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Backgrounds: Imatinib mesylate (STI-571), a tyrosine kinase inhibitor, has previously been demonstrated to attenuate liver fibrogenesis through inhibition of the activation of hepatic stellate cells (HSCs) in CCL(4)-treated rat models.Aims: This study aimed to further evaluate the role of STI-571 in liver regeneration.Materials and Methods: All animals were divided into four groups, and mice were treated with or without CCL(4) and STI-571 (n = 6 for each group).Results: Activated cultured HSCs in vitro with STI-571 administration showed increased apoptosis and reduced proliferation, as determined by flow cytometric analysis, 3-(4, 5-cimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay, and confocal microscopy. STI-571 treatment attenuated liver fibrosis in vivo, as was evident in the results of histology, mRNA level, and expression analysis of smooth muscle actin and type I collagen. Mice treated with STI-571 had increased liver weight ratio and the improvement in liver regeneration was compatible with the change of serum interleukin 6 levels (p < 0.05). Further, increased apoptosis and a reduced proliferation were observed in the CCL(4)-treated mice after STI-571 treatment based on the immunohistochemical staining of Annexin V, phosphorylated STAT3, and PCNA.Conclusion: STI-571 treatment effectively attenuated liver fibrogenesis and improved in liver regeneration in vivo and induced apoptosis in HSCs both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Background: Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.Methods: A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI50 (dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.Results: The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI50 values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.Conclusions: A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effect of Astragalus polysaccharides (PG2) on reducing chemotherapy-induced fatigue (CIF) and toxicity, thereby encouraging compliance to chemotherapy. This was a randomized, placebo-controlled, phase 2 study. Patients with stage II/III early breast cancer planning to undergo adjuvant anthracycline-based chemotherapy were randomly assigned to receive PG2 500 mg or placebo on days 1, 3, and 8 every 21 days. The fatigue global score (FGS) was assessed using the brief fatigue inventory (BFI)-Taiwan. The Breast Cancer-Specific Module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core30 evaluated the health-related quality of life during the first four cycles of adjuvant chemotherapy. Overall, 66 eligible patients were equally randomized into the PG2 and placebo groups between March 01, 2018, and March 09, 2021. The mean change in the FGS and fatigue intensity did not significantly differ between both groups. However, the FGS and fatigue intensity were less aggravated in the first four cycles in the premenopausal-PG2 group than in the placebo group. Our study concluded PG2 combined with adjuvant chemotherapy can reduce CIF, insomnia, the negative effect on future perspectives, and improve global health status, especially for premenopausal patients with breast cancer. Trial registration number: NCT03314805 registered on 19/10/2017., (© 2024. The Author(s).)

Background: The free deep inferior epigastric artery perforator (DIEP) flap is the gold standard in autologous breast reconstruction. Asian patients often present with a smaller body mass index with relatively insufficient tissue. To restore appropriate symmetry, a larger flap inset ratio must be transferred. Supercharging of the second vein or inclusion of bilateral pedicle is commonly required. Current paradigm shifts in mastectomy has also resulted in more minimally invasive surgeries (MIS) espousing smaller lateral incisions, leading to a significant change in available recipient vessels. This study aimed to demonstrate our experience in changing strategies of DIEP flaps following the evolution of mastectomy techniques., Methods: Between October 2008 and March 2022, retrospective data was gathered for 278 patients who underwent breast reconstruction surgery utilizing DIEP flaps by a single plastic surgeon. These patients were divided into two distinct groups based on their operation dates, with November 2018 marking a pivotal moment when the first MIS, including endoscopic-assisted and robot-assisted mastectomy, was introduced., Results: A total of 278 patients were included. Bipedicle vessel utilization for flap supercharge saw a significant increase (15.9% vs. 7%, p < 0.001), while the use of the superior inferior epigastric vein (SIEV) decreased (5.1% vs. 17.1%, p = 0.01). Preceding MIS, SIEV was the primary choice for flap supercharge (96.0%, p < 0.001), whereas post-introduction, the contralateral DIEP pedicle gained prominence (75.9%, p < 0.001). There was also an increased utilization of thoracodorsal artery and lateral thoracic artery following MIS., Conclusion: These findings underscore the profound impact of MIS on the strategic choices made in DIEP flap-based breast reconstruction., Trial Registration: This study is retrospectively registered on ClinicalTrials.gov (NCT06321549)., (© 2024. The Author(s).)

In black porgy (Acanthopagrus schlegelii), the brain-pituitary-testis (Gnrh-Gths-Dmrt1) axis plays a vital role in male fate determination and maintenance, and then inhibiting female development in further (puberty). However, the feedback of gonadal hormones on regulating brain signaling remains unclear. In this study, we conducted short-term sex steroid treatment and surgery of gonadectomy to evaluate the feedback regulation between the gonads and the brain. The qPCR results show that male phase had the highest gths transcripts; treatment with estradiol-17β (E2) or 17α-methyltestosterone (MT) resulted in the increased pituitary lhb transcripts. After surgery, apart from gnrh1, there is no difference in brain signaling genes between gonadectomy and sham fish. In the diencephalon/mesencephalon transcriptome, de novo assembly generated 283,528 unigenes; however, only 443 (0.16%) genes showed differentially expressed between sham and gonadectomy fish. In the present study, we found that exogenous sex steroids affect the gths transcription; this feedback control is related to the gonadal stage. Furthermore, gonadectomy may not affect gene expression of brain signaling (Gnrh-Gths axis). Our results support the communication between ovotestis and brain signaling (Gnrh-Gths-testicular Dmrt1) for the male fate., Competing Interests: Declaration of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acute-on-chronic liver failure (ACLF) implies high short-term mortality rates and usually requires intensive care unit (ICU) admission. Proper prognosis for these patients is crucial for early referral for liver transplantation. The superiority of CLIF-C ACLF score in Asian patients with ACLF admitted to an ICU remains inconclusive when compared to other scoring systems. The purpose of the study is (i) to compare the predictive performance of original MELD, MELD-Lactate, CLIF-C ACLF, CLIF-C ACLF-Lactate, and APACHE-II scores for short-term mortality assessment. (ii) to build and validate a novel scoring system and to compare its predictive performance to that of the original five scores. Two hundred sixty-five consecutive cirrhotic patients with ACLF who were admitted to our ICU were enrolled. The prognostic values for mortality were assessed by ROC analysis. A novel model was developed and internally validated using fivefold cross-validation. Alcohol abuse was identified as the primary etiology of cirrhosis. The AUROC of the five prognostic scores were not significantly superior to each other in predicting 1-month and 3-month mortality. The newly developed prognostic model, incorporating age, alveolar-arterial gradient (A-a gradient), BUN, total bilirubin level, INR, and HE grades, exhibited significantly improved performance in predicting 1-month and 3-month mortality with AUROC of 0.863 and 0.829, respectively, as compared to the original five prognostic scores. The novel ACLF model seems to be superior to the original five scores in predicting short-term mortality in ACLF patients admitted to an ICU. Further rigorous validation is required., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Background: Due to the presence of other comorbidities and multi-therapeutic modalities in breast cancer, renally cleared chemotherapeutic regimens may cause nephrotoxicity. The aim of this retrospective study is to compare the chemotherapy types and outcomes in breast cancer patients with or without chronic renal disease., Patients and Methods: We retrospectively enrolled 62 female patients with breast cancer and underlying late stages (stage 3b, 4, and 5) of chronic kidney disease (CKD) treated from 2000 to 2017. They were propensity score-matched 1:1 with patients in our database with breast cancer and normal renal function (total n = 124)., Results: The main subtype of breast cancer was luminal A and relatively few patients with renal impairment received chemotherapy and anti-Her-2 treatment. The breast cancer patients with late-stage CKD had a slightly higher recurrent rate, especially at the locally advanced stage. The 5-year overall survival was 90.1 and 71.2% for patients without and with late-stage CKD, but the breast cancer-related mortality rate was 88.9 and 24.1%, respectively. In multivariate analyses, dose-reduced chemotherapy was an independent negative predictor of 5-year recurrence-free survival and late-stage CKD was associated with lower 5-year overall survival rate., Conclusions: Breast cancer patients with late-stage CKD may receive insufficient therapeutic modalities. Although the recurrence-free survival rate did not differ significantly by the status of CKD, patients with breast cancer and late-stage CKD had shorter overall survival time but a lower breast cancer-related mortality rate, indicated that the mortality was related to underlying disease., (© 2023. The Author(s).)

