Clinical Intricacies and Advances in Neuroendocrine Tumors: An Organ-Based Multidisciplinary Approach.

ABSTRACT: Neuroendocrine neoplasms (NENs) are rare neoplasms originating from neuroendocrine cells, with increasing incidence due to enhanced detection methods. These tumors display considerable heterogeneity, necessitating diverse management strategies based on factors like organ of origin and tumor size. This article provides a comprehensive overview of therapeutic approaches for NENs, emphasizing the role of imaging in treatment decisions. It categorizes tumors based on their locations: gastric, duodenal, pancreatic, small bowel, colonic, rectal, appendiceal, gallbladder, prostate, lung, gynecological, and others. The piece also elucidates the challenges in managing metastatic disease and controversies surrounding MEN1-neuroendocrine tumor management. The article underscores the significance of individualized treatment plans, underscoring the need for a multidisciplinary approach to ensure optimal patient outcomes.

Carboplatin, paclitaxel, and pembrolizumab followed by pembrolizumab maintenance for primary treatment of incompletely resected epithelial ovarian cancer.

Objective: Incompletely resected epithelial ovarian cancer represents a poor prognostic subset of patients. Novel treatment strategies are needed to improve outcomes for this population. We evaluated a treatment strategy combining platinum-based chemotherapy with pembrolizumab followed by pembrolizumab maintenance therapy in the first-line treatment after incomplete resection of epithelial ovarian cancer patients. Methods: This was a single-arm, non-randomized pilot study of carboplatin, taxane, and immune checkpoint inhibitor, pembrolizumab, followed by 12 months of maintenance pembrolizumab in patients with incompletely resected epithelial ovarian cancer (EOC). Results: A total of 29 patients were enrolled and evaluated for efficacy and safety. The best response to therapy was complete response in 16 (55%) patients, partial response in 9 (31%) patients, and 3 (10%) patients with progression of disease. The median progression-free survival (PFS) was 13.2 months. Grade 3 and 4 toxicities occurred in 20% of patients. In all, 7 patients discontinued therapy due to adverse events. Quality-of-life scores remained high during therapy. Response to therapy did not correlate with PD-L1 tumor expression. Conclusions: Combination platinum-taxane therapy with pembrolizumab did not increase median progression-free survival in this cohort of patients. Key message: EOC is an immunogenic disease, but immune checkpoint inhibitor therapy has yet to impact outcomes. The current study utilized pembrolizumab in combination with standard chemotherapy followed by a maintenance treatment strategy in incompletely resected EOC. Progression-free survival was not extended in this poor prognostic group with combined chemotherapy and immunotherapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT 027766582.

Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti-PD-L1, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer.

BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC). METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized. RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively. CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.

Considerations for pharmacologic thromboprophylaxis following inpatient brachytherapy for gynecologic malignancies.

PURPOSE: Brachytherapy irradiation carries risks of both bleeding and venous thromboembolism (VTE). No screening or management recommendations for VTE in this setting have been developed. Our study aims to understand the incidence of VTE, compile published anticoagulation guidelines, and call for future guidelines to address thromboprophylaxis in this population. METHODS AND MATERIALS: A retrospective, single institution study of patients undergoing brachytherapy irradiation between 2012 and 2022 was undertaken. We analyzed 2 cohorts: 87 patients undergoing brachytherapy with an inpatient admission, and 66 patients assessed for risk of VTE or bleeding after discharge from an inpatient admission for brachytherapy. Caprini risk scores were calculated for each patient, and statistical analyses were performed. RESULTS: Eighty-seven patients were included, and 25% had a VTE diagnosis. Forty-seven (54%) of patients included underwent brachytherapy as definitive treatment of cervical cancer, and 16 (18%) received brachytherapy irradiation to treat recurrent endometrial cancer. In the cohort of 66 patients assessed for risk of VTE or bleeding after brachytherapy discharge, 23 (34.8%) were discharged with thromboprophylaxis, and 43 (65.2%) were discharged without thromboprophylaxis. None of the patients discharged on thromboprophylaxis were diagnosed with a VTE within 90 days of discharge after brachytherapy, whereas 3 of 43 (7%) discharged without thromboprophylaxis were diagnosed with a VTE, OR and 95% CI: 0.25 (0.01-5.29), p = 0.37. Of the 23 patients discharged on thromboprophylaxis, 1 was readmitted for bleeding OR and 95% CI: 5.8 (0.22-155.18), p = 0.29. The median Caprini score was 11. CONCLUSIONS: VTE is a common occurrence in patients undergoing brachytherapy. Patients undergoing brachytherapy irradiation who require inpatient admission represent a unique population, and specialty organizations should develop consensus recommendations to address these clinical challenges.

DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma.

PURPOSE: Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations. METHODS: We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression. RESULTS: DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel. CONCLUSIONS: Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.

Historic Clinical Trial External Control Arm Provides Actionable GEN-1 Efficacy Estimate Before a Randomized Trial.

PURPOSE: To inform continued development of the novel immune agent GEN-1, we compared ovarian cancer patients' end points from a neoadjuvant single-arm phase IB study with those of similar historic clinical trial (HCT) patients who received standard neoadjuvant chemotherapy. METHODS: Applying OVATION-1 trial (ClinicalTrials.gov identifier: NCT02480374) inclusion and exclusion criteria to Medidata HCT data, we identified historical trial patients for comparison. Integrating patient-level Medidata historic trial data (N = 41) from distinct neoadjuvant ovarian phase I-III trials with patient-level OVATION-1 data (N = 18), we selected Medidata patients with similar baseline characteristics as OVATION-1 patients using propensity score methods to create an external control arm (ECA). RESULTS: Fifteen OVATION-1 patients (15 of 18, 83%) were matched to 15 (37%, 15 of 41) Medidata historical trial control patients. Matching attenuated preexisting differences in attributes between the groups. The median progression-free survival time was not reached by the OVATION-1 group and was 15.8 months (interquartile range, 11.40 months to nonestimable) for the ECA. The hazard of progression was 0.53 (95% CI, 0.16 to 1.73), favoring GEN-1 patients. Compared with ECA patients, OVATION-1 patients had more nausea, fatigue, chills, and infusion-related reactions. CONCLUSION: Comparing results of a single-arm early-phase trial to those of a rigorously matched HCT ECA yielded insights regarding comparative efficacy prior to a randomized controlled trial. The effect size estimate itself informed both the decision to continue development and the randomized phase II trial (ClinicalTrials.gov identifier: NCT03393884) sample size. The work illustrates the potential of HCT data to inform drug development.

Simultaneous multislice diffusion-weighted imaging versus standard diffusion-weighted imaging in whole-body PET/MRI.

OBJECTIVE: To compare standard (STD-DWI) single-shot echo-planar imaging DWI and simultaneous multislice (SMS) DWI during whole-body positron emission tomography (PET)/MRI regarding acquisition time, image quality, and lesion detection. METHODS: Eighty-three adults (47 females, 57%), median age of 64 years (IQR 52-71), were prospectively enrolled from August 2018 to March 2020. Inclusion criteria were (a) abdominal or pelvic tumors and (b) PET/MRI referral from a clinician. Patients were excluded if whole-body acquisition of STD-DWI and SMS-DWI sequences was not completed. The evaluated sequences were axial STD-DWI at b-values 50-400-800 s/mm2 and the apparent diffusion coefficient (ADC), and axial SMS-DWI at b-values 50-300-800 s/mm2 and ADC, acquired with a 3-T PET/MRI scanner. Three radiologists rated each sequence's quality on a five-point scale. Lesion detection was quantified using the anatomic MRI sequences and PET as the reference standard. Regression models were constructed to quantify the association between all imaging outcomes/scores and sequence type. RESULTS: The median whole-body STD-DWI acquisition time was 14.8 min (IQR 14.1-16.0) versus 7.0 min (IQR 6.7-7.2) for whole-body SMS-DWI, p < 0.001. SMS-DWI image quality scores were higher than STD-DWI in the abdomen (OR 5.31, 95% CI 2.76-10.22, p < 0.001), but lower in the cervicothoracic junction (OR 0.21, 95% CI 0.10-0.43, p < 0.001). There was no significant difference in the chest, mediastinum, pelvis, and rectum. STD-DWI detected 276/352 (78%) lesions while SMS-DWI located 296/352 (84%, OR 1.46, 95% CI 1.02-2.07, p = 0.038). CONCLUSIONS: In cancer staging and restaging, SMS-DWI abbreviates acquisition while maintaining or improving the diagnostic yield in most anatomic regions. KEY POINTS: • Simultaneous multislice diffusion-weighted imaging enables faster whole-body image acquisition. • Simultaneous multislice diffusion-weighted imaging maintains or improves image quality when compared to single-shot echo-planar diffusion-weighted imaging in most anatomical regions. • Simultaneous multislice diffusion-weighted imaging leads to superior lesion detection.

