Selective targeting of metastatic ovarian cancer using an engineered anthrax prodrug activated by membrane-anchored serine proteases.

Treatments for advanced and recurrent ovarian cancer remain a challenge due to a lack of potent, selective, and effective therapeutics. Here, we developed the basis for a transformative anticancer strategy based on anthrax toxin that has been engineered to be selectively activated by the catalytic power of zymogen-activating proteases on the surface of malignant tumor cells to induce cell death. Exposure to the engineered toxin is cytotoxic to ovarian tumor cell lines and ovarian tumor spheroids derived from patient ascites. Preclinical studies demonstrate that toxin treatment induces tumor regression in several in vivo ovarian cancer models, including patient-derived xenografts, without adverse side effects, supportive of progression toward clinical evaluation. These data lay the groundwork for developing therapeutics for treating women with late-stage and recurrent ovarian cancers, utilizing a mechanism distinct from current anticancer therapies.

Tubulin Complexity in Cancer and Metastasis.

Tubulin plays a fundamental role in cellular function and as the subject for microtubule-active agents in the treatment of ovarian cancer. Microtubule-binding proteins (e.g., tau, MAP1/2/4, EB1, CLIP, TOG, survivin, stathmin) and posttranslational modifications (e.g., tyrosination, deglutamylation, acetylation, glycation, phosphorylation, polyamination) further diversify tubulin functionality and may permit additional opportunities to understand microtubule behavior in disease and to develop microtubule-modifying approaches to combat ovarian cancer. Tubulin-based structures that project from suspended ovarian cancer cells known as microtentacles may contribute to metastatic potential of ovarian cancer cells and could represent an exciting novel therapeutic target.

Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy.

Microtubules are dynamic polymers composed of α- and ß-tubulin heterodimers. Microtubules are universally conserved among eukaryotes and participate in nearly every cellular process, including intracellular trafficking, replication, polarity, cytoskeletal shape, and motility. Due to their fundamental role in mitosis, they represent a classic target of anti-cancer therapy. Microtubule-stabilizing agents currently constitute a component of the most effective regimens for ovarian cancer therapy in both primary and recurrent settings. Unfortunately, the development of resistance continues to present a therapeutic challenge. An understanding of the underlying mechanisms of resistance to microtubule-active agents may facilitate the development of novel and improved approaches to this disease.

In vitro fertilization: a cross-sectional analysis of 58 US insurance companies.

PURPOSE: Infertility affects one in eight women in the USA. In vitro fertilization (IVF) is an effective but costly treatment that lacks uniform insurance coverage. We evaluated the current insurance coverage landscape for IVF in America. METHODS: We conducted a cross-sectional analysis of 58 insurance companies with the greatest state enrollment and market share, calculated to represent the majority of Americans with health insurance. Individual companies were evaluated for a publicly available policy on IVF services by web-based search, telephone interview, or email to the insurer. Coverage status, required criteria, qualifying risk factors, and contraindications to coverage were extracted from available policies. RESULTS: Fifty-one (88%) of the fifty-eight companies had a policy for IVF services. Thirty-five (69%) of these policies extended coverage. Case-by-case coverage was stated in seven policies (14%), while coverage was denied in the remaining nine (18%). The most common criterion to receive coverage was a documented diagnosis of infertility (n = 23, 66%), followed by care from a reproductive endocrinologist (n = 9, 26%). Twenty-three (45%) of the companies with a policy had at least one contraindication to coverage. Three companies (6%) limited the number of IVF cycles to be covered, capping payments after 3-4 lifetime cycles. CONCLUSION: Most Americans with health insurance are provided a public policy regarding IVF. However, there is great variation in coverage and requirements to receive coverage between insurers. Coupled with inconsistencies in state-level mandates and available choices for employer-sponsored plans, this may limit coverage of IVF services and, therefore, access to infertility treatment.

A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability.

BACKGROUND: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). METHODS: Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively. CONCLUSIONS: This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.

Randomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer.

