Enhancing carboplatin sensitivity in ovarian cancer cells by blocking the mercapturic acid pathway transporter.

Ral-binding/interacting protein (RLIP) acts as a transporter that responds to stress and provides protection, specifically against glutathione-electrophile conjugates and xenobiotic toxins. Its increased presence in malignant cells, especially in cancer, emphasizes its crucial antiapoptotic function. This is achieved by selectively regulating the cellular levels of proapoptotic oxidized lipid byproducts. Suppressing the progression of tumors in human xenografts can be achieved by effectively inhibiting RLIP, a transporter in the mercapturic acid pathway, without involving chemotherapy. Utilizing ovarian cancer (OC) cell lines (MDAH2774, OVCAR4, and OVCAR8), we observed that agents targeting RLIP, such as RLIP antisense and RLIP antibodies, not only substantially impeded the viability of OC cells but also remarkably increased their sensitivity to carboplatin. To delve further into the cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin, we conducted investigations in both cell culture and xenografts of OC cells. The outcomes revealed that RLIP depletion via phosphorothioate antisense led to rapid and sustained remissions in established subcutaneous human ovary xenografts. Furthermore, RLIP inhibition by RLIP antibodies exhibited comparable efficacy to antisense and enhanced the effectiveness of carboplatin in MDAH2774 OC xenografts. These investigations underscore RLIP as a central carrier crucial for supporting the survival of cancer cells, positioning it as a suitable focus for cancer treatment.

A phase I study of Mirvetuximab Soravtansine and gemcitabine in patients with FRα-positive recurrent ovarian, primary peritoneal, fallopian tube, or endometrial cancer, or triple negative breast cancer.

OBJECTIVE: Platinum-resistant epithelial ovarian cancer (EOC), recurrent endometrial cancer (EC), and triple negative breast cancer (TNBC) are difficult to treat after failing standard therapies. This phase I study evaluated mirvetuximab soravtansine (MIRV) and gemcitabine in patients with recurrent FRα-positive EOC, EC, or TNBC to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (primary endpoint). METHODS: FRα-positive patients with platinum-resistant EOC, EC, or TNBC with ≤4 prior chemotherapy regimens (2 for EC) were enrolled. FRα expression requirement varied among eligible tumors and changed during the study. RESULTS: Twenty patients were enrolled; 17 were evaluable for DLT. Half the patients received ≥3 prior chemotherapy lines. Most EOC and EC patients (78%) were medium (50-74%) or high(75-100%) FRα expressors. TNBC patients were low (25-49%) FRα expressors. The MTD/RP2D was MIRV 6 mg/kg AIBW D1 and gemcitabine 800 mg/m2 IV, D1 and D8, every 21 days (Dose Level [DL] 3), where 5/7 patients demonstrated a partial response (PR) as their best response, including 2 confirmed ovarian responses whose time-to-progression and duration of response were 7.9/5.4 and 8.0/5.7 months respectively. Most common treatment-related adverse events at MTD were anemia and neutropenia (3/7 each, 43%), diarrhea, hypophosphatemia, thrombocytopenia, and leukopenia (2/7 each, 29%). DLTs were thrombocytopenia (DL1), oral mucositis (DL4) and diarrhea (DL4). Nine of 20 patients (45%; 95% CI: 21.1-68.9%) achieved PR as their best response, with 3/20 patients or 15% (95%CI, 0-32.1%) confirmed PR. CONCLUSION: MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.