Objective: Breast cancer treatment has evolved to the modern skin-sparing mastectomy and nipple-sparing mastectomy. To better perform these surgeries, minimally invasive techniques using the endoscope, or Da Vinci Robotic Surgery platform have been developed. The deep inferior epigastric perforator (DIEP) flap is the gold standard in breast reconstruction, but it is still not commonly performed after minimally invasive mastectomy due technical difficulty. Here the authors introduced six key steps to a successful aesthetic autologous free flap reconstruction in in minimally invasive mastectomies., Methods: There are six main steps to our technique: placement of mastectomy incision, precise flap design after angiography studies, trial of shaping, transcutaneous medial suture, footprint recreation and postoperative shaping with bra. Between November 2018 and July 2022, a total of 67 immediate breast reconstructions using free perforator flaps were performed in 63 patients after minimally invasive nipple-sparing mastectomy., Results: The results from the minimally invasive mastectomy group were compared with a group of conventional mastectomy patients ( n= 41) performed during the same period. There were no significant differences in flap exploration rates. One hundred percent of the flaps survived. In the minimally invasive group, the final scar was placed in the lateral region, where it would be hidden from the anterior view. Only 70.7% of the conventional mastectomy group could achieve a hidden lateral scar ( P <0.001). The aesthetic revision rates were similar between two groups., Conclusion: With attention to the six steps above, autologous free flap reconstruction can be offered reliably in the setting of minimally invasive mastectomy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: To restore sensation after breast reconstruction, a modified surgical approach was employed by identifying the cut fourth intercostal lateral cutaneous branch, elongating it with intercostal nerve grafts, and coapting it to the innervating nerve of the flap or by using direct neurotization of the spared nipple/skin., Methods: This was a retrospective case-control study including 56 patients who underwent breast neurotization surgery. Breast operations included immediate reconstruction after nipple-sparing mastectomy (36 patients), skin-sparing mastectomy (8 patients), and delayed reconstruction with nipple preservation (7 patients) or without nipple preservation (5 patients). Patients who underwent breast reconstruction without neurotization were included as the non-neurotization negative control group. The contralateral normal breasts were included as positive controls., Results: The mean(s.d.) monofilament test values were 0.07(0.10) g for the positive control breasts and 179.13(143.31) g for the breasts operated on in the non-neurotization group. Breasts that underwent neurotization had significantly better sensation after surgery, with a mean(s.d.) value of 35.61(92.63) g (P < 0.001). The mean(s.d.) sensory return after neurotization was gradual; 138.17(143.65) g in the first 6 months, 59.55(116.46) g at 7-12 months, 14.54(62.27) g at 13-18 months, and 0.37(0.50) g at 19-24 months after surgery. Two patients had accidental rupture of the pleura, which was repaired uneventfully. One patient underwent re-exploration due to a lack of improvement 1.5 years after neurotization., Conclusion: Using the lateral cutaneous branch of the intercostal nerve as the innervating stump and elongating it with intercostal nerve grafts is a suitable technique to restore sensation after mastectomy. This method effectively innervates reconstructed breasts and spares the nipple/skin with minimal morbidity., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Acute-on-chronic-liver failure (ACLF) demonstrates high short-term mortality rates and usually requires intensive care unit (ICU) admission. Accurate prognostication of these patients is pivotal for timely referral for liver transplantation. The superiority of CLIF-C ACLF, CLIF-C ACLF lactate, and NACSELD-ACLF scores in Asian patients with ACLF admitted to an ICU remains inconclusive., Aims: To compare the predictive performance of CLIF-C ACLF, CLIF-C ACLF lactate, and NACSELD-ACLF scores for one-month mortality., Methods: 276 consecutive cirrhotic patients with ACLF admitted to ICU were enrolled. The prognostic values for one-month mortality were assessed by AUROC analysis., Results: The primary cause of cirrhosis in this cohort was alcohol abuse (56.5%). AUROC analysis (95% confidence intervals) demonstrated that CLIF-C ACLF lactate [0.802 (0.747-0.856)] outperformed both CLIF-C ACLF [0.791 (0.733-0.848)] and NACSELD-ACLF [0.673 (0.606-0.740)] in predicting one-month mortality. However, no statistically significant difference was observed between the predictive abilities of CLIF-C ACLF and CLIF-C ACLF lactate., Conclusions: In critically ill cirrhotic patients with ACLF admitted to the hepatology ICU, CLIF ACLF-lactate outperformed CLIF-C ACLF and NACSELD-ACLF in predicting one-month mortality. Nevertheless, no statistically significant difference was observed between CLIF-C ACLF and CLIF-C ACLF lactate. Larger-scale multi-center prospective studies are warranted to validate these results.