Human-machine collaboration using artificial intelligence to enhance the safety of donning and doffing personal protective equipment (PPE).

OBJECTIVES: To compare the accuracy of monitoring personal protective equipment (PPE) donning and doffing process between an artificial intelligent (AI) machine collaborated with remote human buddy support system and an onsite buddy, and to determine the degree of AI autonomy at the current development stage. DESIGN AND SETTING: We conducted a pilot simulation study with 30 procedural scenarios (15 donning and 15 doffing, performed by one individual) incorporating random errors in 55 steps. In total, 195 steps were assessed. METHODS: The human-AI machine system and the onsite buddy assessed the procedures independently. The human-AI machine system performed the assessment via a tablet device, which was positioned to allow full-body visualization of the donning and doffing person. RESULTS: The overall accuracy of PPE monitoring using the human-AI machine system was 100% and the overall accuracy of the onsite buddy was 99%. There was a very good agreement between the 2 methods (κ coefficient, 0.97). The current version of the AI technology was able to perform autonomously, without the remote human buddy's rectification in 173 (89%) of 195 steps. It identified 67.3% of all the errors independently. CONCLUSIONS: This study provides preliminary evidence suggesting that a human-AI machine system may be able to serve as a substitute or enhancement to an onsite buddy performing the PPE monitoring task. It provides practical assistance using a combination of a computer mirror, visual prompts, and verbal commands. However, further studies are required to examine its clinical efficacy with a diverse range of individuals performing the donning and doffing procedures.

Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial.

PURPOSE: In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting. METHODS: This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up. RESULTS: The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76; P = .0004 [P < .0001 required to declare statistical significance]). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups. CONCLUSION: Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.

A case series of triplet anti-hormonal therapy in androgen receptor-positive recurrent adult ovarian granulosa cell tumor.

Therapeutic options for recurrent adult granulosa cell tumors (AGCT) are limited. After examining the hormonal pathways involved in FOXL2-mutated granulosa cell tumor development, a novel treatment regimen was utilized for recurrent AGCT: a combination of an androgen receptor antagonist, a gonadotropin-releasing hormone receptor agonist, and an aromatase inhibitor for hormonal blockade. In this case series, seven patients at our institution were treated with bicalutamide 50 mg orally once daily, Leuprolide acetate 7.5 mg intramuscular (IM) injection every 4 weeks, and a daily oral aromatase inhibitor. These patients had recurrent AGCT with androgen receptor positive tumors and had failed prior aromatase inhibitor therapy. All patients had undergone multiple surgical resections and many cycles of chemotherapy. Patients were monitored for toxicities and for response to treatment. Of the seven patients receiving the triple therapy, six saw clinical benefit. Two patients demonstrated a partial response and four patients had stable disease. One patient had progressive disease on the regimen. For the two patients who had a partial response to the triple therapy, there was strong expression of the androgen receptor (AR) noted on tumor immunohistochemistry. This drug combination was well-tolerated except for severe hot flashes in one patient. In conclusion, the triple therapy combination of an androgen receptor antagonist, aromatase inhibitor, and GnRH agonist demonstrated measurable responses in patients with recurrent AGCTs after multiple previous treatments. A prospective clinical trial is planned to further investigate these findings.

Same-Day Discharge After Robotic Hysterectomy: A Resource Utilization and Quality Improvement Project.

BACKGROUND: We implemented a low-cost education initiative to improve the rate of same-day discharge following hysterectomy performed for malignancy and assessed feasibility and impact on resource utilization. METHODS: Development and implementation of faculty, patient, clinical, and perioperative staff education regarding the goal of same-day discharge for patients undergoing robotic hysterectomy and staging by gynecologic oncologists was started in July 2019. Chart review of 103 patients prior to the intervention and 112 patients after the start of the intervention was completed. RESULTS: The rate of same-day discharge increased from 5% to 32% following the low-cost process change initiative, and a total of approximately 682 inpatient care hours were saved per 31 patients. DISCUSSION: The rate of same-day discharges after hysterectomy and staging performed by gynecologic oncologists can be safely increased with a simple educational intervention, which can save significant patient care resources.

