Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) experience in patients with recurrent low grade serous ovarian carcinoma (LGSOC): sub-cohort report of phase 1 clinical trial.

Introduction: Low grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer (OC) that is challenging to treat due to its relative chemoresistance. Given that LGSOC patients often recur in the peritoneal cavity, novel intraperitoneal (IP) chemotherapy should be explored. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a method that has demonstrated peritoneal disease control in cancers with peritoneal metastases. Methods: NCT04329494 is a US multicenter phase 1 trial evaluating the safety of PIPAC in recurrent ovarian, uterine, and GI cancers with peritoneal metastases. This analysis describes the outcomes of a sub-cohort of four LGSOC patients treated with IP cisplatin 10.5 mg/m2, doxorubicin 2.1 mg/m2 PIPAC q4-6 weeks. Primary endpoints included dose-limiting toxicities (DLT) and incidence of adverse events (AE). Secondary endpoints were progression free survival (PFS) and treatment response based on radiographic, intraoperative, and pathological findings. Results: Four patients with LGSOC were enrolled of which three were heavily pretreated. Median prior lines of therapy was 5 (range 2-10). Three patients had extraperitoneal metastases, and two patients had baseline partial small bowel obstructive (SBO) symptoms. Median age of patients was 58 (38-68). PIPAC completion rate (≥2 PIPACs) was 75%. No DLTs or Clavien-Dindo surgical complications occurred. No G4/G5 AEs were observed, and one G3 abdominal pain was reported. One patient had a partial response after 3 cycles of PIPAC and completed an additional 3 cycles with compassionate use amendment. Two patients came off study after 2 cycles due to extraperitoneal progressive disease. One patient came off study after 1 cycle due to toxicity. Median decrease in peritoneal carcinomatosis index between cycles 1 and 2 was 5.0%. Ascites decreased in 2 out of 3 patients who had ≥2 PIPACs. Median PFS was 4.3 months (1.7-21.6), median overall survival was 11.6 months (5.4-30.1), and objective response rate was 25%. Conclusion: PIPAC with cisplatin/doxorubicin is well tolerated in LGSOC patients without baseline SBO symptoms. IP response was seen in 2 out of 3 patients that completed ≥2 PIPAC cycles. Further study of PIPAC for patients with recurrent disease limited to the IP cavity and with no partial SBO symptoms should be considered.

Short-term complication rates of open reduction and plate fixation and intramedullary nailing in the treatment of humeral shaft fractures: a propensity score matched analysis.

INTRODUCTION: This is a retrospective cohort study designed to compare short-term postoperative complication rates between closed humeral shaft fractures treated by open reduction and internal fixation (ORIF) versus intramedullary nailing (IMN), as well as secondary independent risk factors for adverse outcomes. MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried using CPT codes to identify patients that underwent an open reduction and plate fixation or intramedullary nailing procedure for a closed humeral shaft fracture from 2010 to 2021. Cohorts were matched using propensity scores to account for demographic differences and rates of complications were compared between the two groups. RESULTS: From the database, a total of 4,222 patients were identified who met inclusion criteria, with 3,326 and 896 undergoing ORIF and IMN respectively. After propensity score matching, 866 of the nearest-neighbor matches were included in each cohort for a total of 1,732 patients in the final analysis. The rate of any adverse event (AAE) was significantly higher in the ORIF cohort (16.3%) than the IMN cohort (12.1%, p = 0.01). The ORIF group had higher rates of postoperative transfusion (p = 0.002), return to OR (p = 0.005), and surgical site infection (SSI, p = 0.03). After multivariate analysis, ASA class 4, increasing age, increasing operative time, and history of bleeding disorder were found to increase the risk of AAE in both ORIF and IMN patients. CONCLUSIONS: While prior studies have claimed higher complication rates in IMN patients, this study found a significantly higher short-term risk of AAE in ORIF patients when compared in matched cohorts. However, individual 30-day complication rates do not differ significantly between procedures, and both have been shown to be safe and effective tools in the management of humeral shaft fractures.