Summary: To minimize donor-site damage, robot-assisted (RA) deep inferior epigastric perforator (DIEP) flap harvest has been suggested. Current robotic approaches favor port placement, which either does not allow a bilateral DIEP flap harvest through the same ports or necessitates additional scars. In this article, the authors propose a modification of port configuration. In a retrospective controlled cohort study, RA-DIEP and conventional DIEP surgery were compared. The perforator and pedicle were visualized conventionally until the level behind the rectus abdominis muscle. Next, the robotic system was installed to dissect the retromuscular pedicle. The authors assessed patient age; body mass index; history of smoking, diabetes mellitus, and hypertension; and additional surgical time. The length of the anterior rectus sheath (ARS) incision was measured. Pain was quantified using the visual analogue scale. Donor-site complications were assessed. Thirteen RA-DIEP flaps (11 unilateral and two bilateral) and 87 conventional DIEP flaps were harvested without flap loss. The bilateral DIEP flaps were raised without readjustments of the ports. The mean time for pedicle dissection was 53.2 ± 13.4 minutes. The length of the ARS incision was significantly shorter in the RA-DIEP group (2.67 ± 1.13 cm versus 8.14 ± 1.69 cm; 304.87% difference; P < 0.0001). There was no statistical difference in postoperative pain (day 1: 1.9 ± 0.9 versus 2.9 ± 1.6, P = 0.094; day 2: 1.8 ± 1.2 versus 2.3 ± 1.5, P = 0.319; day 3: 1.6 ± 0.9 versus 2.0 ± 1.3, P = 0.444). Preliminary results show that the authors' RA-DIEP approach is safe and allows dissection of bilateral RA-DIEP flaps with short ARS incision lengths., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: The majority of English literature has reported on the somewhat conflicted outcomes of the effect of radiotherapy on immediate breast reconstruction. However, data specifically related to patients of Asian descent has been scarce. This retrospective study aims to shed light on this topic to aid in the management of this group of patients., Methods: All patients who received immediate free perforator flap-based breast reconstruction under a single surgeon over a 10-year period were included in the study. Patient characteristics, oncological and surgical data were collected. Patients were divided into post-mastectomy radiotherapy (PMRT) and non-PMRT groups. The final aesthetic outcome was assessed by a surgeon-reported outcome questionnaire. Patient satisfaction and psychological outcomes were assessed using validated patient-reported outcome (PRO) questionnaire (BREAST-Q), breast reconstruction, and postoperative module., Results: A total of 101 women, with an average age of 44.7 ± 8.4 underwent perforator flap-based reconstruction. Fifteen patients received PMRT, with remaining 86 patients in the non-PMRT group. The mean duration of follow-up was over 5 years ( p  = 0.514). The recurrence rate was acceptable in the PMRT group (3/15, p  = 0.129). There were no significant differences in complication rates between the two groups ( p  = 1.000). The aesthetic outcomes were comparable ( p  = 0.342). PRO appears to be lower in the PMRT group., Conclusions: Immediate breast reconstruction with PMRT in the local patient cohort is oncologically safe, acceptable complication profile, revision rate, and aesthetic outcome. PRO showed lower scores in several categories, which differ from normative data generated in the Western population. Further studies will need to examine the confounding effects of radiation in this specific population., Competing Interests: The authors declare that they have no conflict of interest., (© 2023 The Author(s).)

Germline pathogenic variants of BRCA1 or BRCA2 cause hereditary breast and ovarian cancer syndromes. The present study investigated the participants' understanding and awareness of germline BRCA1/2 pathogenic variants before genetic counseling, the expectations and obstacles for genetic testing from the perspective of participants and their families, and their attitudes towards genetic testing after counseling. In this single-country, multicenter, non-interventional, patient-reported outcome study, untested cancer patients and their families who visited genetic counseling clinics or who wanted to receive pre-test genetic counseling were eligible to fill in the questionnaire after pre-test counseling for germline BRCA1/2 testing. Demographic information, clinical characteristics, and information collected from the questionnaires, including the understanding of BRCA1/2 pathogenic variants before genetic counseling, understanding of BRCA1/2 pathogenic variants and feelings after genetic counseling, willingness to share results of genetic testing with family, and willingness to receive genetic testing, were summarized using descriptive statistics. A total of 88 participants were enrolled. The proportion of slight understanding of BRCA1/2 pathogenic variants increased from 11.4% to 67.0%, and the proportion of full understanding increased from 0% to 8.0%. After genetic counseling, most participants were willing to undergo genetic testing (87.5%) and share the results with their families (96.6%). The main factors that may affect participants' willingness to undergo BRCA1/2 testing were management (61.2%) and testing costs (25.9%). After pre-test counseling, there was a high acceptance of BRCA1/2 testing and in-family information sharing in Taiwanese patients with cancer and their families, which may serve as a reference for implementing genetic counseling in Taiwan., (© 2023 National Society of Genetic Counselors.)

Co-infection of Helicobacter pylori and Fusobacterium nucleatum is a microbial biomarker for poor prognosis of gastric cancer patients. Fusobacterium nucleatum is associated with microsatellite instability and the accumulation of mutations in colorectal cancer. Here, we investigated the mutation landscape of Fusobacterium nucleatum -positive resected gastric cancer tissues using Illumina TruSight Oncology 500 comprehensive panel. Sequencing data were processed to identify the small nucleotide variants, small insertions and deletions, and unstable microsatellite sites. The bioinformatic algorithm also calculated copy number gains of preselected genes and tumor mutation burden. The recurrent genetic aberrations were identified in this study cohort. For gene amplification events, ERBB2, cell cycle regulators, and specific FGF ligands and receptors were the most frequently amplified genes. Pathogenic activation mutations of ERBB2, ERBB3, and PIK3CA, as well as loss-of-function of TP53, were identified in multiple patients. Furthermore, Fusobacterium nucleatum infection is positively correlated with a higher tumor mutation burden. Survival analysis showed that the combination of Fusobacterium nucleatum infection and high tumor mutation burden formed an extremely effective biomarker to predict poor prognosis. Our results indicated that the ERBB2-PIK3-AKT-mTOR pathway is frequently activated in gastric cancer and that Fusobacterium nucleatum and high mutation burden are strong biomarkers of poor prognosis for gastric cancer patients., Competing Interests: The authors declare no conflict of interest.

Closed-incision negative-pressure wound therapy (iNPWT) is known to enhance wound healing and tissue regeneration. The main aim of the present study is to investigate its effectiveness on enhancing wound healing under tension. An animal study was designed using a swine model by removing a skin flap to create a wound that could be closed primarily under tension, and iNPWT was applied. The enhancement of angiogenesis, lymphangiogenesis, collagen deposition, and tissue proliferation with reduced inflammation by iNPWT was confirmed by histology. The effect of iNPWT was further verified in patients receiving a profunda artery perforator (PAP) free flap for breast reconstruction. iNPWT was applied on the transversely designed donor site in continuous mode for 7 days, in which the wound was always closed under tension. A significant improvement in off-bed time was noted with the application of iNPWT (4.6 ± 1.1st and 5.5 ± 0.8th postoperative days in the iNPWT and control groups, respectively, p = 0.028). The control group (without iNPWT treatment) presented more cases of poor wound healing in the acute (23.1% vs. 0%) and wound breakdown in the late (23.1% vs. 8.3%) stages. The treatment of closed incisions under tension with iNPWT clinically enhances wound healing and tissue regeneration and with histological evidence.