Correlation between a 2-week change in platelet count and clinical outcomes after the initiation of ravulizumab treatment in adult patients with atypical hemolytic uremic syndrome: post-hoc analysis of the phase III trial.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease with poor outcomes when untreated, in which ravulizumab or eculizumab are the standard of care where available. It has been proposed to regularly monitor platelet counts as an early response to ravulizumab or eculizumab. This study aimed to investigate the association between the early response to ravulizumab treatment and renal outcomes through 26 weeks in complement inhibitor-naïve adults with aHUS. METHODS: Adult patients with aHUS enrolled in the ALXN1210-aHUS-311 phase III study of ravulizumab were divided into two groups according to the achievement of complete thrombotic microangiopathy (TMA) response, i.e., platelet count and lactate dehydrogenase (LDH) normalization and ≥ 25% improvement in serum creatinine (sCr) from baseline, by 26 weeks and baseline characteristics were compared. Changes in hematologic parameters, platelet count and LDH, were compared between the two groups. Finally, we examined whether early hematologic improvement was associated with renal recovery (dialysis discontinuation or ≥ 25% improvement in sCr from baseline) through 26 weeks. RESULTS: Of 56 ravulizumab-treated patients, 30 achieved complete TMA response for 26 weeks, and 26 did not. Patients with complete TMA response showed rapid improvements in platelet counts. In patients without complete TMA response, delayed normalization of platelet counts was observed. By day 15, 93.3% (28/30) of patients with complete TMA response at 26 weeks and 26.9% (7/26) of patients without complete TMA response achieved platelet normalization. At 26 weeks, 62.5% (35/56) achieved renal recovery; however, 37.5% (21/56) did not. In patients with renal recovery, 85.7% (30/35) of patients had platelet count normalization by day 15; in patients without renal recovery, 23.8% (5/21) of patients had platelet count normalization (P < 0.0001). Receiver operator characteristic curve analysis showed a moderate association between platelet counts on day 8/15 and renal recovery within 26 weeks (day 8: area under the curve [AUC] = 0.7985; day 15: AUC = 0.8406). CONCLUSIONS: Platelet count normalization occurred in 62.5% (35/56) by day 15 after ravulizumab initiation and was associated with renal recovery through 26 weeks in complement inhibitor-naïve adults with aHUS. TRIAL REGISTRATION: This study was performed as a post-hoc analysis of the ALXN1210-aHUS-311 phase III clinical trial (NCT02949128, registered October 25, 2016).

A prospective study of nightmare disorder among Chinese adults in Hong Kong: Persistence and mental health outcomes.

OBJECTIVES: Previous studies showed that nightmares are prevalent and are associated with negative health outcomes. However, no empirical data is available demonstrating the extent to which nightmare disorder persists over time. Current literature provides a limited understanding of the trajectory and wider mental health outcomes of nightmare disorder. This longitudinal study examined the persistence and mental health outcomes of nightmare disorder. METHODS: A total of 230 Hong Kong Chinese adults completed standardized assessments twice with an interval of about 6 months. RESULTS: Over half (66.7%) of the participants with probable nightmare disorder at baseline remained to meet the DSM-5 criteria for the disorder at follow-up. Participants with probable nightmare disorder at baseline were significantly more likely to screen positive for PTSD (82.1% vs 18.3%) (p < .001) (p < .001), and they reported higher rates of mental health service usage at both timepoints (p = .001 to .003). Baseline nightmare disorder severity was negatively associated with subsequent self-rated mental health (ß = -.151, p = .010) and self-esteem (ß = -.141, p = .009) and it also predicted subsequent PTSD symptoms (ß = .122, p = .012). CONCLUSIONS: This study provides first empirical data showing that nightmare disorder could be persistent over time. Nightmare disorder symptoms are associated not only with PTSD symptoms but also with a broader range of mental health issues. This study points to the public health importance of identifying and managing nightmare disorder symptoms in the community. Additionally, the presence of nightmare disorder symptoms may be a helpful indicator for identifying post-traumatic stress.

Thoracoscopic Left Atrial Appendage Occlusion with the AtriClip PRO2: An Experience of 144 Patients.

