Brca1L63X/L63X ) were embryonic lethal, whereas heterozygotes (Brca1L63X/+ ) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild-type (WT) littermates during their lifetime. Intraperitoneal injection of 1-methyl-1-nitrosourea (25 or 50 mg/kg) at 7 weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1-2 Gy) at 7 weeks of age, the heterozygotes, but not WT littermates, displayed dose-dependent mammary carcinogenesis with 0.8 Gy-1 excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3 weeks of age. The heterozygotes had tumors with a lower estrogen receptor α immunopositivity and no evidence of somatic mutations of the WT allele. The Brca1L63X/+ rats thus offer the first single-mutation, heterozygous model of BRCA1-associated breast cancer, especially with exposure to a DNA break-inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high-risk BRCA1 mutations.

Absolute lymphocyte count decreases with disease progression and is a potential prognostic marker for metastatic breast cancer.

PURPOSE: Peripheral blood parameters such as the neutrophil-to-lymphocyte ratio (NLR) are prognostic markers for breast cancer patients. For instance, patients with a high NLR have a poor prognosis. Meanwhile, high absolute lymphocyte count (ALC) is reportedly a predictive factor for some chemotherapies. However, the underlying mechanisms behind how these markers relate to patient outcomes and how these markers change during the clinical course of patients with metastatic breast cancer (MBC) remains unknown. METHODS: We retrospectively investigated 156 patients who were treated for MBC and eventually transitioned to best supportive care (BSC) at our hospital between January 2017 and December 2021. Changes in peripheral blood parameters during MBC treatments and their association with patient outcomes were examined. RESULTS: From the time of MBC diagnosis (baseline) through to the transition to BSC, ALC became significantly lower, while the NLR and platelet-to-lymphocyte ratio (PLR) became significantly higher (p < 0.001 for all). This association was independent of hormone receptor status. Cox proportional hazard modeling found patients with hormone receptor-negative and a lower baseline ALC had a significantly shorter overall survival (p = 0.030 and p = 0.019, respectively). CONCLUSION: We observed that peripheral blood markers gradually changed with MBC disease progression. Our data suggest that baseline ALC may be a potential prognostic marker after recurrence.

Comparison of tumors with HER2 overexpression versus HER2 amplification in HER2-positive breast cancer patients.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive tumors are defined by protein overexpression (3+) or gene amplification using immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), respectively. HER2-positive tumors have historically included both IHC(3+) and IHC(2+, equivocal)/FISH(+) tumors and received the same treatment. Differences in biology between these two tumor types, however, are poorly understood. Considering anti-HER2 drugs bind directly to HER2 protein on the cell surface, we hypothesized anti-HER2 therapies would be less effective in IHC(2+)/FISH(+) tumors than in IHC(3+) tumors, leading to differences in patient outcomes. METHODS: A total of 447 patients with HER2-positive invasive carcinoma who underwent curative surgery were retrospectively investigated. HER2 status was assessed in surgical specimens, except in patients who received neo-adjuvant chemotherapy, where biopsy specimens were employed. RESULTS: Age, tumor size, lymph node status and ER status were independent factors relating to disease-free-survival, but no difference was observed between IHC(3+) and IHC(2+)/FISH(+) tumors. Kaplan-Meier analysis found patient outcomes did not differ, even after stratifying into those that did (n = 314), or did not (n = 129), receive chemotherapy with anti-HER2 drugs. In 134 patients who received NAC, pathological complete response rates in IHC(3+) and IHC(2+)/FISH(+) tumors were 45% and 21%, respectively. Survival after developing metastasis was significantly shorter in the IHC(2+)/FISH(+) group. CONCLUSIONS: The prognosis of patients with IHC(2+)/FISH(+) tumors did not differ from IHC(3+) tumors. However, the significance of HER2 protein overexpression in relation to treatment response remains unclear and warrants further investigations.

Depressive and anxiety symptoms among Japanese cancer survivors: Japan cancer survivorship research project.