Background: In patients with non-transfusion-dependent β-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent β-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent β-thalassaemia., Methods: We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of β-thalassaemia or haemoglobin E/β-thalassaemia (concomitant α-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10·0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (≥8·5 g/dL vs <8·5 g/dL) and baseline Non-Transfusion-Dependent β-thalassaemia-Patient-Reported Outcome Tiredness/Weakness domain score (≥3 vs <3). All patients, study site staff, and sponsor representatives (who reviewed the data), except for designated individuals, were masked to drug assignment until the time the study was unblinded. Luspatercept or placebo was given once subcutaneously every 3 weeks for 48 weeks in the double-blind treatment period. Luspatercept was started at 1·0 mg/kg with titration up to 1·25 mg/kg, or reduction in the event of toxicity or excessive haemoglobin concentration increase. The primary endpoint was achievement of an increase from baseline of 1·0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03342404, and is ongoing., Findings: Between Feb 5, 2018, and Oct 14, 2019, 160 patients were screened for eligiblity, of whom 145 were randomly assigned to luspatercept (n=96) or placebo (n=49). 82 (57%) patients were female and 63 (43%) were male. 44 (30%) patients were Asian, 87 (60%) were White, and 14 (10%) identified as another race. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1·0 g/dL in haemoglobin concentration (common risk difference 77·1 [95% CI 68·7-85·5]; p<0·0001). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported during the study., Interpretation: Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent β-thalassaemia, for whom effective approved treatment options are scarce., Funding: Celgene and Acceleron Pharma., Competing Interests: Declaration of interests ATT reports receiving consulting fees from Agios Pharmaceuticals; and research funding and consulting fees from Celgene/Bristol Myers Squibb, Ionis Pharmaceuticals, Novartis Pharmaceuticals, and Vifor Pharma. MDC reports receiving advisory board fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Novo Nordisk, Sanofi Genzyme, Silence Therapeutics, and Vifor Pharma. AK reports receiving advisory board fees and consulting fees from Agios Pharmaceuticals, Amgen, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor Pharma; and research support, paid to his institution, from Celgene/Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb, Chiesi Farmaceutuici, CRISPR Therapeutics/Vertex, and Novartis; and personal fees from Bristol Myers Squibb. SP reports receiving grant support, paid to his institution, from Novartis, and personal fees from bluebird bio and Celgene. AGP reports receiving grant support, paid to his institution, from Acceleron Pharma and Celgene, and advisory board fees from Celgene. AF reports advisory board fees from Celgene and grant support, paid to his institution, from bluebird bio and Novartis. JBP reports receiving advisory board fees from bluebird bio, Bristol Myers Squibb, Silence Therapeutics, and Vifor Pharma. TDC reports receiving consultancy fees from Agios Pharmaceuticals, bluebird bio, Bristol Myers Squibb/Celgene, Chiesi Farmaceutici, and Vifor Pharma. GLF reports receiving consulting fees and grant support, paid to his institution, from Agios Pharmaceuticals, Bristol Myers Squibb, and Novartis; and advisory board fees from Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb and Novartis. AA Thompson reports receiving grant support from Baxalta, Biomarin, bluebird bio, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Editas Medicine, and Novartis; and consulting fees from bluebird bio, Celgene/Bristol Myers Squibb, and CRISPR Therapeutics/Vertex; fees for leadership of fiduciary role in a committee or advocacy group from Global Blood Therapeutics; previous employment (last 12 months) at Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; and current employment at Children's Hospital of Philadelphia, Philadelphia, PA, USA. IT reports receiving honoraria from Celgene. KMM reports receiving consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Novartis, and Vifor Pharma. JTB reports ending employment at Acceleron Pharma in the last 12 months and owning stock in Acceleron Pharma, and Bristol Myers Squibb. OE, W-LK, and DM report being employed by Bristol Myers Squibb. ACG, JL-B, AY, and JKS report being employed by and owning stock in Bristol Myers Squibb. TZ reports ending employment at Bristol Myers Squibb in the last 24 months and owning stock in Bristol Myers Squibb. EV and VV report no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Adequate axillary lymph node (ALN) staging is critical for patients with invasive breast cancer. However, neoadjuvant chemotherapy (NAC) was associated with a lower risk of ALN metastasis compared with those who underwent primary surgery among clinically node-negative (cN0) patients. This study aimed to investigate the factors associated with ALN status among patients with cN0 breast cancer undergoing NAC. A total of 222 consecutive patients with cN0 breast cancer undergoing NAC between January 2012 and December 2021 were reviewed. Univariate and multivariate analyses were performed to compare factors associated with positive ALN status. Seventeen patients (7.7%) had ALNs metastases. Here, 90 patients (40.5%) achieved pathologic complete response in the breast (breast-pCR), and all had negative ALN status. Lymphovascular invasion (odds ratio: 29.366, p < 0.0001) was an independent risk predictor of ALN metastasis in all study populations. Among patients without breast-pCR, mastectomies were performed more frequently in patients with ALN metastasis (52.9%) than in those without metastasis (20.9%) (p = 0.013). Our findings support the omission of axillary surgery in patients who achieve breast-pCR. Prospective studies are needed to confirm the feasibility of a future two-stage surgical plan for breast-conserving surgery in patients who are likely to achieve breast-pCR during clinical evaluation.

Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly improved survival. In mouse models, VitE increased ICT antitumor efficacy, which depended on dendritic cells (DC). VitE entered DCs via the SCARB1 receptor and restored tumor-associated DC functionality by directly binding to and inhibiting protein tyrosine phosphatase SHP1, a DC-intrinsic checkpoint. SHP1 inhibition, genetically or by VitE treatment, enhanced tumor antigen cross-presentation by DCs and DC-derived extracellular vesicles (DC-EV), triggering systemic antigen-specific T-cell antitumor immunity. Combining VitE with DC-recruiting cancer vaccines or immunogenic chemotherapies greatly boosted ICT efficacy in animals. Therefore, combining VitE supplement or SHP1-inhibited DCs/DC-EVs with DC-enrichment therapies could substantially augment T-cell antitumor immunity and enhance the efficacy of cancer immunotherapies., Significance: The impacts of nutritional supplements on responses to immunotherapies remain unexplored. Our study revealed that dietary vitamin E binds to and inhibits DC checkpoint SHP1 to increase antigen presentation, prime antitumor T-cell immunity, and enhance immunotherapy efficacy. VitE-treated or SHP1-silenced DCs/DC-EVs could be developed as potent immunotherapies. This article is highlighted in the In This Issue feature, p. 1599., (©2022 American Association for Cancer Research.)

Background: Sentinel lymph node biopsy (SLNB) is the standard axillary staging approach for early breast cancer with clinically negative axillary involvement. Adequate SLNB should include the removal of not only radioactive tracer-labeled lymph nodes (hot nodes or SLNs) but also suspicious unlabeled nodes (non-hot nodes or non-SLNs). However, the biopsy of non-hot nodes is highly dependent on the surgeons' experiences. This article aims to facilitate the surgeon's decision making by elucidating parameters that correlate with non-hot node metastasis., Methods: From 2013 to 2016, clinically node-negative (cN0) breast cancer patients receiving axillary SLNB using single Tc-99m tracer method at our institute were recruited. Patients were excluded if they had received prior neoadjuvant chemotherapy. Among them, cases that have at least one non-isotope-hot node biopsied were retrospectively reviewed with a particular focus on patients with pathologically negative isotope-hot SLNs. The correlation of clinicopathological data with metastasis to axillary lymph nodes and sentinel lymph nodes was analyzed with the Chi-squared test, Fisher's exact test, and multivariate logistic regression. Receiver operating curve (ROC) was applied for continuous variables that predicted non-hot node metastasis; relapse-free survival (RFS) and locoregional relapse-free survival (LRRFS) were compared by Kaplan-Meier analysis., Results: In 632 isotope-hot SLN negative patients, T stage showed a correlation with non-isotope-hot SLN metastasis (p = 0.035, odds ratio (OR) 9.65). Tumors larger than 2.5 cm best predict non-isotope-hot SLN metastasis (area under curve (AUC) = 0.71). With a median follow up of 41.80 months, locoregional relapse-free survival was significantly worse in cases with non-hot node metastasis (66.2% vs. 69.0%, p = 0.001)., Conclusion: In the setting of SLNB using single radioisotope tracer, non-hot node metastasis in cases with negative hot SLN still carries a higher locoregional recurrence rate (13.3%). For early breast cancer larger than 2.5 cm, removal of suspicious non-hot nodes should be included for a precision therapy., (Copyright © 2021 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Purpose: Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations., Methods: A total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical-pathologic characteristics, survival, and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method., Results: The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, p < 0.001). The risk of CBC was significantly higher in BRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients., Conclusion: Our study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Unlike gonochoristic fishes, sex is fixed after gonadal differentiation (primary sex determination), and sex can be altered in adults (secondary sex determination) of hermaphroditic fish species. The secondary sex determination of hermaphroditic fish has focused on the differences between testicular tissue and ovarian tissue during the sex change process. However, comprehensive studies analyzing ovarian tissue or testicular tissue independently have not been performed. Hermaphroditic black porgy shows a digonic gonad (ovarian tissue with testicular tissue separated by connective tissue). Protandrous black porgy has stable maleness during the first two reproductive cycles (<2 years old), and approximately 50% enter femaleness (natural sex change) during the third reproductive cycle. Precocious femaleness is rarely observed in the estradiol-17β (E 2 )-induced female phase (oocytes maintained at the primary oocyte stage), and a reversible female-to-male sex change is found after E 2 is withdrawn in <2-year-old fish. However, precocious femaleness (oocytes entering the vitellogenic oocyte stage) is observed in testis-removed fish in <2-year-old fish. We used this characteristic to study secondary sex determination (femaleness) in ovarian tissue via transcriptomic analysis. Cell proliferation analysis showed that BrdU (5-bromo-2'-deoxyuridine)-incorporated germline cells were significantly increased in the testis-removed fish (female) compared to the control (sham) fish (male) during the nonspawning season (2 months after surgery). qPCR analysis showed that there were no differences in pituitary-releasing hormones ( lhb and gtha ) in pituitary and ovarian steroidogenesis-related factors ( star , cyp11a1 , hsd3b1 , and cyp19a1a ) or female-related genes ( wnt4a , bmp15 , gdf9 , figla , and foxl2 ) in ovarian tissues between intact and testis-removed fish (2 months after surgery). Low expression of pituitary fshb and ovarian cyp17a1 was found after 2 months of surgery. However, we did find small numbers of genes (289 genes) showing sexual fate dimorphic expression in both groups by transcriptomic analysis (1 month after surgery). The expression profiles of these differentially expressed genes were further examined by qPCR. Our present work identified several candidate genes in ovarian tissue that may be involved in the early period of secondary sex determination (femaleness) in black porgy. The data confirmed our previous suggestion that testicular tissue plays an important role in secondary sex determination in protandrous black porgy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tseng, Wu, Kuo, Tseng and Chang.)

