Results of Vertical Infra-Axillary Thoracotomy for Total Repair of Tetralogy of Fallot.

OBJECTIVE: To demonstrate the efficacy of minimally invasive surgery via a vertical infra-axillary incision for complete tetralogy of Fallot (TOF) correction. METHODS: In a study conducted from April to October 2023, 33 patients with TOF underwent total repair using this approach. On average, the patient age was 5.94 ± 2.68 months, weight was 6.49 ± 0.97 kg, and mean z-score index for the pulmonary valve annulus was -1.38 ± 0.92. Results also highlighted abnormal coronary artery pathways in 18.2% of cases, including 1 patient with dextrocardia and situs inversus. RESULTS: The average incision length was 4.01 ± 0.6 cm, with bypass and clamping times of 95.42 ± 33.19 min and 69.24 ± 28.15 min, respectively. Preservation of the pulmonary valve annulus was achieved in 67% of patients. No postoperative deaths occurred, and there were no significant ventilation differences between groups. After surgery, no severe pulmonary valve regurgitation was observed, with patients remaining in excellent condition throughout the 7-month follow-up. The pulmonary valve pressure gradient after the procedure was 23.97 ± 10.65 mm Hg, and no heart failure cases were reported per the Ross classification at the latest follow-up. CONCLUSIONS: The vertical infra-axillary incision approach for total TOF repair is safe, effective, and cosmetically advantageous.

Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy.

Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.

Impact of the COVID-19 pandemic on HPV vaccine uptake in a predominantly Hispanic Border Community: A retrospective cross-sectional analysis of the "Tiempo de Vacunarte Program".

BACKGROUND: Human Papillomavirus (HPV) is implicated in the pathogenesis of cancer in the cervix, vagina, throat and anogenital region. Although HPV vaccination rates in the Hispanic community have increased owing to public health efforts, the COVID-19 pandemic has brought unique public health challenges and contributed to health inequity in this population. METHODS: To evaluate the impact of the COVID-19 pandemic on HPV vaccine uptake in a program designed to improve HPV vaccination rate in a predominantly Hispanic community in the border region of Texas (Tiempo de Vacunarte [time to get vaccinated]), we performed a retrospective cross-sectional analysis to evaluate the uptake of the first dose of HPV vaccine series among eligible adolescents and adults before (2016-2019), during (2020-2021), and after the COVID-19 pandemic (2022-2023). RESULTS: We observed a decrease in HPV vaccine uptake during the pandemic (69.59% vs. 89.92%) and post-pandemic (76% vs. 89.92%) compared to the pre-pandemic period. After adjusting for confounding factors, the reduction in the odds ratio was more pronounced in the pandemic (OR = 0.091, p < 0.001) and post-pandemic (OR = 0.109, p < 0.001) periods. CONCLUSION: Our findings suggest that the COVID-19 pandemic significantly impacted the uptake of the HPV vaccine in a comprehensive intervention program to increase HPV vaccination in a border community.

Electron transport chain inhibition increases cellular dependence on purine transport and salvage.

Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts from patients with various mitochondrial disorders and cancer cells with electron transport chain (ETC) blockade. These analyses revealed extensive perturbations in purine metabolism, and stable isotope tracing demonstrated that ETC defects suppress de novo purine synthesis while enhancing purine salvage. In human lung cancer, tumors with markers of low oxidative mitochondrial metabolism exhibit enhanced expression of the salvage enzyme hypoxanthine phosphoribosyl transferase 1 (HPRT1) and high levels of the HPRT1 product inosine monophosphate. Mechanistically, ETC blockade activates the pentose phosphate pathway, providing phosphoribosyl diphosphate to drive purine salvage supplied by uptake of extracellular bases. Blocking HPRT1 sensitizes cancer cells to ETC inhibition. These findings demonstrate how cells remodel purine metabolism upon ETC blockade and uncover a new metabolic vulnerability in tumors with low respiration.

Palliative procedures for malignant gastric outlet obstruction: a network meta-analysis.