Additional Procedures at the Time of Total Ankle Replacement Do Not Increase Risk of Short-term Complications: A Matched Cohort Analysis.

Background: This retrospective cohort study compared short-term complication rates following total ankle arthroplasty (TAA), alone or with concomitant procedures. Secondary independent risk factors were also examined as they related to postoperative outcomes. Methods: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database was queried using Current Procedural Terminology (CPT) codes to identify patients who underwent TAA (27702) between 2010 to 2021. Patients were divided into cohorts based on the presence or absence of ancillary procedures. Propensity score matching was employed to account for demographic differences, and statistical analyses were performed to compare short-term complication rates between matched cohorts. Results: A total of 2225 patients were identified, with 1432 (64.4%) receiving TAA alone and 793 (35.6%) with ancillary procedure(s). After matching, 793 patients were included in each cohort. The ancillary cohort had longer operative times (P < .001) and length of hospital stay (LOS) (P < 0.001). Rates for extended LOS were significantly higher in the ancillary cohort than in the simple cohort (P = .01). No other complications varied significantly between cohorts, including the incidence of any adverse event (AAE). American Society of Anesthesiologists classification of 4 was found to be an independent risk factor for development of AAE (odds ratio [OR] = 1.091, P = .04). Matched subgroup analysis excluding tendon lengthening as a concomitant procedure found that the ancillary cohort still had longer operative time (P < .001) and LOS (P < .05) than patients undergoing simple TAA. Conclusion: Without significant difference in rates of AAE other than extended LOS, the relative safety of ancillary TAA appears similar to that of TAA alone. Such knowledge can help inform surgical decision-making and assuage safety concerns for patients requiring additional corrective procedures at the time of TAA. Level of Evidence: Level III, retrospective comparative study.

Open Biceps Tenodesis and Tenotomy Have Low 30-Day Postoperative Complication Rates.

Purpose: To compare 30-day postoperative rates of adverse events, particularly infection rates, between open biceps tenodesis and biceps tenotomy. Methods: The American College of Surgeons National Surgical Quality Improvement Program was filtered using Current Procedural Terminology codes to identify patients undergoing open biceps tenodesis and tenotomy from 2010 to 2021. Patients were divided into cohorts based on procedure type. Propensity score matching was used to account for confounding variables. Statistical analyses were conducted to compare 30-day postoperative outcomes between cohorts, as well as to evaluate secondary risk factors for complications. Results: Overall, 12,367 patients were included in the study with 11,417 undergoing open biceps tenodesis and 950 undergoing biceps tenotomy. After matching, 1,900 patients were included in the final analysis. The rate of outpatient procedures in the tenodesis cohort was significantly higher than in the tenotomy cohort. Rates of any adverse event (AAE), sepsis, pneumonia, reoperation, and extended length of stay (LOS) were significantly higher in the tenotomy cohort compared with the tenodesis cohort. There was no difference in infection rates or wound dehiscence between the 2 groups. After multivariable analysis, increasing age, longer operative time, and history of bleeding disorders were associated with significantly higher odds of developing AAE. Conclusions: In this study, we found that tenotomy and open tenodesis are both safe options for treatment of biceps pathology. The overall rate of developing AAE and the rate of postoperative sepsis were higher in the tenotomy cohort. In addition, rates of postoperative infection and wound dehiscence did not vary between the 2 groups. Small differences were additionally observed in rates of pneumonia, return to the operating room, and extended LOS, and these rates were higher in the tenotomy cohort. Level of Evidence: Level III, retrospective comparative study.

Periacetabular osteotomy with and without concomitant arthroscopy: a systematic review of evidence on post-operative activity levels and return to sport.