BACKGROUND: This study aimed to clarify predictors of depressive symptoms and anxiety symptoms after cancer diagnosis among Japanese cancer survivors (CSs). METHODS: As part of a Japanese cancer survivorship research project commissioned by the Ministry of Health, Labour and Welfare (MHLW) of Japan, we conducted a web-based nationwide survey of CSs in 2018. We analyzed the risk factors for depressive and anxiety symptoms, as measured by the Hospital Anxiety and Depression Scale Japanese version (HADS). RESULTS: Of 1,234 Japanese CSs, mean score of HADS-depression and HADS-anxiety were 4.08 and 4.78, respectively. At the time of the study, the number of CSs with symptoms of depression and anxiety were 111 (9.0%) and 269 (21.8%), respectively. After multivariable analysis, CSs ≥ 60 years old (reference: ≤ 39 years old, odds ratios (OR): 0.39, 95%CI: 0.17-0.90) and those ≥ 10 years from cancer diagnosis (reference: 0-4 years, OR: 0.55, 95%CI: 0.32-0.96) had lower odds for depressive symptoms. And CSs ≥ 60 years old (reference: ≤ 39 years old, OR: 0.27, 95%CI: 0.15-0.49) and those ≥ 10 years from cancer diagnosis (reference: 0-4 years, OR: 0.62, 95%CI: 0.42-0.90) also had lower odds for anxiety symptoms. CSs who received chemotherapy (OR: 1.56, 95%CI: 1.10-2.20) had higher odds for anxiety symptoms. CONCLUSIONS: Based on manifestation of symptoms, CSs who were younger, closer to the time of cancer diagnosis, had advanced-staged cancer, or received chemotherapy may be at higher risk for depressive or anxiety symptoms. Those CSs who have higher risk for depression and anxiety symptoms, should be followed-up more carefully for better cancer survivorship, by medical professionals, companies, and society.

Short somatic alterations at the site of copy number variation in breast cancer.

Copy number variation (CNV) is a polymorphism in the human genome involving DNA fragments larger than 1 kb. Copy number variation sites provide hotspots of somatic alterations in cancers. Herein, we examined somatic alterations at sites of CNV in DNA from 20 invasive breast cancers using a Comparative Genomic Hybridization array specifically designed to detect the genome-wide CNV status of approximately 412 000 sites. Somatic copy number alterations (CNAs) were detected in 39.9% of the CNV probes examined. The most frequently altered regions were gains of 1q21-22 (90%), 8q21-24 (85%), 1q44 (85%), and 3q11 (85%) or losses of 16q22-24 (80%). Gene ontology analyses of genes within the CNA fragments revealed that cascades related to transcription and RNA metabolism correlated significantly with human epidermal growth factor receptor 2 positivity and menopausal status. Thirteen of 20 tumors showed CNAs in more than 35% of sites examined and a high prevalence of CNAs correlated significantly with estrogen receptor (ER) negativity, higher nuclear grade (NG), and higher Ki-67 labeling index. Finally, when CNA fragments were categorized according to their size, CNAs smaller than 10 kb correlated significantly with ER positivity and lower NG, whereas CNAs exceeding 10 Mb correlated with higher NG, ER negativity, and a higher Ki-67 labeling index. Most of these findings were confirmed or supported by quantitative PCR of representative DNA fragments in 72 additional breast cancers. These results suggest that most CNAs are caused by gain or loss of large chromosomal fragments and correlate with NG and several malignant features, whereas solitary CNAs of less than 10 kb could be involved in ER-positive breast carcinogenesis.

Predictors of resignation and sick leave after cancer diagnosis among Japanese breast cancer survivors: a cross-sectional study.

BACKGROUND: In Japan, 55.5% of breast cancer survivors (BCSs) are of working age, so various perspectives regarding return to work (RTW) after cancer diagnosis need to be considered. Therefore, this study aimed to clarify the risk factors for resignation and taking sick leave (SL) among BCSs in continued employment at the time of diagnosis. METHODS: A web-based retrospective cross-sectional survey was conducted on BCSs using data from a 2018 Japanese national research project (Endo-Han) commissioned by the Ministry of Health, Labour and Welfare of Japan. The subjects were women aged 18-69 years who had been diagnosed with breast cancer for the first time at least 1 year previously. The risk factors for resignation and taking SL after breast cancer diagnosis, including age at diagnosis, education level, cancer stage, surgery, chemotherapy, radiotherapy, employment status, and occupational type, were then analyzed using a logistic regression model. RESULTS: In total, 40 (14.9%) of 269 BCSs quit their jobs at least 1 year after being diagnosed with breast cancer. The results of the multivariable analysis indicated that lower education level (odds ratio [OR]: 3.802; 95% confidence interval [CI]: 1.233-11.729), taking SL (OR: 2.514; 95%CI: 1.202-5.261), and younger age at diagnosis (OR: 0.470; 95%CI: 0.221-0.998) were predictors of resignation. Of 229 patients who continued working, SL was taken by 72 (31.4%). In addition, undergoing surgery was found to be a predictor of taking SL (OR: 8.311; 95%CI: 1.007-68.621). CONCLUSIONS: In total, 40 (14.9%) of 269 BCSs quit their jobs at least 1 year after being diagnosed with breast cancer. The results of this study indicated that younger age, lower education level, and taking SL were predictors of resignation after breast cancer diagnosis.