AIM: To report the clinical outcomes of thoracoscopic left atrial appendage occlusion (LAAO) with the AtriClip PRO2 device (Atricure Inc, Mason, OH, USA). Stroke risk reduction with LAAO in patients with atrial fibrillation is now well-established. Many surgical and percutaneous techniques have been used, with varying rates of success. The percutaneous devices have had issues with procedural complications and peridevice flow. Thoracoscopic AtriClip offers an epicardial linear closure of the appendage at its ostium. This study sought to evaluate its safety and efficacy in achieving complete LAA closure. METHOD: This is a prospective series of thoracoscopic AtriClip PRO2 as a standalone procedure or a thoracoscopic AtriClip deployed as an adjunct to minimal access cardiac and thoracic surgery. Study ethical approval was granted by the hospital Human Research Ethics Committee. RESULTS: In total, 144 thoracoscopic AtriClip procedures were conducted by a single surgeon from 2017 to 2022, 56 standalone and 88 concomitant. There was no mortality or major morbidities. A 100% success in complete LAA closure was observed, with 87% complete follow-up imaging. For patients that underwent standalone AtriClip after cessation of anticoagulation, no thromboembolic phenomena were seen in the 180 patient-years of follow-up. CONCLUSIONS: This study demonstrates that thoracoscopic placement of AtriClip is safe and effective in achieving consistent and complete LAAO. Future randomised trials will be useful to compare outcomes with percutaneous devices.

Preoperative Dehydration Is an Underrecognized Modifiable Risk Factor in Total Hip Arthroplasty.

Dehydration is an overlooked modifiable risk factor that should be optimized prior to elective total hip arthroplasty (THA) to reduce postoperative complications and inpatient costs. All primary THA from 2005 - 2019 were queried from the National Surgical Quality Improvement Program database, and patients were compared based on dehydration status: blood urea nitrogen (BUN): creatinine ratio (Cr) (BUN/Cr) < 20 (nondehydrated), 20 ≤ BUN/Cr ≤ 25 (moderately dehydrated), 25 < BUN/Cr (severely dehydrated). A subgroup analysis involving only elderly patients > 65 years and normalized gender-adjusted Cr values was also performed. The analysis included 212,452 patients who underwent THA. Adjusted multivariate logistic regression analysis showed that the severely dehydrated cohort had a greater risk of overall complications, postoperative anemia requiring transfusion, nonhome discharge, and increased length of stay (all p < 0.01). Among the elderly, dehydrated patients had a greater risk of postoperative transfusion, cardiac complications, and nonhome discharge (all p < 0.01). BUN/Cr > 20 is an important preoperative diagnostic tool to identify at-risk dehydrated patients. Providers should optimize dehydration to prevent complications, decrease costs, and improve discharge planning. (Journal of Surgical Orthopaedic Advances 33(1):017-025, 2024).

Preoperative chronic steroid use as a risk factor for complications following open reduction internal fixation for proximal humerus fracture.

PURPOSE: The primary objective of this study was to investigate the association between preoperative chronic steroid use and postoperative complications following open reduction internal fixation (ORIF) for proximal humerus fractures (PHF). METHODS: The American College of Surgeons National Surgical Quality Improvement (ACS-NSQIP) database was queried for all patients who underwent PHF ORIF between 2015 and 2021. A total of 6,273 patients were included in this study, of which 3.4% (n = 212) were in the chronic steroid use cohort. Patient characteristics including demographics, comorbidities, and 30-day postoperative complications after PHF ORIF were collected. Bivariate logistic regression and multivariate logistic regression analysis, adjusted for all significantly associated variables, was conducted to investigate the relationship between preoperative chronic steroid use and postoperative complications. RESULTS: Chronic steroid use was significantly associated with age ≥ 75 (p < 0.001), male gender (p =0.006), dependent functional status (p = 0.008), American Society of Anesthesiologist (ASA) ≥ 3 (p < 0.001), CHF (p = 0.007), hypertension (p < 0.001), COPD (p < 0.001), bleeding disorder (p = 0.007), ascites (p = 0.040), disseminated cancer (p< 0.001), and systemic sepsis (p < 0.001). After adjusting for all significantly associated variables, chronic steroid use was independently associated with major complication (OR 1.60, 95% CI 1.06-2.43; p = 0.026), and non-home discharge (OR 1.05, 95% CI 1.01-1.08; p = 0.014). CONCLUSION: Preoperative chronic steroid use is associated with increasing rate of postoperative complications following PHF ORIF. Better understanding and characterizing chronic steroid use as a preoperative risk factor can aid physicians in risk stratification to reduce rates of postoperative complications following PHF ORIF. LEVEL OF EVIDENCE: III. Retrospective Cohort Comparison; Prognosis Study.