Updated guideline on equipment to manage difficult airways: Australian and New Zealand College of Anaesthetists.

The Australian and New Zealand College of Anaesthetists (ANZCA) recently reviewed and updated the guideline on equipment to manage a difficult airway. An ANZCA-established document development group, which included representatives from the Australasian College for Emergency Medicine and the College of Intensive Care Medicine of Australia and New Zealand, performed the review, which is based on expert consensus, an extensive literature review, and bi-nationwide consultation. The guideline (PG56(A) 2021, https://www.anzca.edu.au/getattachment/02fe1a4c-14f0-4ad1-8337-c281d26bfa17/PS56-Guideline-on-equipment-to-manage-difficult-airways) is accompanied by a detailed background paper (PG56(A)BP 2021, https://www.anzca.edu.au/getattachment/9ef4cd97-2f02-47fe-a63a-9f74fa7c68ac/PG56(A)BP-Guideline-on-equipment-to-manage-difficult-airways-Background-Paper), from which the current recommendations are reproduced on behalf of, and with the permission of, ANZCA. The updated 2021 guideline replaces the 2012 version and aims to provide an updated, objective, informed, transparent, and evidence-based review of equipment to manage difficult airways.

Efficacy of niraparib by time of surgery and postoperative residual disease status: A post hoc analysis of patients in the PRIMA/ENGOT-OV26/GOG-3012 study.

OBJECTIVE: To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence. METHODS: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population. RESULTS: In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37). CONCLUSIONS: In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance.

Combat-Related Invasive Fungal Wound Infections.

INTRODUCTION: During Operation Enduring Freedom in Afghanistan, an outbreak of combat-related invasive fungal wound infections (IFIs) emerged among casualties with dismounted blast trauma and became a priority issue for the Military Health System. METHODS: In 2011, the Trauma Infectious Disease Outcomes Study (TIDOS) team led the Department of Defense IFI outbreak investigation to describe characteristics of IFIs among combat casualties and provide recommendations related to management of the disease. To support the outbreak investigation, existing IFI definitions and classifications utilized for immunocompromised patients were modified for use in epidemiologic research in a trauma population. Following the conclusion of the outbreak investigation, multiple retrospective analyses using a population of 77 IFI patients (injured during June 2009 to August 2011) were conducted to evaluate IFI epidemiology, wound microbiology, and diagnostics to support refinement of Joint Trauma System (JTS) clinical practice guidelines. Following cessation of combat operations in Afghanistan, the TIDOS database was comprehensively reviewed to identify patients with laboratory evidence of a fungal infection and refine the IFI classification scheme to incorporate timing of laboratory fungal evidence and include categories that denote a high or low level of suspicion for IFI. The refined IFI classification scheme was utilized in a large-scale epidemiologic assessment of casualties injured over a 5.5-year period. RESULTS: Among 720 combat casualties admitted to participating hospitals (2009-2014) who had histopathology and/or wound cultures collected, 94 (13%) met criteria for an IFI and 61 (8%) were classified as high suspicion of IFI. Risk factors for development of combat-related IFIs include sustaining a dismounted blast injury, experiencing a traumatic transfemoral amputation, and requiring resuscitation with large-volume (>20 units) blood transfusions. Moreover, TIDOS analyses demonstrated the adverse impact of IFIs on wound healing, particularly with order Mucorales. A polymerase chain reaction (PCR)-based assay to identify filamentous fungi and support earlier IFI diagnosis was also assessed using archived formalin-fixed, paraffin-embedded tissue specimens. Although the PCR-based assay had high specificity (99%), there was low sensitivity (63%); however, sensitivity improved to 83% in tissues collected from sites with angioinvasion. Data obtained from the initial IFI outbreak investigation (37 IFI patients) and subsequent TIDOS analyses (77 IFI patients) supported development and refinement of a JTS clinical practice guideline for the management of IFIs in war wounds. Furthermore, a local clinical practice guideline to screen for early tissue-based evidence of IFIs among blast casualties at the Landstuhl Regional Medical Center was critically evaluated through a TIDOS investigation, providing additional clinical practice support. Through a collaboration with the Uniformed Services University Surgical Critical Care Initiative, findings from TIDOS analyses were used to support development of a clinical decision support tool to facilitate early risk stratification. CONCLUSIONS: Combat-related IFIs are a highly morbid complication following severe blast trauma and remain a threat for future modern warfare. Our findings have supported JTS clinical recommendations, refined IFI classification, and confirmed the utility of PCR-based assays as a complement to histopathology and/or culture to promote early diagnosis. Analyses underway or planned will add to the knowledge base of IFI epidemiology, diagnostics, prevention, and management.