Microsatellite instability and mismatch repair protein expressions in lymphocyte-predominant breast cancer.

The frequency of microsatellite instability (MSI) is reportedly extremely low in breast cancer, despite widespread clinical expectations that many patients would be responsive to immune-checkpoint inhibitors (ICI). Considering that some triple-negative breast cancers (TNBC) responded well to ICI in a clinical trial and that a high density of tumor-infiltrating lymphocytes (TILs) is frequently observed in other cancers with high levels of microsatellite instability (MSI-H), we hypothesized that some TNBC with a high density of TILs would be MSI-H. Medullary carcinoma (MedCa) of the breast, a rare histological type, is characterized by a high density of TILs. Considering that MedCa of the colon is often MSI-H, we suspected that MedCa in breast cancer might also include MSI-H tumors. Therefore, we conducted MSI tests on such breast cancers with a high density of TILs. The MSI status of 63 TIL-high TNBC and 38 MedCa tumors, all from Asian women who had undergone curative surgery, were determined retrospectively. DNA mismatch repair (MMR) proteins and PD-L1 expression were also investigated immunohistochemically. All samples were microsatellite stable, being negative for all microsatellite markers. TIL-high TNBC with low MLH1 protein had higher levels of PD-L1 in stromal immune cells (P = .041). MedCa tumors showed significantly higher PD-L1 expression in immune cells than in TIL-high TNBC (<.001). We found that MSI-H tumors were absent in TIL-high breast cancers. Examination of MMR proteins, not a purpose of Lynch syndrome screening, may merit further studies to yield predictive information for identifying patients who are likely to benefit from ICI.

Ribociclib, a CDK 4/6 inhibitor, plus endocrine therapy in Asian women with advanced breast cancer.

The ongoing, Phase Ib MONALEESASIA study is evaluating the efficacy and safety of ribociclib plus endocrine therapy in Asian patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Eligible patients from Japan, Hong Kong, and Singapore were enrolled in this 2-phase study consisting of a dose-escalation phase to determine the maximum-tolerated dose and the recommended Phase II dose of ribociclib plus letrozole, and a dose-expansion phase to evaluate safety and tolerability of ribociclib plus letrozole, fulvestrant, or tamoxifen. An exploratory biomarker analysis evaluating expression of target genes was also conducted. In the dose-escalation phase, the maximum-tolerated/recommended Phase II doses of ribociclib were lower in Japanese patients (300 mg) than in Asian non-Japanese patients (600 mg). Ribociclib plus endocrine therapy at the recommended Phase II dose had a manageable safety profile, with neutropenia and elevated liver transaminases being the most common adverse events leading to dose modifications or discontinuations, and it demonstrated evidence of clinical activity in both Japanese and Asian non-Japanese patients. Preliminary efficacy in Asian populations is similar to that observed in White populations studied in previous ribociclib (MONALEESA) trials. Biomarker analysis demonstrated suppression of pharmacodynamic biomarker gene expression, indicating inhibition of target genes by ribociclib combined with endocrine therapy. Results from the ongoing study support the use of ribociclib in combination with letrozole in Asian non-Japanese patients at the same dose (600 mg) as White patients. In Japanese patients, a lower dose of ribociclib (300 mg) should be considered. Clinicaltrials.gov: NCT02333370.

High FOXA1 protein expression might predict late recurrence in patients with estrogen-positive and HER2-negative breast cancer.