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The application of minimal invasive mastectomy has allowed surgeons to perform nipplesparing mastectomy via a shorter, inconspicuous incision under clear vision and with more precise hemostasis. However, it poses new challenges in microsurgical breast reconstruction, such as vascular anastomosis and flap insetting, which are considerably more difficult to perform through the shorter incision on the lateral breast border. We propose an innovative technique of transcutaneous medial fixation sutures to help in flap insetting and creating and maintaining the medial breast border. The sutures are placed after mastectomy and before flap transfer. Three 4-0 nylon suture loops are placed transcutaneously and into the pocket at the markings of the preferred lower medial border of the reconstructed breast. After microvascular anastomosis and temporary shaping of the flap on top of the mastectomy skin, the three corresponding points for the sutures are identified. The three nylon loops are then sutured to the dermis of the corresponding medial point of the flap. The flap is placed into the pocket by a simultaneous gentle pull on the three sutures and a combined lateral push. The stitches are then tied and buried after completion of flap inset.

We retrospectively enrolled 139 patients who developed metachronous isolated supraclavicular lymph node metastasis (miSLNM) from 8129 consecutive patients who underwent primary surgery between 1990 and 2008 at a single medical center. The median age was 47 years. The median follow-up time from date of primary tumor surgery was 73.1 months, and the median time to the date of neck relapse was 43.9 months in this study. Sixty-one (43.9%) patients underwent selective neck dissection (SND). The 5-year distant metastasis-free survival (DMFS), post-recurrence survival, and overall survival (OS) rates in the SND group were 31.1%, 40.3%, and 68.9%, respectively, whereas those of the no-SND group were 9.7%, 32.9%, and 57.7%, respectively ( p = 0.001). No SND and time interval from primary tumor surgery to neck relapse ≤24 months were the only significant risk factors in the multivariate analysis of DMFS (hazard ratio (HR), 1.77; 95% confidence interval (CI), 1.23-2.56; p = 0.002 and HR, 1.76, 95% CI, 1.23-2.52; p = 0.002, respectively) and OS (HR, 1.77; 95% CI, 1.22-2.55; p = 0.003 and HR, 3.54, 95% CI, 2.44-5.16; p < 0.0001, respectively). Multimodal therapy, including neck dissection, significantly improved the DMFS and OS of miSLNM. Survival improvement after miSLNM control by intensive surgical treatment suggests that miSLNM is not distant metastasis.

Caenorhabditis elegans (C. elegans) is a popular and excellent model for studies of aging due to its short lifespan. Methods for precisely measuring the physiological age of C. elegans are critically needed, especially for antiaging drug screening and genetic screening studies. The effects of various antiaging interventions on the rate of aging in the early stage of the aging process can be determined based on the quantification of physiological age. However, in general, the age of C. elegans is evaluated via human visual inspection of morphological changes based on personal experience and subjective judgment. For example, the rate of motor activity decay has been used to predict lifespan in early- to mid-stage aging. Using image processing, the physiological age of C. elegans can be measured and then classified into periods or classes from childhood to elderhood (e.g., 3 periods comprising days 0-2, 4-6 and 10-12) by using texture entropy (Shamir, L. et al., 2009). Our dataset consists of 913 microscopic images of C. elegans, with approximately 60 images per day from day 1 to day 14 of adulthood. We present quantitative methods to measure the physiological age of C. elegans with convolution neural networks (CNNs), which can measure age with a granularity of days rather than periods. The methods achieved a mean absolute error (MAE) of less than 1 day for the measured age of C. elegans. In our experiments, we found that after training and testing our dataset, 5 popular CNN models, 50-layer residual network (ResNet50), InceptionV3, InceptionResNetV2, 16-layer Visual Geometry Group network (VGG16) and MobileNet, measured the physiological age of C. elegans with an average testing MAE of 1.58 days. Furthermore, based on the results, we propose two models, one model for linear regression analysis and the other model for logistic regression, that combine a CNN model and a new attribute: curved&#95;or&#95;straight. The linear regression analysis model achieved a test MAE of 0.94 days; the logistic regression model achieved an accuracy of 84.78 percent with an error tolerance of 1 day.