Correction: Parashar et al. Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance. Cancers 2022, 14, 958.

The authors would like to correct the author byline to include Dr [...].

Foul Ball Rates and Injuries at Major League Baseball Games: A Retrospective Analysis of Data from Three Stadiums.

IMPORTANCE: This paper provides a large-scale, per Major League Baseball (MLB) game analysis of foul ball (FB) injury data and provides estimates of injury frequency and severity. OBJECTIVE: This study's goal was to quantify and describe the rate and type of FB injuries at MLB games. DESIGN: This was a retrospective review of medical care reports for patients evaluated by on-site health care providers (HCPs) over a non-contiguous 11-year period (2005-2016). Data were obtained using Freedom of Information Act (FOIA) requests. SETTING: Data were received from three US-based MLB stadiums. RESULTS: The review reported 0.42-0.55 FB injuries per game that were serious enough to warrant presentation at a first aid center. This translated to a patients per 10,000 fans rate (PPTT) of 0.13-0.23. The transport to hospital rate (TTHR) was 0.02-0.39. Frequently, FB injuries required analgesics but were overwhelmingly minor and occurred less often than non-FB traumatic injuries (5.2% versus 42%-49%). However, FB injured fans were more likely to need higher levels of care and transport to hospital (TH) as compared to people suffering other traumatic injuries at the ballpark. Contusions or head injuries were common. Finally, FB injured fans were often hit in the abdomen, upper extremity, face, or head. It was found that FB injuries appeared to increase with time, and this increase in injuries aligns with the sudden increase in popularity of smartphones in the United States. CONCLUSIONS AND RELEVANCE: These data suggest that in roughly every two or three MLB games, a foul ball causes a serious enough injury that a fan seeks medical attention. This rate is high enough to warrant attention, but is comparable in frequency to other diagnostic categories. Assessing the risk to fans from FBs remains difficult, but with access to uniform data, researchers could answer persistent questions that would lead to actionable changes and help guide public policy towards safer stadiums.

Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance.

Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis and chemotherapeutic agents. However, the precise mechanism as an oncogenic addiction that makes 3D spheroids resistant to apoptosis and chemotherapeutic agents is not understood. To study the signaling addiction mechanism that occurs during cancer progression in patients, we developed an endometrioid subtype ovarian cancer cell line named 'MCW-OV-SL-3' from the ovary of a 70-year-old patient with stage 1A endometrioid adenocarcinoma of the ovary. We found that the cell line MCW-OV-SL-3 exhibits interstitial duplication of 1q (q21-q42), where this duplication resulted in high expression of the PIK3C2B gene and aberrant activation of PI3K-AKT-ERK signaling. Using short tandem repeat (STR) analysis, we demonstrated that the cell line exhibits a unique genetic identity compared to existing ovarian cancer cell lines. Notably, the MCW-OV-SL-3 cell line was able to form 3D spheroids spontaneously, which is an inherent property of tumor cells when plated on cell culture dishes. Importantly, the tumor spheroids derived from the MCW-OV-SL-3 cell line expressed high levels of c-Kit, PROM1, ZEB1, SNAI, VIM, and Twist1 compared to 2D monolayer cells. We also observed that the hyperactivation of ERK and PI3K/AKT signaling in these cancer cells resulted in resistance to cisplatin. In summary, the MCW-OV-SL3 endometrioid cell line is an excellent model to study the mechanism of cancer stemness and chemoresistance in endometrioid ovarian cancer.

Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: There is a high unmet need for treatment regimens that increase the chance of long-term remission and possibly cure for women with newly diagnosed advanced ovarian cancer. In the primary analysis of SOLO1/GOG 3004, the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib significantly improved progression-free survival versus placebo in patients with a BRCA mutation; median progression-free survival was not reached. Here, we report an updated, post-hoc analysis of progression-free survival from SOLO1, after 5 years of follow-up. METHODS: SOLO1 was a randomised, double-blind, placebo-controlled, phase 3 trial, done across 118 centres in 15 countries, that enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1 and with BRCA-mutated, newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer with a complete or partial clinical response after platinum-based chemotherapy. Patients were randomly assigned (2:1) via a web-based or interactive voice-response system to receive olaparib (300 mg twice daily) or placebo tablets orally as maintenance monotherapy for up to 2 years; randomisation was by blocks and was stratified according to clinical response after platinum-based chemotherapy. Patients, treatment providers, and data assessors were masked to group assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy is reported in the intention-to-treat population and safety in patients who received at least one dose of treatment. The data cutoff for this updated, post-hoc analysis was March 5, 2020. This trial is registered with ClinicalTrials.gov (NCT01844986) and is ongoing but closed to new participants. FINDINGS: Between Sept 3, 2013, and March 6, 2015, 260 patients were randomly assigned to olaparib and 131 to placebo. The median treatment duration was 24·6 months (IQR 11·2-24·9) in the olaparib group and 13·9 months (8·0-24·8) in the placebo group; median follow-up was 4·8 years (2·8-5·3) in the olaparib group and 5·0 years (2·6-5·3) in the placebo group. In this post-hoc analysis, median progression-free survival was 56·0 months (95% CI 41·9-not reached) with olaparib versus 13·8 months (11·1-18·2) with placebo (hazard ratio 0·33 [95% CI 0·25-0·43]). The most common grade 3-4 adverse events were anaemia (57 [22%] of 260 patients receiving olaparib vs two [2%] of 130 receiving placebo) and neutropenia (22 [8%] vs six [5%]), and serious adverse events occurred in 55 (21%) of 260 patients in the olaparib group and 17 (13%) of 130 in the placebo group. No treatment-related adverse events that occurred during study treatment or up to 30 days after discontinuation were reported as leading to death. No additional cases of myelodysplastic syndrome or acute myeloid leukaemia were reported since the primary data cutoff, including after the 30-day safety follow-up period. INTERPRETATION: For patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, after, to our knowledge, the longest follow-up for any randomised controlled trial of a PARP inhibitor in this setting, the benefit derived from 2 years' maintenance therapy with olaparib was sustained beyond the end of treatment, extending median progression-free survival past 4·5 years. These results support the use of maintenance olaparib as a standard of care in this setting. FUNDING: AstraZeneca; Merck Sharpe & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.

Patient-reported outcome changes at the end of life in recurrent platinum-resistant ovarian cancer: An NRG oncology/GOG study.

OBJECTIVES: In a prospective study of platinum-resistant ovarian cancer patients, we examined whether the Disease-related Symptoms-Physical (DRS--P) scale of the NCCN/FACT-Ovarian Cancer Symptom Index-18 (NFOSI-18) is responsive to clinical change in patients estimated by their provider to survive at least six months. METHODS: The NFOSI-18, and other FACT measures, was collected at study entry and 3 and 6 months post-enrollment. Measures were compared for those who died or dropped off study prior to 3 months or prior to 6 months (assumed as health deterioration over time), or those who stayed on study through 6 months (presumed as stable disease over time). Statistical analyses included a fitted linear mixed model for estimating the group differences over time, Cox regression to assess the probability of survival with patient-reported outcomes, and effect size. RESULTS: DRS-P scores of patients who completed only one assessment were significantly lower compared to patients who were able to complete two assessments [5.9 points lower (2.0-9.8); p < 0.01], or three assessments [8.1 points lower (4.8-11.5); p < 0.01]. Measures of abdominal discomfort, functional well-being, emotional well-being, and quality of life were also significant, but treatment side effects were not. Further, in every scale except for neurotoxicity, higher (better) baseline scores were associated with a decreased likelihood of death, after adjusting for age, performance and disease status. CONCLUSION: The NFOSI-18 DRS-P scale is responsive to clinical change. It has potential as an indicator of changing health status with ovarian cancer disease progression, distinct from treatment side effects.