The purpose of this systematic review is to (i) compare post-operative activity levels after periacetabular osteotomy (PAO) versus PAO + HA (concomitant PAO and hip arthroscopy) using patient-reported outcomes that specifically assess activity and sports participation [Hip Disability and Osteoarthritis Outcome Score-Sport and Recreation subscale (HOOS-SR), University of California Los Angeles (UCLA) activity score, Hip Outcome Score-Sport-Specific Subscale (HOS-SSS)] and (ii) compare post-operative return to sport (RTS) data between PAO and PAO + HA groups. A systematic review of literature was conducted on 1 June 2023, utilizing PubMed, Cochrane and Embase (OVID). Articles were screened for inclusion using specific inclusion and exclusion criteria. Twenty-six out of 1610 articles met all inclusion criteria, without meeting any exclusion criteria. In the 12 studies containing only subjects who underwent PAO alone, 11 demonstrated an average score improvement in UCLA, HOOS-SR or HOS-SSS post-operatively (P < 0.05). In the three studies containing subjects who underwent PAO with concomitant HA, significant improvements were seen in the HOS-SS and UCLA scores (P < 0.05). In the five studies that directly compared UCLA, HOS-SSS and HOOS-SSS scores between PAO groups and PAO + HA groups, all demonstrated statistically significant improvement post-operatively (P < 0.05). The rate of RTS ranged from 63% to 90.8% among PAO studies and was found to be 81% in the single PAO + HA study that assessed RTS. When performed in patients with intra-articular pathology, concomitant PAO + HA may provide similar sport-related outcomes to PAO alone in patients without intra-articular pathology.

Successful Liver Retransplantation in a Patient With Disseminated Aspergillosis and Nocardiosis: A Case Report.

BACKGROUND: Clinical guidelines list active fungal infection and sepsis as contraindications to liver transplantation due to the risk of worsening infection with immunosuppression postoperatively. Mortality from systemic opportunistic infections in transplant recipients is high, approaching 100% for disseminated aspergillosis. However, the optimal duration of treatment required before transplant is unclear. Additionally, delaying surgery while the infection is treated risks death from hepatic decompensation and physical deconditioning, preventing progression to transplantation. CASE REPORT: Here, we present a patient who underwent successful repeat liver transplantation for recurrent autoimmune hepatitis and graft rejection while undergoing treatment for disseminated aspergillosis and nocardiosis. He had pulmonary, hepatic, and central nervous system involvement. He had received 2 months of antimicrobials but had ongoing radiologic evidence of infection when listed for retransplantation. He remains well and infection-free 1 year postoperatively. CONCLUSION: Few cases of successful liver transplantation in the setting of disseminated aspergillosis have been reported previously. To our knowledge, this is the first successful liver transplant in a patient with disseminated nocardial infection.

Multiplexed Biosensing of Proteins and Virions with Disposable Plasmonic Assays.

Our growing ability to tailor healthcare to the needs of individuals has the potential to transform clinical treatment. However, the measurement of multiple biomarkers to inform clinical decisions requires rapid, effective, and affordable diagnostics. Chronic diseases and rapidly evolving pathogens in a larger population have also escalated the need for improved diagnostic capabilities. Current chemical diagnostics are often performed in centralized facilities and are still dependent on multiple steps, molecular labeling, and detailed analysis, causing the result turnaround time to be over hours and days. Rapid diagnostic kits based on lateral flow devices can return results quickly but are only capable of detecting a handful of pathogens or markers. Herein, we present the use of disposable plasmonics with chiroptical nanostructures as a platform for low-cost, label-free optical biosensing with multiplexing and without the need for flow systems often required in current optical biosensors. We showcase the detection of SARS-CoV-2 in complex media as well as an assay for the Norovirus and Zika virus as an early developmental milestone toward high-throughput, single-step diagnostic kits for differential diagnosis of multiple respiratory viruses and any other emerging diagnostic needs. Diagnostics based on this platform, which we term "disposable plasmonics assays," would be suitable for low-cost screening of multiple pathogens or biomarkers in a near-point-of-care setting.

Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.

Correlation between Objective Measures of Sun Exposure and Self-Reported Sun Protective Behavior and Attitudes in Predominantly Hispanic Youth.