BACKGROUND: The optimal treatment for malignant gastric outlet obstruction (GOO) remains uncertain. This systematic review aimed to comprehensively investigate the efficacy and safety of four palliative treatments for malignant GOO: gastrojejunostomy, endoscopic ultrasound-guided gastroenterostomy (EUS-GE), stomach-partitioning gastrojejunostomy (PGJ), and endoscopic stenting. METHODS: We searched PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform for randomized controlled trials (RCTs) and cohort studies comparing the four treatments for malignant GOO. We included studies that reported at least one of the following clinical outcomes: clinical success, 30-day mortality, reintervention rate, or length of hospital stay. Evidence from RCTs and non-RCTs was naïve combined to perform network meta-analysis through the frequentist approach using an inverse variance model. Treatments were ranked by P score. RESULTS: This network meta-analysis included 3617 patients from 4 RCTs, 4 prospective cohort studies, and 32 retrospective cohort studies. PGJ was the optimal approach in terms of clinical success and reintervention (P scores: 0.95 and 0.90, respectively). EUS-GE had the highest probability of being the optimal treatment in terms of 30-day mortality and complications (P scores: 0.82 and 0.99, respectively). Cluster ranking to combine the P scores for 30-day mortality and reintervention indicated the benefits of PGJ and EUS-GE (cophenetic correlation coefficient: 0.94; PGJ and EUS-GE were in the same cluster). CONCLUSION: PGJ and EUS-GE are recommended for malignant GOO. PGJ could be the alternative choice in centers with limited resources or in patients who are unsuitable for EUS-GE.

Prevalence and determinants of constipation in children in Asia: a systematic review and meta-analysis.

Background: Constipation is prevalent worldwide, significantly increasing healthcare costs and diminishing the quality of life in children affected. Current studies have yielded mixed results regarding the factors associated with constipation, and mainly focusing on patients outside of Asia. Moreover, most of these studies lack focus on the paediatric population. This study aimed to identify the prevalence and associated factors of constipation among children in Asia. Methods: In this systematic review and meta-analysis, we systematically searched PubMed, Scopus, and Cochrane for cohort and cross-sectional studies published from database inception up to October 12, 2022, and continued with manual searching until September 2, 2023. Eligible studies were those that included children in Asia aged 0-18 years old suffering from idiopathic constipation, with prevalence value provided in the English abstract. The analysis included clinical and general population. Children with organic constipation, who had undergone gastrointestinal surgery, or with congenital defects were excluded, as these factors affect the incidence of constipation. Data included in the analysis were extracted from published reports only. The extracted data were pooled using random-effects model to analyse the prevalence of constipation in children in Asia. This study is registered with PROSPERO, CRD42022367122. Findings: Out of 4410 systematically searched studies and 36 manually searched ones, a total of 50 studies were included in the final analysis, encompassing data from 311,660 children residing in Asia. The pooled prevalence of constipation was 12.0% (95% CI 9.3-14.6%, I2 = 99.8%). There was no significant difference in constipation prevalence observed by sex and geographical location. Nonetheless, adolescents and children aged 1-9 years exhibited a significantly higher prevalence constipation compared to infants (p < 0.0001) Additionally, significant differences in constipation rates were observed across various diagnostic methods, population sources, and mental health conditions. Interpretation: Despite the high heterogeneity resulting from varying diagnostic tools or definitions used among studies, our review adds to the literature on constipation among children in Asia. It reveals a notably high prevalence of constipation in this demographic. Diagnostic methods, age, and compromised mental health emerged as significant influencers of constipation among children in Asia, highlighting potential strategies to mitigate constipation prevalence in children in Asia. Funding: The National Science and Technology Council, Taiwan.

A Clinicopathologic Continuum of Eosinophilic Gastrointestinal Diseases in an Adult With Tuberculosis and Latent Hepatitis B Virus Infection.

Eosinophilic gastroenteritis (EGE) is considered distinct from eosinophilic colitis (EC). A 59-year-old man presented with a colonic tumor, who had resolution of pain and diarrhea after surgery, then 7 months later developed proton-pump inhibitor-responsive dysphagia with esophagitis, and 9 months later presented again with pain and diarrhea where EGE with concurrent eosinophilic esophagitis was diagnosed. Review of the resected tumor specimen identified EC with an adenoma. Workup revealed tuberculosis and latent hepatitis B virus requiring treatment before commencing immunosuppressive therapy plus a 6-food elimination diet that led to complete resolution within 3 weeks. EC may precede EGE and eosinophilic esophagitis.

Primary immature teratoma of the liver in an adult: Case report.