The association of hyponatremia and early postoperative complications in aseptic revision total shoulder arthroplasty.

PURPOSE: This study investigates the association between preoperative serum sodium levels and 30-day postoperative complications following aseptic revision total shoulder arthroplasty (TSA). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent aseptic revision TSA from 2015 to 2022. The study population was divided into two groups based on preoperative serum sodium levels: eunatremia (135-144 mEq/L) and hyponatremia (< 135 mEq/L). Logistic regression analysis was performed to investigate the relationship between hyponatremia and early postoperative complications. RESULTS: Compared to eunatremia, hyponatremia was independently associated with a significantly greater likelihood of experiencing any complication (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.14-2.40; P = .008), blood transfusions (OR 2.45, 95% CI 1.24-4.83; P = .010), unplanned reoperation (OR 2.27, 95% CI 1.07-4.79; P = .032), and length of stay > 2 days (OR 1.63, 95% CI 1.09-2.45; P = .017). CONCLUSION: Hyponatremia was associated with a greater rate of early postoperative complications following noninfectious revision TSA. This study sheds light on the role of preoperative hyponatremia as a risk factor for postoperative complications and may help surgeons better select surgical candidates and improve surgical outcomes in the setting of revision TSA.

Is delayed time to surgery associated with increased postoperative complications in patients with pathologic humerus fractures?

INTRODUCTION: Delayed time to surgery, in the case of orthopedic trauma, is well known to be associated with higher morbidity and mortality, an extended duration of hospitalization, and an associated rise in overall cost. Delayed time to surgery of at least 3 days following hospital admission is associated with elevated risk of complications following surgery for a standard, non-pathologic, humeral shaft fracture. To our knowledge, it is unknown whether the same association is present for pathologic humerus fractures. The primary objective of this study was to identify risk factors, including patient characteristics, comorbidities, and postoperative complications, that are associated with delayed time to surgery following pathologic humeral fracture. METHODS: All patients undergoing surgical management of pathologic humerus fractures across a 6-year period from 2015 to 2021 were queried using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Postoperative complications were reported within 30 days of procedure. Delayed time to surgery was defined by ≥ 2 days from hospital admission to surgery. We identified a total of 248 patients, and 39.9% (n = 99) of patients had delayed time to surgery. Multivariate logistic regression adjusted for all significantly associated variables was employed to identify predictors of delayed time to surgery for pathologic humerus fractures. RESULTS: The characteristics of patients significantly associated with delayed time to surgery were ASA classification ≥ 3 (p = 0.016), dependent functional status (p = 0.041), and congestive heart failure (p = 0.008). After adjusting for all significantly associated patient variables, the characteristics of patients independently associated with delayed time to surgery were non-home discharge (OR: 2.93, 95% CI 1.53-5.63; p = 0.001) and extended length of stay (OR: 2.00, 95% CI 1.06-3.77; p = 0.033). CONCLUSION: Delayed time to surgery of at least 2 days was independently associated with non-home discharge and extended postoperative length of stay. After controlling for baseline patient characteristics and comorbidities, delayed time to surgery was not independently associated with increased 30-day complications after surgical treatment of pathologic humeral fractures. This is in contrast to standard, non-pathologic humerus fractures in which delayed time to surgery is associated with an increased risk of postoperative complications. LEVEL OF EVIDENCE III: Retrospective Cohort Comparison; Prognosis Study.

Role of insulin-dependent and non-insulin-dependent diabetes in aseptic revision total shoulder arthroplasty.