BACKGROUND: This multi-center RP2 study assessed activity/safety of ixabepilone + bevacizumab compared to ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional objectives were to examine the role of prior bevacizumab and taxanes, and explore class III-ß-tubulin (TUBB3) as a predictive biomarker. METHODS: Participants were randomised to receive ixabepilone 20 mg/m2 days 1, 8, 15 with (IXA + BEV) or without (IXA) bevacizumab 10 mg/kg days 1, 15 every 28 days. Patients were stratified by prior BEV. The primary endpoint was PFS. OS, safety, and ORR served as secondary endpoints. RESULTS: Among 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA (n = 37), the ORR was 33% (n = 13) versus 8% (n = 3)(P = 0.004), durable at 6 months in 37% (n = 14) and 3% (n = 1) (P < 0.001). BEV significantly improved PFS (median:5.5 vs 2.2 months, HR = 0.33, 95%CI 0.19-0.55, P < 0.001) and OS (median:10.0 vs 6.0 months, HR = 0.52, 95%CI 0.31-0.87, P = 0.006). Both regimens were well-tolerated. TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV. CONCLUSIONS: IXA + BEV is a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extends PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker. CLINICAL TRIAL REGISTRATION: NCT3093155.

Synergistic activity of neratinib in combination with olaparib in uterine serous carcinoma overexpressing HER2/neu.

INTRODUCTION: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with a poor prognosis. Approximately 30% of USC overexpress HER2/neu, a recognized target for trastuzumab in advanced/recurrent HER2/neu-positive USC. We evaluated the efficacy of the pan-c-erb inhibitor neratinib and the poly (ADP-ribose)-polymerase (PARP) inhibitor olaparib as single agents and in combination against USC cell lines and xenografts. METHODS: In-vitro cell-viability assays with olaparib, neratinib, and olaparib/neratinib were assessed using flow-cytometry based assays against a panel of USC cell lines with high and low HER2/neu expression. Homologous recombination deficiency (HRD) signatures were evaluated as described by Alexandrov et al. (Nature;2020;578:94-101) while downstream signaling affected by neratinib/olaparib exposure was assessed with immunoblotting. Efficacy of single- versus dual-agent inhibition was evaluated in-vivo using two USC-xenografts with 3+ HER2/neu expression. RESULTS: Neratinib was more potent than olaparib in suppression of in-vitro growth of HER2/neu 3+ cell lines (ARK1: p = 0.0047; ARK2: p = 0.0428) while no difference was noted against HER2/neu 1+ tumors (ARK4). Importantly, the combination of olaparib with neratinib synergistically improved tumor suppression compared to either single-agent in vitro. USC cells exposed to olaparib upregulated HER2/neu expression, while neratinib treatment increased PARP activity (ARK1: p < 0.0001; ARK2: p < 0.0001). Single-agent neratinib transiently inhibited in vivo growth of USC xenografts harboring HER2/neu gene amplification (ARK1: p < 0.05; ARK2: p < 0.05). In contrast, the combination of the two inhibitors caused a stronger and durable growth inhibition in both USC xenografts (ARK1: p < 0.05; ARK2: p < 0.05). CONCLUSION: The combination of olaparib and neratinib is active and synergistic against primary HER2/neu + USC. This combination may represent a novel therapeutic option for USC patients with HER2/neu+, homologous recombination-proficient tumors resistant to chemotherapy.

Malignant Sex Cord-Stromal Tumor, Not Otherwise Specified, Harboring FOXL2, p53, and TERT Promoter Mutations: Report of a Case.

Rare sex cord-stromal tumors of the ovary cannot be further subclassified and are therefore designated "sex cord-stromal tumor-not otherwise specified." These tumors have highly varied morphology, and the literature describing them is limited. Herein, we report the pathology and clinical course of a 46-yr-old woman diagnosed with sex cord-stromal tumor-not otherwise specified. The tumor was composed predominantly of juvenile granulosa cell tumor histology, with elements of thecoma, adult granulosa, Sertoli, as well as poorly differentiated epithelioid and sarcomatoid components. Next-generation sequencing revealed a FOXL2 C134W mutation, seen most commonly in adult granulosa cell tumors, as well as mutations in TP53 (V172F) and TERT promoter (-124C>T). The patient exhibited an aggressive clinical course involving rapid recurrence with distant metastases that responded to 4 cycles of cisplatin, bleomycin, and etoposide.

Review of Immune Therapies Targeting Ovarian Cancer.

OPINION STATEMENT: The rise of immunotherapy is the greatest advance in oncology to occur over the last several years, but applications in gynecologic malignancies lag behind other tumors. The term "immunotherapy" envelops monoclonal antibodies as receptor mediators, including immune checkpoint inhibitors (ICPI), cancer vaccines, and adoptive immunotherapies alone or in combination with other therapeutic approaches. The purpose of this review is to summarize the status of immunotherapy trials in ovarian cancer and to specifically highlight data published in the last 1-2 years.