Teratoma is an uncommon germ cell tumor and develops from at least 2 of the 3 germ cell layers: ectoderm, mesoderm, and endoderm. The origin of teratoma is primordial germ cells that migrate from the allantois to the gonadal ridges during embryogenesis. The teratomas can be intragonadal or extragonadal. Primary extragonadal teratoma is defined as if there is no evidence of a primary tumor in the testicles or ovaries. Common extragonadal sites include the anterior mediastinum, retroperitoneum, sacral region, and intracranial cavity. Primary intrahepatic teratomas are extremely rare, accounting for less than 1% of all teratoma cases. Hepatic teratomas are more common in children than in adults. We present a case of an immature primary hepatic teratoma in an adult woman.

Electron transport chain inhibition increases cellular dependence on purine transport and salvage.

Cancer cells reprogram their metabolism to support cell growth and proliferation in harsh environments. While many studies have documented the importance of mitochondrial oxidative phosphorylation (OXPHOS) in tumor growth, some cancer cells experience conditions of reduced OXPHOS in vivo and induce alternative metabolic pathways to compensate. To assess how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts and plasma from patients with inborn errors of mitochondrial metabolism, and in cancer cells subjected to inhibition of the electron transport chain (ETC). All these analyses revealed extensive perturbations in purine-related metabolites; in non-small cell lung cancer (NSCLC) cells, ETC blockade led to purine metabolite accumulation arising from a reduced cytosolic NAD + /NADH ratio (NADH reductive stress). Stable isotope tracing demonstrated that ETC deficiency suppressed de novo purine nucleotide synthesis while enhancing purine salvage. Analysis of NSCLC patients infused with [U- 13 C]glucose revealed that tumors with markers of low oxidative mitochondrial metabolism exhibited high expression of the purine salvage enzyme HPRT1 and abundant levels of the HPRT1 product inosine monophosphate (IMP). ETC blockade also induced production of ribose-5' phosphate (R5P) by the pentose phosphate pathway (PPP) and import of purine nucleobases. Blocking either HPRT1 or nucleoside transporters sensitized cancer cells to ETC inhibition, and overexpressing nucleoside transporters was sufficient to drive growth of NSCLC xenografts. Collectively, this study mechanistically delineates how cells compensate for suppressed purine metabolism in response to ETC blockade, and uncovers a new metabolic vulnerability in tumors experiencing NADH excess.

The Correlation between Peripheral Blood Index and Immune Cell Expansion in Vietnamese Elderly Lung Cancer Patients.

(1) Background: The dysfunction and reduced proliferation of peripheral CD8+ T cells and natural killer (NK) cells have been observed in both aging and cancer patients, thereby challenging the adoption of immune cell therapy in these subjects. In this study, we evaluated the growth of these lymphocytes in elderly cancer patients and the correlation of peripheral blood (PB) indices to their expansion. (2) Method: This retrospective study included 15 lung cancer patients who underwent autologous NK cell and CD8+ T cell therapy between January 2016 and December 2019 and 10 healthy individuals. (3) Results: On average, CD8+ T lymphocytes and NK cells were able to be expanded about 500 times from the PB of elderly lung cancer subjects. Particularly, 95% of the expanded NK cells highly expressed the CD56 marker. The expansion of CD8+ T cells was inversely associated with the CD4+:CD8+ ratio and the frequency of PB-CD4+ T cells in PB. Likewise, the expansion of NK cells was inversely correlated with the frequency of PB-lymphocytes and the number of PB-CD8+ T cells. The growth of CD8+ T cells and NK cells was also inversely correlated with the percentage and number of PB-NK cells. (4) Conclusion: PB indices are intrinsically tied to immune cell health and could be leveraged to determine CD8 T and NK cell proliferation capacity for immune therapies in lung cancer patients.

A rare case of synchronous follicular thyroid carcinoma arising within a mature cystic ovarian teratoma and stage IV differentiated thyroid cancer in iodine-deficient area in Viet Nam.