PURPOSE: This study investigates the association between insulin-dependent and non-insulin-dependent diabetes and 30-day postoperative complications following aseptic revision total shoulder arthroplasty (TSA). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent aseptic revision TSA from 2015 to 2021. The study population was divided into three groups based on diabetic status: nondiabetes, insulin-dependent diabetes, and non-insulin-dependent diabetes. Logistic regression analysis was conducted to investigate the relationship between diabetic status and postoperative complications. RESULTS: Compared to nondiabetes, insulin-dependent diabetes was independently associated with a significantly greater likelihood of experiencing any complication (OR 1.59, 95% CI 1.08-2.35; P = 0.020) and LOS > 2 days (OR 1.73, 95% CI 1.13-2.65; P = 0.012). Compared to nondiabetes, non-insulin-dependent diabetes was not independently associated with a significantly greater likelihood of experiencing complications. Preoperative insulin-dependent diabetic status was significantly associated with a greater rate of early postoperative complications following aseptic revision TSA, while preoperative non-insulin-dependent diabetic status was not. CONCLUSION: Preoperative insulin-dependent diabetic status was significantly associated with a greater rate of early postoperative complications following aseptic revision TSA. A better understanding of the role diabetes, both insulin-dependent and non-insulin-dependent, as a risk factor may help physicians better risk stratify and select surgical candidates for revision TSA.

Hypoalbuminemia predicts early postoperative complications following noninfectious revision total shoulder arthroplasty.

PURPOSE: This study investigates the association between preoperative hypoalbuminemia and 30-day postoperative complications following noninfectious revision total shoulder arthroplasty (TSA). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent noninfectious revision TSA from 2015 to 2021. The study population was divided into two groups based on preoperative serum albumin: normal albumin (≥ 3.5 g/dL) and hypoalbuminemia (< 3.5 g/dL). Logistic regression analysis was conducted to investigate the relationship between preoperative hypoalbuminemia and postoperative complications. RESULTS: Compared to normal albumin, hypoalbuminemia was independently associated with a significantly greater likelihood of experiencing any complication (odds ratio [OR] 3.26, 95% confidence interval [CI] 2.04-5.19; P < .001), sepsis (OR 9.92, 95% CI 1.29-76.35; P = .028), blood transfusions (OR 2.89, 95% CI 1.20-6.93; P = .017), non-home discharge (OR 2.88, 95% CI 1.55-5.35; P < .001), readmission (OR 3.46, 95% CI 1.57-7.58; P = .002), and length of stay > 2 days (OR 3.00, 95% CI 1.85-4.86; P < .001). CONCLUSIONS: Preoperative hypoalbuminemia was associated with early postoperative complications following revision TSA. LEVEL OF EVIDENCE: Level III; Retrospective Cohort Comparison; Prognosis Study.

Postoperative complications associated with congestive heart failure in aseptic revision total shoulder arthroplasty.

PURPOSE: The aim of this study is to explore potential complications and risk factors associated with revision TSA in patients with congestive heart failure (CHF). METHODS: This study examined all individuals who underwent revision total shoulder arthroplasty (TSA) from 2015 to 2022, sourced from the American College of Surgeons National Surgical Quality Improvement database. The analysis encompassed patient demographics, comorbidities, and 30-day postoperative complications. Logistic regression was employed to analyze the postoperative complications linked to patients with preoperative CHF. RESULTS: Compared to patients without CHF, patients with CHF were significantly associated with dependent functional status (P < .001), chronic obstructive pulmonary disease (P < .001), and hypertension (P = .002). Compared to patients without CHF, patients with CHF were independently associated with a significantly greater likelihood of experiencing any complication (OR 2.19, 95% CI 1.12-4.29; P = .022) and non-home discharge (OR 3.02, 95% CI 1.37-6.65; P = .006). CONCLUSION: Congestive heart failure was identified as an independent risk factor for experiencing any complication and non-home discharge in patients undergoing revision TSA. Awareness of the cardiovascular health status of a patient and its severity can influence the decision-making process when considering revision TSA. LEVEL OF EVIDENCE III: Retrospective Cohort Comparison Using Large Database; Prognosis Study.

Elevated alkaline phosphatase independently predicts early postoperative complications in noninfectious revision total shoulder arthroplasty.

