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Background Amputation is the standard of care even for early-stage subungual melanomas (SUMs), known as nail apparatus melanoma, because the nail bed and nail matrix are close to the distal phalanx. However, a recent study demonstrated that not all patients with SUMs had histologic invasion of the underlying distal phalanx. As most SUMs occur in the thumb or big toe, amputation of either the thumb or big toe substantially interferes with activities of daily living, including poor cosmesis, loss of function, and phantom pain. Non-amputative digit preservation surgery can thus be applied in such cases without compromising patient prognosis. Methods We are conducting a multi-institutional single-arm trial to confirm the safety and efficacy of non-amputative digit preservation surgery. We will compare our results with those reported in the Japanese Melanoma Study, in which patients underwent amputation for SUMs as a traditional standard of care. Patients aged between 20 and 80 years with stage I, II, or III without evidence of tumor invasion to the underlying distal phalanx on preoperative radiograph are included in the study. The primary endpoint is major relapse-free survival (major RFS), which does not include local recurrence as an event; secondary endpoints include overall survival, digit-preservation survival, relapse-free survival, local relapse-free survival, partial relapse-free survival, and incidence of adverse events. A total of 85 patients from 21 Japanese institutions will be recruited within 5.5 years, and the follow-up period will last at least 5 years. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in August 2017, and patient enrollment began in November 2017. Ethical approval was obtained from each institution’s Institutional Review Board prior to patient enrollment. Discussion This is the first prospective trial to confirm the safety and efficacy of non-amputative digit preservation surgery for SUM without distant metastasis or bony invasion. The results of this trial could provide evidence to support this less-invasive surgery as a new standard of care to preserve adequately functioning digits. Trial registration Registry number: UMIN000029997 . Date of Registration: 16/Nov/2017. Date of First Participant Enrollment: 12/Dec/2017.

Background In JCOG0306 trial, a phase II study to examine the efficacy of neoadjuvant chemotherapy followed by radiation therapy (NAC-RT) to primary breast cancer, pathological complete response (pCR) was evaluated from specimens of the representative cross-section including the tumor center that had been accurately marked [representative specimen (RS) method]. In this ancillary study, we examined if the RS method was comparable to the conventional total specimen (TS) method, which is widely employed in Japan, to identify the pCR group showing excellent prognosis. Methods We obtained long-term follow-up data of 103 patients enrolled in JCOG0306 trial. As histological therapeutic effect, pCR (ypT0 and ypT0/is) and quasi-pCR [QpCR, ypT0/is plus Grade 2b (only a few remaining invasive cancer cells)] were evaluated with RS and TS methods. Concordance of pCR between these two methods and associations of the pCR with prognosis were examined. Results ypT0, ypT0/is, and QpCR were observed in 28 (27.2%), 39 (37.9%), and 45 (43.7%) patients with RS method, whereas these were 20 (19.4%), 25 (24.3%) and 40 (38.9%) with TS method, respectively. Between RS and TS methods, concordance proportions of ypT0 and ypTis were 92.2% and 86.4%, respectively. Risk of recurrence of ypT0/is group was lower than that of non-ypT0/is group (HR 0.408, 95% CI [0.175–0.946], P  = 0.037) and risk of death of ypT0/is group was lower than that of non-ypT0/is group (HR 0.251, 95% CI [0.073–0.857], P  = 0.027). The ypT0 and ypT0/is groups with RS method showed excellent prognosis similarly with those with TS method, and RS method was able to differentiate the OS and RFS between pCR and non-pCR than TS method significantly even if pCR was classified ypT0 or ypT0/is. With TS method, QpCR criteria stratified patients into the better and worse prognosis groupsmore clearly than pCR criteria of ypT0 or ypT0/is. Conclusions RS method was comparable to TS method for the evaluation of pCR in the patients who received NAC-RT to primary breast cancer provided the tumor center was accurately marked. As pCR criteria with RS method, ypT0/is appeared more appropriate than ypT0.

PurposeMale breast cancer (MBC) is a rare cancer accounting for only 1% of all male cancers and is, therefore, poorly studied. We aimed to characterize the subtypes of MBC in Japanese patients based on genetic profiling, the presence of tumor-infiltrating cells, and the expression of immunohistochemical markers.MethodsThis retrospective study included 103 patients with MBC diagnosed between January 2009 and December 2019 at various hospitals in Japan. Clinicopathological patient characteristics were obtained from medical records, and formalin-fixed paraffin-embedded tissue specimens were analyzed for histological markers, mutations of 126 genes, BRCA1 methylation, and stromal tumor-infiltrating lymphocytes.ResultsThe median patient age was 71 (range 31–92) years. T1-stage tumors were the most frequent (47.6%), and most were node negative (77.7%). The majority of tumors were positive for estrogen receptor (98.1%), progesterone receptor (95.1%), and androgen receptor (96.1%), and BRCA2 was the most frequently mutated gene (12.6%). The most common treatment was surgery (99.0%), either total mastectomy (91.1%) or partial mastectomy (7.0%). Survival analysis showed a 5-year recurrence-free survival rate of 64.4% (95% confidence interval [CI] 46.7–88.8) and a 5-year overall survival rate of 54.3% (95% CI 24.1–100.0).ConclusionJapanese MBC is characterized by a high rate of hormonal receptor positivity and BRCA2 somatic mutation. Due to the observed clinicopathological differences in MBC between the Western countries and Japan, further prospective studies are needed to evaluate the most suitable treatment strategies.