Background: The application of robotic-assisted nipple-sparing mastectomy (R-NSM) has allowed mastectomy to be performed via a small incision. Breast reconstruction with free autologous tissue results in the most natural and long-lasting results, however, its application in R-NSM can be difficult via the small incision and haven't been explored in depth. The purpose of the study was to investigate the feasibility and aesthetic outcome of free perforator flap breast reconstruction via small lateral chest wall incision after R-NSM., Materials and Methods: A retrospective chart review was conducted to identify patients who received R-NSM and free perforator flap reconstruction as the study group and patients who received conventional nipple-sparing mastectomy (C-NSM) and free perforator flap reconstruction as the control group from January 2018 to August 2020 by single reconstructive surgeon. Patient demographic data, complications from both mastectomy and reconstruction, status of resection margin and oncological outcome were reviewed. Aesthetic outcome was evaluated by 9 plastic surgeons., Results: A total of 63 patients were included of which 22 (34.9%) received R-NSM and 41 (65.1%) received C-NSM. Their demographic data, reconstruction flaps, overall complication rate and follow up time were similar. Unlike C-NSM, majority of the R-NSM groups used the thoracodorsal or lateral thoracic vessels as the recipient vessels. Patients in the R-NSM group has smaller scar and better aesthetic outcome in the symmetry of breast inframammary fold, scar location and visibility, and overall aesthetic outcome., Conclusion: Although with difficulty in microvascular anastomosis and flap inset and shaping, R-NSM with perforator flap reconstruction presented with equal surgical and oncological safety with C-NSM and even better aesthetic results., (Copyright © 2021 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Bilateral breast cancer is a strong predictor of BRCA 1/2 mutation and hence one criterion indicated for hereditary genetic testing. The purpose of this study is to assess the characteristics of synchronous bilateral breast cancer (SBBC) and its association with personal and familial cancer traits. Patients diagnosed with SBBC in our institute between 1992 and 2018 were retrospectively reviewed, and the information of clinicopathological features, personal and family cancer history were analyzed. Of the 307 SBBCs enrolled, the growing case number generally aligned with the regional breast cancer incidence after the era of population-based mammography screening. SBBC patients had similar cancer stages but worse survival outcomes than those in the standard scenario. A total of 42.0% had mixed pathological diagnoses, and 22.8% had discordant immunohistochemistry (IHC) subtypes from both sides, which contributed to treatment challenges. The correlation of SBBC with hereditary breast and ovarian cancer (HBOC) syndrome was strongly implied, as 20.7% of our SBBC patients with known familial cancer histories had HOBC-related familial cancers (breast, ovarian, or prostate cancers). These findings highlight the need for genetic counseling and germline mutation testing in patients with SBBC. Early PARP inhibitor treatment should also be considered in high-risk cases for outcome improvement.

Background: Direct-to-implant (DTI) breast reconstruction after nipple-sparing mastectomy (NSM) with the use of acellular dermal matrix (ADM) provides reliable outcomes; however, the use of ADM is associated with a higher risk of complications. We analyzed our experiences of post-NSM DTI without ADM and identified the predictive factors of adverse surgical outcomes., Methods: Patients who underwent NSM and immediate DTI or two-stage tissue expander (TE) breast reconstruction from 2009 to 2020 were enrolled. Predictors of adverse endpoints were analyzed., Results: There were 100 DTI and 29 TE reconstructions. The TE group had a higher rate of postmastectomy radiotherapy (31% vs. 11%; P=0.009), larger specimens (317.37±176.42 g vs. 272.08±126.33 g; P=0.047), larger implants (360.84±85.19 g vs. 298.83±81.13 g; P=0.004) and a higher implant/TE exposure ratio (10.3% vs. 1%; P=0.035). In DTI reconstruction, age over 50 years (odds ratio [OR], 5.43; 95% confidence interval [CI], 1.50-19.74; P=0.010) and a larger mastectomy weight (OR, 1.65; 95% CI, 1.08-2.51; P=0.021) were associated with a higher risk of acute complications. Intraoperative radiotherapy for the nipple-areolar complex increased the risk of acute complications (OR, 4.05; 95% CI, 1.07-15.27; P=0.039) and the likelihood of revision surgery (OR, 5.57; 95% CI, 1.25-24.93; P=0.025)., Conclusions: Immediate DTI breast reconstruction following NSM is feasible in Asian patients with smaller breasts.

Predictive metabolic biomarkers for the recurrent luminal breast cancer (BC) with hormone receptor (HR)-positive and human epidermal growth factor receptor type 2 (HER2)-negative are lacking. High levels of O -GlcNAcylation ( O -GlcNAc) and pyruvate kinase isoenzyme M2 (PKM2) are associated with malignancy in BC; however, the association with the recurrence risk remains unclear. We first conduct survival analysis by using the METABRIC dataset to assess the correlation of PKM2 expression with BC clinical outcomes. Next, patients with HR + /HER2- luminal BC were recruited for PKM2/ O -GlcNAc testing. Logistic regression and receiver operating characteristic curve analysis were performed to evaluate the 10-year DFS predicted outcome. Survival analysis of the METABRIC dataset revealed that high expression of PKM2 was significantly associated with worse overall survival in luminal BC. The high expression of O -GlcNAc or PKM2 was a significant independent marker for poor 10-year DFS using immunohistochemical analysis. The PKM2 or O -GlcNAc status was a significant predictor of DFS, with the combination of PKM2- O -GlcNAc status and T stage greatly enhancing the predictive outcome potential. In summary, O -GlcNAc, PKM2, and T stage serve as good prognostic discriminators in HR + /HER2 - luminal BC.

Few studies have analyzed the discrepancy between breast pathologic complete response (B-pCR) and axillary node pCR (N-pCR) rates and their impact on survival outcomes in different intrinsic subtypes of early breast cancer after neoadjuvant chemotherapy (NAC). We retrospectively reviewed B-pCR, N-pCR, and total (breast and axillary node) pCR (T-pCR) after NAC to assess the discrepancy and outcomes between 2005 and 2017. A total of 968 patients diagnosed with cT1-4c, N1-2, and M0 breast cancer were enrolled in the study. The median age was 49 years and the median follow-up time was 45 months. Of these patients, 213 achieved T-pCR, 31 achieved B-pCR with axillary node pathologic non-complete response (N-non pCR), 245 achieved N-pCR with breast pathologic non-complete response (B-non pCR), and 479 achieved total (breast and axillary node) pathologic non-complete response (T-non pCR) after NAC. The highest B-pCR and N-pCR rates were found in the hormone receptor-negative, human epidermal growth factor receptor 2-positive HR(-)HER2(+) subtype, while the lowest B-pCR rate was found in the HR(+)HER2(-) subtype. The N-pCR rate was correlated to the B-pCR rate (P<0.001), but was higher than the B-pCR rate in all subtypes. The 5-year overall survival (OS) rates for patients with T-pCR, B-pCR, and N-pCR were 91.2%, 91.7%, and 91.9%, respectively. For non-pCR, non-pCR, and non-pCR, the 5-year OS rates were 73.6%, 78.9%, and 74.7%, respectively (P<0.0001). B-non pCR patients had a lower risk of recurrence than T-non pCR or N-non-pCR patients, although there were no differences in OS among them. In conclusion, the N-pCR rate was higher than the B-pCR rate after NAC in all intrinsic subtypes, and N-non pCR or T-non pCR patients had the worst outcomes., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background:  Robotic-assisted techniques are a tremendous revolution in modern surgery, and the advantages and indications were well discussed in different specialties. However, the use of robotic technique in plastic and reconstructive surgery is still very limited, especially in the field of peripheral nerve reconstruction. This study aims to identify current clinical applications for peripheral nerve reconstruction, and to evaluate the advantages and disadvantages to establish potential uses in the future., Methods:  A review was conducted in the literatures from PubMed focusing on currently published robotic peripheral nerve intervention techniques. Eligible studies included related animal model, cadaveric and human studies. Reviews on robotic microsurgical technique unrelated to peripheral nerve intervention and non-English articles were excluded. The differences of wound assessment and nerve management between robotic-assisted and conventional approach were compared., Results:  Total 19 studies including preclinical experimental researches and clinical reports were listed and classified into brachial plexus reconstruction, peripheral nerve tumors management, peripheral nerve decompression or repair, peripheral nerve harvesting, and sympathetic trunk reconstruction. There were three animal studies, four cadaveric studies, eight clinical series, and four studies demonstrating clinical, animal, or cadaveric studies simultaneously. In total 53 clinical cases, only 20 (37.7%) cases were successfully approached with minimal invasive and intervened robotically; 17 (32.1%) cases underwent conventional approach and the nerves were intervened robotically; 12 (22.6%) cases converted to open approach but still intervened the nerve by robot; and 4 (7.5%) cases failed to approach robotically and converted to open surgery entirely., Conclusion:  Robotic-assisted surgery is still in the early stage in peripheral nerve surgery. We believe the use of the robotic system in this field will develop to become popular in the future, especially in the fields that need cooperation with other specialties to provide the solutions for challenging circumstances., Competing Interests: None declared., (Thieme. All rights reserved.)