PURPOSE: This study investigates the association between preoperative serum alkaline phosphatase levels and 30 day postoperative complications following noninfectious revision total shoulder arthroplasty (TSA). We hypothesize that elevated alkaline phosphatase levels are significantly associated with an increased 30 day postoperative complication rate. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent noninfectious revision TSA from 2015 to 2022. The study population was divided into two groups based on preoperative serum alkaline phosphatase: normal (44-147 IU/L) and elevated (> 147 IU/L). Logistic regression analysis was conducted to investigate the relationship between elevated alkaline phosphatase levels and postoperative complications. RESULTS: Compared to normal levels, elevated alkaline phosphatase was independently associated with a significantly greater likelihood of experiencing any complications (odds ratio [OR] 2.54, 95% confidence interval [CI] 1.41-4.55; P = .002), sepsis (OR 9.96, 95% CI 1.67-59.29; P = .012), blood transfusions (OR 3.77, 95% CI 1.48-9.61; P = .005), readmission (OR 3.65, 95% CI 1.48-9.01; P = .005), and length of stay > 2 days (OR 2.37, 95% CI 1.31-4.30; P = .004). CONCLUSIONS: Elevated preoperative alkaline phosphatase was associated with a greater rate of early postoperative complications following noninfectious revision TSA. LEVEL OF EVIDENCE: Level III; Retrospective Cohort Comparison; Prognosis Study.

Unplanned Excision of Soft Tissue Sarcomas of the Extremities in a Low-to-Middle-Income Country.

BACKGROUND: Outcomes of unplanned excisions of extremity soft tissue sarcomas (STSE) range from poor to even superior compared with planned excisions in developed countries. However, little is known regarding outcomes in low-to-middle-income countries. This study aimed to determine whether definitively treated STSE patients with a previous unplanned excision have poorer oncologic outcomes compared with those with planned excisions. PATIENTS AND METHODS: Using the database of a single sarcoma practice, we reviewed 148 patients with STSE managed with definitive surgery-78 with previous unplanned excisions (UE) and 70 with planned excisions (PE). RESULTS: Median follow-up was 4.4 years. UE patients had more surgeries overall and plastic reconstructions (P < 0.001). On multivariate analysis, overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were not worse among UE patients compared with PE patients. Negative predictors for LRFS were high tumor grade (P = 0.031) and an R1 surgical margin (P < 0.001). High grade (P <0.001), local recurrence (P = 0.001), and planned excisions (P = 0.009) predicted poorer DMFS, while age over 65 years (P = 0.011) and distant metastasis predicted poorer OS (P < 0.001). CONCLUSIONS: We recommend systematic re-excision for patients with unplanned excisions. Our study shows that STSE patients with UE, when subjected to re-excision with appropriate surgical margins, can achieve oncologic results similar to those for PE patients. However, there is an associated increased number of surgeries and plastic reconstruction for UE patients. This underscores the need, especially in a resource-limited setting, for education and collaborative policies to raise awareness about STSE among patients and physicians.

Impact of Sodium Thiosulfate on Prevention of Nephrotoxicities in HIPEC: An Ancillary Evaluation of Cisplatin-Induced Toxicities in Ovarian Cancer.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC) but is associated with renal toxicity. Sodium thiosulfate (ST) is used for nephroprotection for HIPEC with cisplatin, but standard HIPEC practices vary. METHODS: A prospective, nonrandomized, clinical trial evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during cytoreductive surgery (CRS) in patients with EOC (n = 34) and endometrial cancer (n = 6). Twenty-one patients received no ST (nST), and 19 received ST. Adverse events (AEs) were reported according to CTCAE v.5.0. Serum creatinine (Cr) was collected preoperatively and postoperatively (Days 5-8). Progression-free survival (PFS) was followed. Normal peritoneum was biopsied before and after HIPEC for whole transcriptomic sequencing to identify RNAseq signatures correlating with AEs. RESULTS: Forty patients had HIPEC at the time of interval or secondary CRS. Renal toxicities in the nST group were 33% any grade AE and 9% grade 3 AEs. The ST group demonstrated no renal AEs. Median postoperative Cr in the nST group was 1.1 mg/dL and 0.5 mg/dL in the ST group (p = 0.0001). Median change in Cr from preoperative to postoperative levels were + 53% (nST) compared with - 9.6% (ST) (p = 0.003). PFS did not differ between the ST and nST groups in primary or recurrent EOC patients. Renal AEs were associated with downregulation of metabolic pathways and upregulation of immune pathways. CONCLUSIONS: ST significantly reduces acute renal toxicity associated with HIPEC with cisplatin in ovarian cancer patients. As nephrotoxicity is high in HIPEC with cisplatin, nephroprotective agents should be considered.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer.

BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.

Interpersonal stress mediates the relationship between childhood trauma and depressive symptoms: Findings from two culturally different samples.

OBJECTIVE: Childhood trauma is associated with adulthood depressive symptoms, but very few studies explored potential social and interpersonal mediators behind this association. This study made the first attempt to test the potential mediating effects of interpersonal stress in the associations between childhood betrayal and non-betrayal trauma and depressive symptoms. METHOD: We analyzed data in a sample of English-speaking adults from diverse backgrounds (from 19 different countries, mainly from Western countries) (N = 468). We then replicated and compared the results with those in another convenience sample of Chinese-speaking younger adults with different cultural backgrounds and mental health status (N = 205). RESULTS: The results in both samples indicated that (1) childhood betrayal trauma had a stronger relationship with depressive symptoms than childhood non-betrayal trauma and that (2) interpersonal stress was a significant mediator in the relationship between childhood betrayal trauma and depressive symptoms, even when childhood non-betrayal trauma was included as a covariate. The indirect effect of childhood non-betrayal trauma on depressive symptoms through interpersonal stress was not consistent in two samples. CONCLUSIONS: Our findings point to the importance of taking social and interpersonal contexts into account when investigating, preventing and managing depression in trauma-exposed populations. Early social interventions such as family interventions, interpersonal skills training and building social resources may have the potential to change the trajectory of the development of mental health problems in trauma survivors.

Left Upper Lobe Multi-Segmentectomy Versus Lobectomy for Early-Stage Lung Cancer: A Meta-Analysis.

INTRODUCTION: The left upper lobe (LUL) has unique hilar anatomy, and LUL multi-segmentectomy (apical trisegmentectomy and lingulectomy) may result in different outcomes than both single anatomical segmentectomy and left upper lobectomy in the management of early-stage primary lung cancer; however no meta-analyses have been performed. The aim of this meta-analysis is to determine if LUL multi-segmentectomy is non-inferior to left upper lobectomy for long-term survival outcomes, or superior for in-hospital outcomes. METHODS: Electronic databases searches were performed on PubMed, Embase, and the Cochrane Library to identify studies comparing outcomes in LUL multi-segmentectomy vs left upper lobectomy in early-stage lung cancer (clinical stage T2 N0 or less). Long-term postoperative overall and disease-free survival were assessed via reconstruction of Kaplan-Meier survival curves. In-hospital complications and length of stay, as well as long term recurrence were analysed via random effects models. RESULTS: Five relevant studies were identified, including 1,196 patients. Overall survival did not differ at 5 years (multi-segmentectomy 92.6% vs lobectomy 89.3%, P=0.188), but patients undergoing LUL multi-segmentectomy had better disease-free survival at 5 years (93.1% vs 88.4%, P=0.041). Patients undergoing LUL multi-segmentectomy had a shorter mean length of hospital stay (mean difference -0.26 days, 95% CI; -0.39 to 0.14, P<0.01, I2=0.00%). There was no difference in combined in-hospital complications (P=0.14), local recurrence (P=0.35), distant recurrence (P=0.23), or overall recurrence (P=0.39). CONCLUSION: LUL multi-segmentectomy is associated with reduced hospital length of stay, but no difference in long-term overall survival compared with left upper lobectomy in the management of early-stage primary lung cancer.

Characterizing impact of positive lymph node number in endometrial cancer using machine-learning: A better prognostic indicator than FIGO staging?