Melanoma incidence is increasing, with poor prognosis cases growing faster in California Hispanics than in non-Hispanic whites. Ultraviolet Radiation (UVR) exposure as a child has been found to disproportionately increase the risk of melanoma. To determine correlates of UVR exposure in this high-risk population, we conducted a study in predominately Hispanic 4th and 5th grade classrooms in Los Angeles County, a high UVR environment, during the spring. To address potential reporting bias, electronic UV dosimeters were utilized to objectively measure the association between UVR exposure and constructs (acculturation, sun protective behavior and knowledge, family interventions) obtained on baseline questionnaires (n = 125). Tanning attitude (wanting to get a tan) was associated with lower median time spent outside (1.73 min versus 22.17, AUC 82.08, Sensitivity 0.78, Specificity 0.73) and standard erythemal dose (SED) on weekends, but positively associated with sun protective knowledge. Sun protective knowledge and family discussion of sunscreen were also inversely associated with objectively measured time outside. Students spent a median 30.61 (IQR 19.88) minutes outside per day (SED 0.30, IQR 0.20), with only 35.70% of it occurring in nonschool hours. We determined the majority of UVR exposure in this population occurs at school, providing valuable guidance for future interventions.

Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19.

Introduction: Diamond Blackfan anemia (DBA) is an autosomal dominant ribosomopathy caused predominantly by pathogenic germline variants in ribosomal protein genes. It is characterized by failure of red blood cell production, and common features include congenital malformations and cancer predisposition. Mainstays of treatment are corticosteroids, red blood cell transfusions, and hematologic stem cell transplantation (HSCT). Despite a better understanding of the genotype of DBA, the biological mechanism resulting in the clinical phenotype remains poorly understood, and wide heterogeneity can be seen even within a single family as depicted here. Case Description: Thirty family members enrolled in the National Cancer Institute inherited bone marrow failure syndromes study were evaluated with detailed medical questionnaires and physical examinations, including 22 in the family bloodline and eight unrelated partners. Eight participants had been previously told they had DBA by clinical criteria. Targeted germline RPS19 testing was done on all family members. A pathogenic heterozygous missense mutation in RPS19 (p.R62Q, c.185G > A) was detected in ten family members, including one person previously presumed unaffected. Eight family members presented with macrocytic anemia in infancy; all of whom were responsive to prednisone. Four family members became treatment independent; however, one individual became transfusion-dependent 36 years later following an episode of pneumonia. One prednisone responsive individual electively discontinued steroid treatment, and lives with severe anemia. One prednisone responsive individual died at age 28 from a stroke. Two family members developed colorectal cancer in their fifties; one had never required treatment for anemia. None had major congenital anomalies. Discussion: This large family with DBA demonstrates the heterogeneity of phenotypes that can be seen within the same genotype. Most family members presented with steroid-responsive anemia in infancy and subtle congenital malformations, findings consistent with recent genotype-phenotype studies of RPS DBA. However, two family members were relatively unaffected, underscoring the importance of further studies to assess modifier genes, and epigenetic and/or environmental factors which may result in normal erythropoiesis despite underlying ribosome dysfunction. This large, multigenerational family highlights the need for individualized treatment, the importance of early cancer surveillance even in individuals with clinically mild phenotypes, and the benefit of long-term follow-up to identify late complications.

The Neutralizing Antibody Responses of Individuals That Spontaneously Resolve Hepatitis C Virus Infection.

Hepatitis C virus (HCV) infection is a major global health problem. In the majority of cases the virus is not cleared by the host immune response and progresses to chronic infection. Studies of the neutralizing antibody responses in individuals that naturally clear infection are limited. Understanding what constitutes a successful antibody response versus one that has 'failed' and resulted in chronic infection is important to understand what type of antibody response would need to be elicited by a protective vaccine. Samples from spontaneous clearers are difficult to obtain therefore studies are often limited. In our study through HCV Research UK, we had access to a cohort of over 200 samples. We identified the samples that contained HCV neutralizing antibodies using ELISA and HCV pseudoparticle (HCVpp) assays. We then utilised mutagenesis and cross-competition analysis to determine the profile of the neutralizing antibody responses. In addition, we analysed a cohort of samples from chronic infection using the same techniques to enable direct comparison of the antibody profiles observed in both cohorts. We conclude that similar profiles are present in both cohorts indicating that it is not the neutralizing antibody response per se that determines the outcome of infection. These data will provide useful information for future HCV vaccine design.