Rationale: The progression of prostate cancer (PCa) to castration-resistant PCa (CRPC) despite continuous androgen deprivation therapy is a major clinical challenge. Over 90% of patients with CRPC exhibit sustained androgen receptor (AR) signaling. KDM4B that removes the repressive mark H3K9me3/2 is a transcriptional activator of AR and has been implicated in the development of CRPC. However, the mechanisms of KDM4B involvement in CRPC remain largely unknown. Here, we sought to demonstrate the molecular pathway mediated by KDM4B in CRPC and to provide proof-of-concept evidence that KDM4B is a potential CRPC target. Methods: CRPC cells (C4-2B or CWR22Rv1) depleted with KDM4B followed by cell proliferation ( in vitro and xenograft), microarray, qRT-PCR, Seahorse Flux, and metabolomic analyses were employed to identify the expression and metabolic profiles mediated by KDM4B. Immunoprecipitation was used to determine the KDM4B-c-Myc interaction region. Reporter activity assay and ChIP analysis were used to characterize the KDM4B-c-Myc complex-mediated mechanistic actions. The clinical relevance between KDM4B and c-Myc was determined using UCSC Xena analysis and immunohistochemistry. Results: We showed that KDM4B knockdown impaired CRPC proliferation, switched Warburg to OXPHOS metabolism, and suppressed gene expressions including those targeted by c-Myc. We further demonstrated that KDM4B physically interacted with c-Myc and they were co-recruited to the c-Myc-binding sequence on the promoters of metabolic genes ( LDHA , ENO1 , and PFK ). Importantly, KDM4B and c-Myc synergistically promoted the transactivation of the LDHA promoter in a demethylase-dependent manner. We also provided evidence that KDM4B and c-Myc are co-expressed in PCa tissue and that high expression of both is associated with worse clinical outcome. Conclusions: KDM4B partners with c-Myc and serves as a coactivator of c-Myc to directly enhance c-Myc-mediated metabolism, hence promoting CRPC progression. Targeting KDM4B is thus an alternative therapeutic strategy for advanced prostate cancers driven by c-Myc and AR., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Neoadjuvant chemotherapy (NACT) was initially applied to locally advanced breast cancer to convert advanced lesions to an operable status. Currently, its application has been expanded to enhance overall oncological results, especially in patients with triple-negative or HER-2-positive breast cancer. With more NACT being applied, the role and impact of this approach on breast reconstruction needs to be determined. This study aimed to perform a complete reconstructive outcome analysis of patients receiving NACT who underwent immediate breast reconstruction., Methods: A retrospective review of a single reconstructive surgeon's immediate breast reconstructions performed from July 2008 to December 2018 was undertaken. The results were stratified by the use of NACT. Patient demographics, delivery of NACT, adjuvant treatment, incidence of surgical complications, and postoperative photographs were analyzed., Results: A total of 269 patients were included. The mean follow-up was 46.3 months. Forty-six out of 269 patients received NACT and were included in the NACT group. The other patients were included in the non-NACT group. When implant-based reconstruction was planned, the NACT group had a higher rate of two-stage tissue expander-implant reconstruction than direct-to-implant reconstruction (p < 0.001). The requirement for postmastectomy radiotherapy was higher in the NACT group (p < 0.001). The surgical complication rates were similar between groups after adjusting for confounding factors. The objective aesthetic outcomes assessed by 6 plastic surgeons were also similar between groups., Conclusions: Immediate breast reconstruction is a safe and reliable procedure, with an acceptable reconstructive complication rate and satisfactory aesthetic outcomes, for patients treated with NACT.

Background: Neoadjuvant chemotherapy (NAC) has been the standard treatment for locally advanced breast cancer for the purpose of downstaging or for conversion from mastectomy to breast conservation surgery (BCS). Locoregional recurrence (LRR) rate is still high after NAC. The aim of this study was to determine predictive factors for LRR in breast cancer patients in association with the operation types after NAC., Methods: Between 2005 and 2017, 1047 breast cancer patients underwent BCS or mastectomy after NAC in Chang Gung Memorial Hospital, Linkou. We obtained data regarding patient and tumor characteristics, chemotherapy regimens, clinical tumor response, tumor subtypes and pathological complete response (pCR), type of surgery, and recurrence., Results: The median follow-up time was 59.2 months (range 3.13-186.75 months). The mean initial tumor size was 4.89 cm (SD ± 2.95 cm). Of the 1047 NAC patients, 232 (22.2%) achieved pCR. The BCS and mastectomy rates were 41.3% and 58.7%, respectively. One hundred four patients developed LRR (9.9%). Comparing between patients who underwent BCS and those who underwent mastectomy revealed no significant difference in the overall LRR rate of the two groups, 8.8% in BCS group vs 10.7% in mastectomy group (p = 0.303). Multivariate analysis indicated that independent factors for the prediction of LRR included clinical N2 status, negative estrogen receptor (ER), and failure to achieve pCR. In subgroups of multivariate analysis, only negative ER was the independent factor to predict LRR in mastectomy group (p = 0.025) and hormone receptor negative/human epidermal growth factor receptor 2 positive (HR-/HER2 +) subtype (p = 0.006) was an independent factor to predict LRR in BCS patients. Further investigation according to the molecular subtype showed that following BCS, non-pCR group had significantly increased LRR compared with the pCR group, in HR-/HER2 + subtype (25.0% vs 8.3%, p = 0.037), and HR-/HER2- subtype (20.4% vs 0%, p = 0.002)., Conclusion: Clinical N2 status, negative ER, and failure to achieve pCR after NAC were independently related to the risk of developing LRR. Operation type did not impact on the LRR. In addition, the LRR rate was higher in non-pCR hormone receptor-negative patients undergoing BCS comparing with pCR patients.

Objectives: To achieve a consensus statement on robotic mastectomy., Background: Robotic-assisted surgery has gained much attention especially the results of few case series reporting on the technical feasibility, safety and early oncologic outcomes of robotic-assisted mastectomy in a few centers worldwide. The aim of this consensus statement was to develop and provide standardized guidelines on robotic mastectomy based on consensus statement by a panel of experts from indications to outcome measures and indicators, thereby providing a valuable guide for breast surgeons worldwide., Methodology: An internationally representative expert panel of 10 surgeons was invited to participate in the generation of a consensus statement. 52 statements were created in 6 domains: indications, contraindications, technical considerations, patient counseling, outcome measures and indicators, training and learning curve assessment. Experts were asked to vote if they agree, disagree or of the opinion that the statement should be rephrased. Two electronic rounds via online survey of iterative rating and feedback were anonymously completed, followed by a final round of in-person meeting during the inaugural International Endoscopic and Robotic Breast Surgery Symposium 2019 from May 24 to 25, 2019. Consensus was reached when there was at least 80% agreement on each statement., Results: A total of 53 statements with at least 80% agreement were generated after 3 rounds of voting; 21 statements from first round of voting, 20 statements from second round of voting and 12 statements from the final round of in-person meeting. All experts agreed that the consensus statement served as expert recommendations but not mandatory for a successful and safe practice of robotic mastectomy., Conclusion: Robotic mastectomy is a promising technique and could well be the future of minimally invasive breast surgery whereas proving to be safe and feasible. The first consensus statement on robotic mastectomy from an international panel of experts serves as an extremely important milestone and provides recommendations for breast surgeons keen to embark on this technique.