: Although surgical resection is necessary to cure the locally advanced gastric cancer, it is sometimes difficult for extensive nodal metastasis such as para-aortic nodal disease or bulky nodal metastasis around the major gastric branched arteries. We had conducted several Phase II studies and clarified preoperative chemotherapy with doublet regimen followed by surgery markedly improved the survival for this disease. Recently, preoperative chemotherapy with docetaxel, oxaliplatin and S-1 (DOS) showed promising efficacy and acceptable feasibility for resectable advanced gastric cancer. To describe the design and rationale for the multi-institutional, single-arm, Phase II trial of systemic chemotherapy with DOS followed by surgery in advanced gastric cancer with extensive lymph node metastasis (JCOG1704). If efficacy and safety of DOS can be shown, we will conduct a Phase III trial comparing preoperative DOS and current standard cisplatin and S-1. Trial registration: jRCTs031180028.

It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH). In human liver biopsy samples, elevated LECT2 mRNA levels were positively correlated with body mass index (BMI) and increased in patients who have steatosis and inflammation in the liver. LECT2 mRNA levels were also positively correlated with the mRNA levels of the inflammatory genes CCR2 and TLR4 . In C57BL/6J mice fed with a high-fat diet, mRNA levels of the inflammatory cytokines Tnfa and Nos2 were significantly lower in Lect2 KO mice. In flow cytometry analyses, the number of M1-like macrophages and M1/M2 ratio were significantly lower in Lect2 KO mice than in WT mice. In KUP5, mouse kupffer cell line , LECT2 selectively enhanced the LPS-induced phosphorylation of JNK, but not that of ERK and p38. Consistently, LECT2 enhanced the LPS-induced phosphorylation of MKK4 and TAB2, upstream activators of JNK. Hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifts liver residual macrophage to the M1-like phenotype, and contributes to the development of liver inflammation. These findings shed light on the hepatokine LECT2 as a potential therapeutic target that can dissociate liver steatosis from inflammation.

Aim Selenoprotein P (SeP, encoded by SELENOP in humans) is a hepatokine that causes insulin resistance in the liver and skeletal muscle. It was found that polyunsaturated fatty acid eicosapentaenoic acid (EPA) downregulates Selenop expression by inactivating SREBP‐1c. The present study aimed to examine the effect of EPA for 12 weeks on circulating SeP levels and insulin sensitivity in humans with type 2 diabetes. Methods A total of 20 participants with dyslipidemia and type 2 diabetes were randomly assigned to an EPA (900 mg, twice daily) group and a control group. The primary endpoint was a change in serum SeP levels. Organ‐specific insulin sensitivity in the liver (HGP and %HGP), skeletal muscle (Rd), and adipose tissue (FFA and %FFA) were assessed using a hyperinsulinemic‐euglycemic clamp study with stable isotope‐labeled glucose infusion. Results Serum SeP levels were not changed in either group at the end of the study. In the EPA group, the changes in SeP levels were positively correlated with the change in serum EPA levels (r = 0.709, P = 0.022). Treatment with EPA significantly enhanced %FFA but not %HGP and Rd. The change in serum EPA levels was significantly positively correlated with the change in %HGP, and negatively correlated with changes in Rd. Conclusions The change in serum EPA levels was positively correlated with serum SeP levels, hepatic insulin sensitivity, and negatively with skeletal muscle insulin sensitivity in humans with type 2 diabetes. The EPA‐induced enhancement of hepatic insulin sensitivity might be associated with a mechanism independent of serum SeP levels. The increase in serum EPA level was significantly correlated positively with an increase in the suppression of hepatic glucose production by insulin during a clamp study. The increase in serum EPA level tended to be negatively correlated with changes in insulin‐stimulated glucose disposal.

Selenoprotein P is released from the liver and acts through LRP1 in the muscle to contribute to exercise resistance in mouse and man by inhibiting ROS levels via inhibition of AMPK and PGC-1α. Exercise has numerous health-promoting effects in humans 1 ; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly 2 , 3 , 4 . This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) 5 , 6 , 7 causes exercise resistance through its muscle receptor low-density lipoprotein receptor–related protein 1 (LRP1) 8 . SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation 9 and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a ) 10 expression in skeletal muscle. Supplementation with the anti-oxidant N -acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle—effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP–LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.

The optimal treatment for Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) has not been established in the high-intensity chemotherapy era. The outcomes of patients with Ph-negative ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched related or unrelated donor in CR1 (HSCT-MRD group and HSCT-MUD group) were obtained from a Japanese registry database. Patients aged 16–24 years and 25–65 years were analyzed separately, and their outcomes were compared to those of patients who continued high-intensity chemotherapy in CR1 in studies (202U group and 202O group) by the Japan Adult Leukemia Study Group (JALSG). In the HSCT-MRD group, patients younger than 25 years had lower overall survival (OS) than the 202U group, presumably due to the higher non-relapse mortality (NRM) in the HSCT-MRD group. Patients 25 years and older had similar OS to the 202O group. The lower relapse rate was counterbalanced by higher NRM in the HSCT-MRD group. In the HSCT-MUD group, patients in both age groups had similar OS to their corresponding groups in the JALSG studies. In conclusion, high-intensity chemotherapy may change the role of HSCT for Ph-negative ALL.