Osteosarcoma: A Surveillance, Epidemiology, and End Results program-based analysis from 1975 to 2017.

BACKGROUND: Osteosarcoma is the most common primary bone malignancy. As a rare cancer, population-based studies remain small with limited information on finer demographic categories. Recent studies have reported important genetic differences based on age and ethnicity, and more detailed studies are needed to better understand potentially important osteosarcoma risk groups. METHODS: Incidence and survival rates for 5016 patients with osteosarcoma from the Surveillance, Epidemiology, and End Results (SEER) program (1975-2017) were analyzed by age (0-9, 10-24, 25-59, and >60 years old), race/ethnicity, histologic subtype, stage, and tumor location using SEER*Stat software. RESULTS: For cases 0 to 9 years old, incidence of primary osteosarcoma was similar between the sexes, increased significantly throughout the study period (P < .05), and the 5-year relative survival has steadily increased over time. Blacks had the highest incidence in all aged cases combined and a significant increase in incidence throughout the study period (P < .05). Overall, survival rates for all cases have remained relatively unchanged over recent decades, with worse survival observed in males, American Indian/Alaska Native cases, older patients, metastatic disease, axial tumors, and subsequent osteosarcoma cases. For cases 0 to 24 years old, the incidence of subsequent osteosarcoma increased 3-fold since the 2000s. CONCLUSION: Important differences in osteosarcoma incidence and survival, particularly for the youngest children, ethnic minorities, and subsequent osteosarcoma, are identified. A genetic risk factor may be associated with observed ancestry-specific incidence differences and illustrates the importance of analyzing osteosarcoma by specific age groups and ethnicities to better understand their unique epidemiology and underlying biology. LAY SUMMARY: Osteosarcoma is the most common bone cancer, but still a relatively rare disease, and previous studies have had limited information on finer demographics. Using a large database, osteosarcoma incidence and survival patterns are thoroughly evaluated and important differences, especially for the youngest children, ethnic minorities, and subsequent osteosarcoma cases, are identified.

Cumulative menstrual months and breast cancer risk by hormone receptor status and ethnicity: The Breast Cancer Etiology in Minorities Study.

Reproductive and hormonal factors may influence breast cancer risk via endogenous estrogen exposure. Cumulative menstrual months (CMM) can be used as a surrogate measure of this exposure. Using harmonized data from four population-based breast cancer studies (7284 cases and 7242 controls), we examined ethnicity-specific associations between CMM and breast cancer risk using logistic regression, adjusting for menopausal status and other risk factors. Higher CMM was associated with increased breast cancer risk in non-Hispanic Whites, Hispanics and Asian Americans regardless of menopausal status (all FDR adjusted P trends = .0004), but not in African Americans. In premenopausal African Americans, there was a suggestive trend of lower risk with higher CMM. Stratification by body mass index (BMI) among premenopausal African American women showed a nonsignificant positive association with CMM in nonobese (BMI <30 kg/m2 ) women and a significant inverse association in obese women (OR per 50 CMM = 0.56, 95% CI 0.37-0.87, Ptrend  = .03). Risk patterns were similar for hormone receptor positive (HR+; ER+ or PR+) breast cancer; a positive association was found in all premenopausal and postmenopausal ethnic groups except in African Americans. HR- (ER- and PR-) breast cancer was not associated with CMM in all groups combined, except for a suggestive positive association among premenopausal Asian Americans (OR per 50 CMM = 1.33, P = .07). In summary, these results add to the accumulating evidence that established reproductive and hormonal factors impact breast cancer risk differently in African American women compared to other ethnic groups, and also differently for HR- breast cancer than HR+ breast cancer.