Objective: The characteristics of patients with metachronous breast and ovarian malignancies and the pathogenic role of BRCA1/2 mutations remain poorly understood. We investigated these issues through a review of hospital records and nationwide Taiwanese registry data, followed by BRCA1/2 mutation analysis in hospital-based cases., Methods: We retrospectively retrieved consecutive clinical records of Taiwanese patients who presented with these malignancies to our hospital between 2001 and 2017. We also collected information from the Data Science Center of the Taiwan Cancer Registry (TCR) between 2007 and 2015. Next-generation sequencing and multiplex ligation-dependent probe amplification were used to identify BRCA1/2 mutations and large genomic rearrangements, respectively. When BRCA1/2 mutations were identified in index cases, pedigrees were reconstructed and genetic testing was offered to family members., Results: A total of 12,769 patients with breast cancer and 1,537 with ovarian cancer were retrieved from our hospital records. Of them, 28 had metachronous breast and ovarian malignancies. We also identified 113 cases from the TCR dataset. Eighteen hospital-based cases underwent BRCA1/2 sequencing and germline pathogenic mutations were detected in 7 patients (38.9%, 5 in BRCA1 and 2 in BRCA2 ). All BRCA1/2 mutation carriers had ovarian high-grade serous carcinomas. Of the 12 patients who were alive at the time of analysis, 5 were BRCA1/2 mutation carriers. All of them had family members with BRCA1/2 -associated malignancies., Conclusions: Our results provide pilot evidence that BRCA1/2 mutations are common in Taiwanese patients with metachronous breast and ovarian malignancies, supporting the clinical utility of genetic counseling., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Purpose: Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis-related liver cancers., Experimental Design: We conducted loss-of-function screening to elucidate the roles of RTKs in the development of HCC in vitro and in vivo ., Results: Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical-induced hepatitis transcriptionally activated Tyro3 expression via IL-6/IL6R-STAT3 signaling. Moreover, hepatitis-associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3-mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC- and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice., Conclusions: Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3-mediated signaling in HCC cells, which further elicits the "TYRO3-STAT3-TYRO3" signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis-associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity., (©2019 American Association for Cancer Research.)

Background: This study aimed to identify the factors that predict distant recurrence and survival outcome after patients with primary positive hormone receptor-positive (HR+) invasive breast cancer undergo complete excision for isolated local recurrence (ILR)., Methods: From January 2000 to December 2009, we performed a retrospective review of our database and identified 51 patients with HR + invasive breast cancer who underwent complete excision for ILR as a component of salvage therapy. The distant metastasis-free survival (DMFS) and overall survival (OS) from the time of ILR were calculated using the Kaplan-Meier method, and a Cox regression model was used for multivariate analysis., Results: Of the 51 cases of ILR, 28 were of ipsilateral breast tumor recurrence and 23 were of chest wall recurrence. By receiver operating characteristic curve analyses, the cut-off time point for time to ILR was determined to be 29 months. According to time to ILR (≤29 vs. >29 months) and primary tumor size (≤2 vs. >2 cm), patients were divided into four risk groups as variables for analysis. On multivariate analysis, two independent prognostic factors for DMFS and OS after ILR were identified: risk groups (ILR≤29 months with primary tumor size >2 cm vs. ILR>29 months with primary tumor size ≤ 2 cm, HR = 8.53 for DMFS and HR = 11.18 for OS) and primary tumor grade (2/3 vs. 1, HR = 6.10 for DMFS and 4.27 for OS)., Conclusion: We demonstrated that poor DMFS and OS are associated with high risk group defined as short time to ILR (≤29 months) with primary tumor size (>2 cm) and higher primary tumor grade (2/3) among patients with HR + invasive breast cancer treated with complete excision for ILR. Therapeutic strategies for ILR based on hormone therapy with new agents should be explored in future prospective studies, especially for patients with poor outcome., (Copyright © 2019 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

The accessory nidamental gland (ANG) is a female reproductive organ found in most squid and cuttlefish that contains a consortium of bacteria. These symbiotic bacteria are transmitted from the marine environment and selected by the host through an unknown mechanism. In animals, a common antimicrobial mechanism of innate immunity is iron sequestration, which is based on the development of transferrin (TF)-like proteins. To understand this mechanism of host-microbe interaction, we attempted to characterize the role of transferrin in bigfin reef squid (Sepioteuthis lessoniana) during bacterial transmission. qPCR analysis showed that Tf was exclusively expressed in the outer layer of ANG,and this was confirmed by in situ hybridization, which showed that Tf was localized in the outer epithelial cell layer of the ANG. Western blot analysis indicated that TF is a soluble glycoprotein. Immunohistochemical staining also showed that TF is localized in the outer epithelial cell layer of the ANG and that it is mainly expressed in the outer layer during ANG growth. These results suggest that robust Tf mRNA and TF protein expression in the outer layer of the ANG plays an important role in microbe selection by the host during bacterial transmission.

Purpose: Myelodysplastic syndromes (MDS) with deletion of chromosome 7q/7 [-7/(del)7q MDS] is associated with worse outcomes and needs novel insights into pathogenesis. Reduced expression of signaling protein dedicator of cytokinesis 4 (DOCK4) in patients with -7/(del)7q MDS leads to a block in hematopoietic stem cell (HSC) differentiation. Identification of targetable signaling networks downstream of DOCK4 will provide means to restore hematopoietic differentiation in MDS. Experimental Design: We utilized phosphoproteomics approaches to identify signaling proteins perturbed as a result of reduced expression of DOCK4 in human HSCs and tested their functional significance in primary model systems., Results: We demonstrate that reduced levels of DOCK4 lead to increased global tyrosine phosphorylation of proteins in primary human HSCs. LYN kinase and phosphatases INPP5D (SHIP1) and PTPN6 (SHP1) displayed greatest levels of tyrosine phosphorylation when DOCK4 expression levels were reduced using DOCK4-specific siRNA. Our data also found that increased phosphorylation of SHIP1 and SHP1 phosphatases were due to LYN kinase targeting these phosphatases as substrates. Increased migration and impediment of HSC differentiation were consequences of these signaling alterations. Pharmacologic inhibition of SHP1 reversed these functional aberrations in HSCs expressing low DOCK4 levels. In addition, differentiation block seen in DOCK4 haplo-insufficient [-7/(del)7q] MDS was rescued by inhibition of SHP1 phosphatase., Conclusions: LYN kinase and phosphatases SHP1 and SHIP1 are perturbed when DOCK4 expression levels are low. Inhibition of SHP1 promotes erythroid differentiation in healthy HSCs and in -7/(del)7q MDS samples with low DOCK4 expression. Inhibitors of LYN, SHP1 and SHIP1 also abrogated increased migratory properties in HSCs expressing reduced levels of DOCK4., (©2019 American Association for Cancer Research.)