BACKGROUND: Number of involved lymph nodes (LNs) is a crucial stratification factor in staging of numerous disease sites, but has not been incorporated for endometrial cancer. We evaluated whether number of involved LNs provide improved prognostic value. PATIENTS AND METHODS: Patients diagnosed with node-positive endometrial adenocarcinoma without distant metastasis were identified in the National Cancer Database. We trained a machine-learning based model of overall survival. Shapley additive explanation values (SHAP) based on the model were used to identify cutoffs of number of LNs involved. Results were validated using a Cox proportional hazards regression model. RESULTS: We identified 11,381 patients with endometrial cancer meeting the inclusion criteria. Using the SHAP values, we selected the following thresholds: 1-3 LNs, 4-5 LNs, and 6+ LNs. The 3-year OS was 82.0% for 1-3 LNs, 74.3% for 4-5 LNs (hazard ratio [HR] 1.38; p < 0.001), and 59.9% for 6+ LNs (HR 2.23; p < 0.001). On univariate Cox regression, PA nodal involvement was a significant predictor of OS (HR 1.20; p < 0.001) but was not significant on multivariate analysis when number of LNs was included (HR 1.05; p = 0.273). Additionally, we identified an interaction between adjuvant therapy and number of involved LNs. Patients with 1-3 involved LNs had 3-year OS of 85.2%, 78.7% and 74.2% with chemoradiation (CRT), chemotherapy, and radiation, respectively. Patients with 6+ involved LNs had 3-yr OS of 67.8%, 49.6%, and 48.9% with CRT, chemotherapy, and radiation, respectively (p < 0.001). CONCLUSION: Number of involved LNs is a stronger prognostic and predictive factor compared to PA node involvement.

Anatomic study of an anterior portal for percutaneous internal fixation of capitellum fractures.

BACKGROUND: Fractures of the capitellum are uncommon and difficult to treat surgically. Capitellar open reduction-internal fixation uses a lateral open approach with posterior-to-anterior or anterior-to-posterior screw fixation. We investigated the use of an anterior portal for placement of anterior-to-posterior screw fixation through cadaveric measurement of the anatomic relationships from an anteriorly to posteriorly placed Kirschner wire (K-wire) to anterior elbow structures and calculated the percentage of articular surface accessed from the anterior portal. METHODS: Eight fresh-frozen cadaveric elbows without radiographic or cutaneous evidence of prior trauma or surgery were used for this study. An arthroscopic proximal anteromedial portal was cannulized, and the radiocapitellar joint was evaluated. A single 1-cm portal was placed 1 cm distal to the elbow flexion crease and based lateral to the biceps tendon. The location of the portal was confirmed with a spinal needle, and blunt dissection with a hemostat was performed down to capsular tissue and for arthrotomy. A spinal needle sheath was threaded over a blunt switching stick and served as a cannula for placement of a 0.062 K-wire. Articular mapping was performed with cartilage scraping by the K-wire; the K-wire was then placed at the perceived center along the proximal-to-distal and radial-to-ulnar axis of the capitellum. Fluoroscopic confirmation of the wire's location was performed. Under loupe magnification, anatomic dissection was performed and the shortest distance measurements were recorded with digital calipers from the K-wire to the dissected structures. Capitellar articular measurements were recorded, in addition to the articular area defined by the K-wire. Data analysis was performed, and the average distance and standard deviation (in millimeters) were calculated. For structures that were pierced by or touching the K-wire, the distance was recorded as 0.1 mm. RESULTS: The average distance from the K-wire to the radial, lateral antebrachial cutaneous, and median nerves was 1.8 mm, 11.5 mm, and 28.0 mm, respectively. The average distance from the median cubital vein and biceps tendon was 3.7 mm and 13.4 mm, respectively. The pin track pierced the brachioradialis and supinator muscles in all but 1 specimen. The average capitellar articular surface marked was 39.1% of the calculated articular footprint of the capitellum. CONCLUSIONS: The anterior portal to the capitellum is directly adjacent to the radial nerve and lateral antebrachial cutaneous nerve, where each is susceptible to injury. We recommend blunt dissection and insertion of a cannula to allow drilling and placement of internal fixation in a relatively safe manner with respect to neurovascular structures.