Well-differentiated thyroid carcinoma rarely spreads to soft tissues. Thyroid carcinoma arising within a mature cystic teratoma is even rarer. We report an extremely rare case of synchronous follicular thyroid carcinoma arising within a mature cystic ovarian teratoma and stage IV differentiated thyroid carcinoma. A 62-year-old woman who lived in an iodine-deficient area was accidentally diagnosed with an ovarian cyst during a radiological metastatic work-up for thyroid cancer. Following laparoscopic left salpingo-oophorectomy, histopathological examination revealed a follicular thyroid carcinoma arising within a mature cystic teratoma. After that, total thyroidectomy and surgical resection of the soft tissue lesion in the supraclavicular fossa were performed, and the patient received subsequent 131I ablation therapy, but the disease progression was recorded 3 months later. We believe that iodine deficiency plays a role in the malignant transformation of thyroid tissues within a mature cystic teratoma. In elderly individuals with significant metastases, radioactive iodine therapy is ineffective.

Evaluating the Safety and Quality of Life of Colorectal Cancer Patients Treated by Autologous Immune Enhancement Therapy (AIET) in Vinmec International Hospitals.

(1) Colorectal cancer (CRC) is an increasingly prevalent disease with a high mortality rate in recent years. Immune cell-based therapies have received massive attention among scientists, as they have been proven effective as low-toxicity treatments. This study evaluated the safety and effectiveness of autologous immune enhancement therapy (AIET) for CRC. (2) An open-label, single-group study, including twelve patients diagnosed with stages III and IV CRC, was conducted from January 2016 to December 2021. Twelve CRC patients received one to seven infusions of natural killer (NK)-cell and cytotoxic T-lymphocyte (CTL). Multivariate modelling was used to identify factors associated with health-related quality-of-life (HRQoL) scores. (3) After 20−21 days of culture, the NK cells increased 3535-fold, accounting for 85% of the cultured cell population. Likewise, CTLs accounted for 62.4% of the cultured cell population, which was a 1220-fold increase. Furthermore, the QoL improved with increased EORTC QLQ-C30 scores, decreased symptom severity, and reduced impairment in daily living caused by these symptoms (MDASI-GI report). Finally, a 14.3 ± 14.1-month increase in mean survival time was observed at study completion. (4) AIET demonstrated safety and improved survival time and HRQoL for CRC patients in Vietnam.

Structural basis for gating mechanism of the human sodium-potassium pump.

P2-type ATPase sodium-potassium pumps (Na+/K+-ATPases) are ion-transporting enzymes that use ATP to transport Na+ and K+ on opposite sides of the lipid bilayer against their electrochemical gradients to maintain ion concentration gradients across the membranes in all animal cells. Despite the available molecular architecture of the Na+/K+-ATPases, a complete molecular mechanism by which the Na+ and K+ ions access into and are released from the pump remains unknown. Here we report five cryo-electron microscopy (cryo-EM) structures of the human alpha3 Na+/K+-ATPase in its cytoplasmic side-open (E1), ATP-bound cytoplasmic side-open (E1•ATP), ADP-AlF4- trapped Na+-occluded (E1•P-ADP), BeF3- trapped exoplasmic side-open (E2P) and MgF42- trapped K+-occluded (E2•Pi) states. Our work reveals the atomically resolved structural detail of the cytoplasmic gating mechanism of the Na+/K+-ATPase.

Virtual Reality Cardiac Surgical Planning Software (CorFix) for Designing Patient-Specific Vascular Grafts: Development and Pilot Usability Study.