BACKGROUND: Multi-gene expression assays have been developed with the aim of predicting late recurrence in patients with estrogen receptor (ER)-positive breast cancer. However, establishment of alternative markers based on immunohistochemistry is also important for achieving practical use. Based on our previous study, forkhead box A1 (FOXA1) protein was tested as a potentially useful predictive marker for late recurrence. METHODS: 117 patients with ER-positive HER2-negative invasive breast cancer who developed distant metastasis following curative surgery were retrospectively investigated. We also evaluated responsiveness to endocrine therapy according to FOXA1 expression. Furthermore, publicly available mRNA microarray data were analyzed to examine patterns of metastasis according to FOXA1 mRNA expression, employing the Kaplan-Meier plotter. RESULTS: High expression of FOXA1 was an independent factor predicting long disease-free survival (DFS), along with small tumor size (p = 0.010 and 0.016, respectively). Discrimination of DFS was improved by combining these two factors, i.e., patients with FOXA1-high small tumors had the longest DFS while those with FOXA1-low large tumors had the shortest DFS. Moreover, we revealed that risk of distant metastasis started to increase after the completion of adjuvant endocrine therapy in patients with FOXA1-high tumors. CONCLUSION: Among patients who developed distant metastasis, those with FOXA1-high tumors had significantly longer DFS. We believe our data to raise the possibility of FOXA1 being a useful predictive marker for late recurrence and to provide new insights into the biology of FOXA1-high breast cancers.

Are graduating residents sufficiently competent? Results of a national gap analysis survey of program directors and graduating residents in Japan.

PURPOSE: To evaluate the self-assessed competency of graduating residents (GRs) in Japan upon completion of their residency and to identify the gap between their competency and the competency expected by their program directors (PDs). METHOD: A list of 31 essential surgical procedures was compiled according to the consensus of surgical educators from around the country. A survey with this list was sent to all 909 GRs and their 611 PDs in 2016. The GRs rated their competency to perform these procedures and the PDs were asked to evaluate the expected competency of their GRs using the Zwisch Scale. RESULT: The response rate was 56.3% for the GRs and 76.8% for the PDs. Fewer than half of the GRs who responded felt confident performing ten (32%) of the surgical procedures evaluated. For most procedures, the GRs' self-reported competency was lower than the expectation reported by their PDs. This gap was more than 10% for 13 of the procedures. CONCLUSION: More than half of the GRs in Japan lacked the confidence in their skill to perform one-third of the surgical procedures selected for evaluation in this study. These findings should be used to update the surgical education curriculum in Japan.

Is there disparity between regions and facilities in surgical resident training in Japan? Insights from a national survey.

PURPOSE: This study sought to assess the disparity between regions and facilities in surgical resident training in Japan via a national level needs-assessment. METHODS: A survey was sent to all 909 graduating residents of 2016. Residents trained in the six prefectures with a population of 7 million or more were included in the large prefecture (LP) group. Residents trained in the other 41 prefectures were included in the small prefecture (SP) group. Each group was further divided into a university hospital (UH) group and a non-university hospital (NUH) group. RESULTS: The response rate was 56.3% (n = 512). Excluding nine residents who did not report their prefectures and facilities, surveys from 503 residents were analyzed. The UH group received significantly more years of training. In the SP and UH groups, there were significantly fewer residents who had performed 150 procedures or more under general anesthesia in comparison to the LP and NUH groups, respectively. Self-assessed competencies for several procedures were significantly lower in the SP and UH groups. CONCLUSION: Disparity in surgical resident training was found between regions and facilities in Japan. The surgical residency curriculum in Japan could be improved to address this problem.

A snapshot of surgical resident training in Japan: results of a national-level needs assessment survey.

PURPOSE: To evaluate the status of surgical training in Japan through a national-level needs assessment. METHODS: A survey was sent to all 909 graduating residents (GRs) and their 611 program directors (PDs) for the year 2016. A working group of surgical educators from around the country was formed under the education committee of the Japan Surgical Society. The survey items were developed by consensus of this working group. The survey investigated the knowledge and problems of the current curriculum, and the status of the current residency training. RESULTS: The response rates were 56.3% of the GRs and 76.8% of the PDs. Among the participants, 47.6% of the GRs and 29.4% of the PDs believed that the residency curriculum did not match the clinical experience. Over 80% of the GRs and PDs agreed on the importance of training outside of the OR, whereas only 13% of the GRs had received such training regularly. Trainees also reported a lower satisfaction rate about the opportunity to train outside of the OR. CONCLUSION: This national-level needs assessment of surgical training in Japan identified several gaps in the curriculum. These results provide valuable data to assist the ongoing efforts for surgical residency curriculum improvement.