BACKGROUND: Patients with single ventricle heart defects receive 3 stages of operations culminating in the Fontan procedure. During the Fontan procedure, a vascular graft is sutured between the inferior vena cava and pulmonary artery to divert deoxygenated blood flow to the lungs via passive flow. Customizing the graft configuration can maximize the long-term benefits. However, planning patient-specific procedures has several challenges, including the ability for physicians to customize grafts and evaluate their hemodynamic performance. OBJECTIVE: The aim of this study was to develop a virtual reality (VR) Fontan graft modeling and evaluation software for physicians. A user study was performed to achieve 2 additional goals: (1) to evaluate the software when used by medical doctors and engineers, and (2) to explore the impact of viewing hemodynamic simulation results in numerical and graphical formats. METHODS: A total of 5 medical professionals including 4 physicians (1 fourth-year resident, 1 third-year cardiac fellow, 1 pediatric intensivist, and 1 pediatric cardiac surgeon) and 1 biomedical engineer voluntarily participated in the study. The study was pre-scripted to minimize the variability of the interactions between the experimenter and the participants. All participants were trained to use the VR gear and our software, CorFix. Each participant designed 1 bifurcated and 1 tube-shaped Fontan graft for a single patient. A hemodynamic performance evaluation was then completed, allowing the participants to further modify their tube-shaped design. The design time and hemodynamic performance for each graft design were recorded. At the end of the study, all participants were provided surveys to evaluate the usability and learnability of the software and rate the intensity of VR sickness. RESULTS: The average times for creating 1 bifurcated and 1 tube-shaped graft after a single 10-minute training session were 13.40 and 5.49 minutes, respectively, with 3 out 5 bifurcated and 1 out of 5 tube-shaped graft designs being in the benchmark range of hepatic flow distribution. Reviewing hemodynamic performance results and modifying the tube-shaped design took an average time of 2.92 minutes. Participants who modified their tube-shaped graft designs were able to improve the nonphysiologic wall shear stress (WSS) percentage by 7.02%. All tube-shaped graft designs improved the WSS percentage compared to the native surgical case of the patient. None of the designs met the benchmark indexed power loss. CONCLUSIONS: VR graft design software can quickly be taught to physicians with no engineering background or VR experience. Improving the CorFix system could improve performance of the users in customizing and optimizing grafts for patients. With graphical visualization, physicians were able to improve WSS percentage of a tube-shaped graft, lowering the chance of thrombosis. Bifurcated graft designs showed potential strength in better flow split to the lungs, reducing the risk for pulmonary arteriovenous malformations.

Fat-Free Mass and Skeletal Muscle Mass Gain Are Associated with Diabetes Remission after Laparoscopic Sleeve Gastrectomy in Males but Not in Females.

Besides massive body weight loss, laparoscopic sleeve gastrectomy (LSG) causes massive lean mass, including fat-free mass (FFM) and skeletal muscle mass (SM) that present higher metabolic rates in males. This study examines sex differences in FFM and SM changes of type 2 diabetes (T2D) remission at 12 months post-LSG. This cohort study recruited 119 patients (53.7% females) with T2D and obesity (body mass index 42.2 ± 7.0 kg/m2) who underwent LSG. Fat-mass (FM) loss was higher in males than in females (-12.8 ± 6.2% vs. -9.9 ± 5.0%, p = 0.02) after one-year post-operation. Regardless of the weight-loss difference, males had higher FFM and SM gain than did females (12.8 ± 8.0 vs. 9.9 ± 5.0% p = 0.02 and 6.5 ± 4.3% vs. 4.9 ± 6.2%, p = 0.03, respectively). Positive correlations of triglyceride reduction with FM loss (r = 0.47, p = 0.01) and SM gain (r = 0.44, p = 0.02) over 12 months post-operation were observed in males who achieved T2D remission. The T2D remission rate significantly increased 16% and 26% for each additional percentage of FFM and SM gain one year after LSG, which only happened in males. Increased FFM and SM were remarkably associated with T2D remission in males, but evidence lacks for females.

Outcomes of Sentinel Node Biopsy for Women with Breast Cancer After Neoadjuvant Therapy: Systematic Review and Meta-Analysis of Real-World Data.

BACKGROUND: Evidence on the accuracy of sentinel lymph node biopsy (SLNB) after neoadjuvant therapy (NAT) for patients with breast cancer is inconclusive. This study reviewed the real-world data to determine the acceptability of SLNB after NAT. METHODS: The study searched for articles in the PubMed, EMBASE, and Cochrane Library databases. The primary outcomes were the identification rate for sentinel lymph nodes (SLNs) and the false-negative rate (FNR) for SLNB. The study also evaluated the FNR in subgroups defined by tumor stage, nodal stage, hormone receptor status, human epidermal growth factor receptor-2 status, tumor response, mapping technique, and number of SLNs removed. RESULTS: The study retrieved 61 prospective and 18 retrospective studies with 10,680 initially cN± patients. The pooled estimate of the identification rate was 0.906 (95 % confidence interval [CI], 0.891-0.922), and the pooled FNR was 0.118 (95 % CI, 0.103-0.133). In subgroup analysis, the FNR was significantly higher for the patients with estrogen receptor (ER)-negative status and fewer than three SLNs removed. The FNR did not differ significantly between the patients with and those without complete tumor response. Among the patients with initial clinical negative axillary lymph nodes, the incidence of node metastasis was 26.8 % (275/1041) after NAT. CONCLUSION: Real-world evidence indicates that the FNR of SLNB after NAT in breast cancer is 11.8 %, exceeding only slightly the commonly adopted threshold of 10 %. The FNR is significantly higher for patients with ER-negative status and removal of fewer than three SLNs. Using a dual tracer and removing at least three SLNs may increase the accuracy of SLNB after NAT.

Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor.

KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.

Enhancing plant growth and biomass production by overexpression of GA20ox gene under control of a root preferential promoter.

Overexpression of GA20 oxidase gene has been a recent trend for improving plant growth and biomass. Constitutive expression of GA20ox has successfully improved plant growth and biomass in several plant species. However, the constitutive expression of this gene causes side-effects, such as reduced leaf size and stem diameter, etc. To avoid these effects, we identified and employed different tissue-specific promoters for GA20ox overexpression. In this study, we examined the utility of At1g promoter to drive the expression of GUS (ß-glucuronidase) reporter and AtGA20ox genes in tobacco and Melia azedarach. Histochemical GUS assays and quantitative real-time-PCR results in tobacco showed that At1g was a root-preferential promoter whose expression was particularly strong in root tips. The ectopic expression of AtGA20ox gene under the control of At1g promoter showed improved plant growth and biomass of both tobacco and M. azedarach transgenic plants. Stem length as well as stem and root fresh weight increased by up to 1.5-3 folds in transgenic tobacco and 2 folds in transgenic M. azedarach. Both tobacco and M. azedarach transgenic plants showed increases in root xylem width with xylem to phloem ratio over 150-200% as compared to WT plants. Importantly, no significant difference in leaf shape and size was observed between At1g::AtGA20ox transgenic and WT plants. These results demonstrate the great utility of At1g promoter, when driving AtGA20ox gene, for growth and biomass improvements in woody plants and potentially some other plant species.

Inferred Ancestral Origin of Cancer Cell Lines Associates with Differential Drug Response.

Disparities between risk, treatment outcomes and survival rates in cancer patients across the world may be attributed to socioeconomic factors. In addition, the role of ancestry is frequently discussed. In preclinical studies, high-throughput drug screens in cancer cell lines have empowered the identification of clinically relevant molecular biomarkers of drug sensitivity; however, the genetic ancestry from tissue donors has been largely neglected in this setting. In order to address this, here, we show that the inferred ancestry of cancer cell lines is conserved and may impact drug response in patients as a predictive covariate in high-throughput drug screens. We found that there are differential drug responses between European and East Asian ancestries, especially when treated with PI3K/mTOR inhibitors. Our finding emphasizes a new angle in precision medicine, as cancer intervention strategies should consider the germline landscape, thereby reducing the failure rate of clinical trials.

Outcome after hematopoietic stem cell transplantation in patients with extranodal natural killer/T-Cell lymphoma, nasal type: A French study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

We evaluated the outcome of 65 French patients with Extranodal NK/T-cell lymphoma, nasal type (ENKTL) undergoing hematopoietic stem cell transplantation (HSCT) (19 allogeneic and 46 autologous). Fifty-four patients (83%), most of which receiving L-asparaginase (L-aspa) containing regimens (81%), achieved complete or partial response at time of HCST. After a median follow-up of 79.9 months, 4-years progression-free survival (PFS) and overall survival (OS) were similar in both autologous and allogeneic groups (PFS: 34% vs. 26%, p = .12 and OS: 52% vs. 53%, p = .74). Response status at HSCT was the major independent prognostic factor on survival (OS: HR: 4.013 [1.137; 14.16], p = .031 and PFS: HR: 5.231 [1.625; 16.838], p = .006). As compared to control patients receiving chemotherapy and/or radiotherapy containing regimens only, upfront HSCT did not improve the outcome of responder patients, including those treated by L-aspa. However, it tends to provide survival benefit for relapsed patients with initial high-risk clinical features who achieved second remission. Whereas the place of HSCT in upfront therapy has still to be clarified, these data confirm that HSCT should be considered for consolidation in selected patients with relapsed ENKTL. Based on a large non Asian ENKTL cohort since the L-aspa era, this study provides some insight into the survival patterns of ENKTL patients with HSCT in the Western hemisphere and may give future direction for the next clinical trial design.