Analysis of circulating tumour cell and the epithelial mesenchymal transition (EMT) status during eribulin-based treatment in 22 patients with metastatic breast cancer: a pilot study.

BACKGROUND: Liquid biopsy approaches, such as measuring circulating tumour cells (CTCs), have recently been introduced in several clinical studies. However, the development of CTCs as a predictive marker for treatment effects on breast cancer remains an enormous task. We investigated CTCs, including epithelial mesenchymal transition (EMT) status, from metastatic breast cancer patients who had received eribulin-based treatment, which reportedly suppresses EMT as a means of tumour suppression. Our aim was to test the possibility of this method serving as a tool predicting eribulin efficacy. METHODS: Twenty-two patients were enrolled and peripheral blood samples were collected before eribulin treatment. CTCs were then examined using a Microfluidic Chip device. CTCs positive for vimentin and pan-cytokeratin were defined as mesenchymal and epithelial CTCs, respectively. Progression-free survival (PFS) and clinical response were assessable in 20 and 18 patients, respectively, in relation to the number of CTCs. RESULTS: Numbers of total CTCs were significantly increased in patients with progressive disease during treatment (p = 0.006). Median PFS was 14.6 weeks and patients with more total and mesenchymal CTCs at baseline had significantly shorter PFS (p = 0.0013 and 0.013, respectively). Multivariate logistic regression analysis revealed small number of total baseline CTCs and long disease-free survival to be related to long PFS (p = 0.0004 and 0.020, respectively). CONCLUSIONS: Our data suggest that determining both mesenchymal and epithelial CTCs at baseline might be a good tool for predicting eribulin responsiveness. Evaluation of mesenchymal CTC can be considered as a parameter in larger studies, while most clinical trials are currently employing only the detection of the epithelial cellular adhesion molecule (EpCAM).

Randomized phase II study of nab-paclitaxel as first-line chemotherapy in patients with HER2-negative metastatic breast cancer.

Weekly administration of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open-label phase II study to compare the efficacy and safety of weekly nab-paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2-negative MBC. The primary endpoint was progression-free survival (PFS). Patients were randomized to receive nab-paclitaxel (150 mg/m2 nab-paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m2 docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5-11.2) for nab-paclitaxel and 11.2 months (90% CI: 8.4-13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab-paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab-paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab-paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab-paclitaxel 150 mg/m2 did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab-paclitaxel and docetaxel.

Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial.

PURPOSE: The randomized phase III JO21095 trial compared the efficacy and safety of low-dose capecitabine plus docetaxel combination therapy (XT) versus single-agent administration of docetaxel in anthracycline-pretreated HER2-negative metastatic breast cancer. METHODS: Patients were randomized to either low-dose XT (capecitabine 825 mg/m2 twice daily, days 1-14; docetaxel 60 mg/m2, day 1 every 3 weeks) or docetaxel (70 mg/m2, day 1 every 3 weeks). The primary objective was to demonstrate superior progression-free survival (PFS) with low-dose XT versus single-agent docetaxel. Overall survival (OS) and safety were secondary endpoints. RESULTS: In total, 162 patients were treated. Median PFS was 10.5 months with low-dose XT and 9.8 months with single-agent docetaxel (hazard ratio [HR] 0.62 [95% confidence interval (CI) 0.40-0.97]; p = 0.03). The OS HR was 0.89 (95% CI 0.52-1.53; p = 0.68). Grade ≥3 treatment-related toxicities occurred in 74% of XT-treated patients and 76% of docetaxel-treated patients. The main differences in grade ≥3 treatment-related toxicities were hand-foot syndrome (7.3% of XT-treated patients vs 0% receiving docetaxel), fatigue/malaise (2.4 vs 10.0%), and peripheral edema (1.2 vs 7.5%). Dose modifications were required in 100% of low-dose XT and 49% of docetaxel patients. Toxicity-related treatment discontinuations occurred in 18 and 33%, respectively. CONCLUSION: The improved PFS with low-dose XT versus docetaxel alone is consistent with higher-dose XT phase III experience, but the safety profile was more favorable and manageable.