Pelvic floor disorders in women with gynecologic malignancies: a systematic review.

INTRODUCTION AND HYPOTHESIS: Pelvic floor disorders (PFDs) negatively affect quality of life in the general population, and their prevalence in gynecologic cancer survivors has not been systematically described. This study aimed to determine the prevalence of PFDs in cancer survivors. We hypothesized that the prevalence of PFDs in the gynecologic cancer population would be higher than in the general female population. METHODS: We searched PubMed (1809 to present), EMBASE (1974 to present), and the Cochrane Central Register of Controlled Trials (CENTRAL) through May 2017. The search combined subject headings, title, and abstract words for gynecologic cancer, PFDs, and prevalence. Any studies evaluating the prevalence of PFDs in gynecologic malignancies were included. RESULTS: A total of 550 articles met the designated search criteria and 31 articles were included in this review. In cervical cancer survivors, before treatment the prevalences of stress urinary incontinence (SUI), urgency urinary incontinence (UUI) and fecal incontinence (FI) were 24-29%, 8-18% and 6%, respectively, and after treatment the prevalences of SUI, UUI, urinary retention, FI, fecal urge, dyspareunia and vaginal dryness were 4-76%, 4-59%, 0.4-39%, 2-34%, 3-49%, 12-58% and 15-47%, respectively. In uterine cancer survivors, before treatment the prevalences of SUI, UUI and FI were 29-36%, 15-25% and 3%, respectively, and after treatment the prevalences of urinary incontinence (UI) and dyspareunia were 2-44% and 7-39%, respectively. In vulvar cancer survivors, after treatment the prevalences of UI, SUI and FI were 4-32%, 6-20% and 1-20%, respectively. In ovarian cancer survivors, the prevalences of SUI, UUI, prolapse and sexual dysfunction were 32-42%, 15-39%, 17% and 62-75%, respectively. CONCLUSIONS: PFDs are prevalent in gynecologic cancer survivors and this is an important area of clinical concern and future research.

Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma.

Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRD-chromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7-mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer.

Solitomab, an epithelial cell adhesion molecule/CD3 bispecific antibody (BiTE), is highly active against primary chemotherapy-resistant ovarian cancer cell lines in vitro and fresh tumor cells ex vivo.

BACKGROUND: Solitomab is a novel, bispecific, single-chain antibody that targets epithelial cell adhesion molecule (EpCAM) on tumor cells and also contains a cluster of differentiation 3 (CD3) (T-cell coreceptor) binding region. The authors evaluated the in vitro activity of solitomab against primary chemotherapy-resistant epithelial ovarian carcinoma cell lines as well as malignant cells in ascites. METHODS: EpCAM expression was evaluated by flow cytometry in 5 primary ovarian cancer cell lines and in 42 fresh ovarian tumor cell cultures in ascites from patients with mainly advanced or recurrent, chemotherapy-resistant disease. The potential activity of solitomab against EpCAM-positive tumor cells was evaluated by flow cytometry, proliferation, and 4-hour chromium-release, cell-mediated cytotoxicity assays. RESULTS: EpCAM expression was detected by flow cytometry in approximately 80% of the fresh ovarian tumors and primary ovarian tumor cell lines tested. EpCAM-positive, chemotherapy-resistant cell lines were identified as resistant to natural killer cell-mediated or T-cell-mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean±standard error of the mean, 3.6%±0.7% of cells killed after incubation of EpCAM-positive cell lines with control bispecific antibody). In contrast, after incubation with solitomab, EpCAM-positive, chemotherapy-resistant cells became highly sensitive to T-cell cytotoxicity (mean±standard error of the mean, 28.2%±2.05% of cells killed; P<.0001) after exposure to peripheral blood lymphocytes. Ex vivo incubation of autologous tumor-associated lymphocytes with EpCAM-expressing malignant cells in ascites with solitomab resulted in a significant increase in T-cell activation markers and a reduction in the number of viable ovarian tumor cells in ascites (P<.001). CONCLUSIONS: Solitomab may represent a novel, potentially effective agent for the treatment of chemotherapy-resistant ovarian cancers that overexpress EpCAM.

Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary peritoneal/fallopian tube cancers: A retrospective review.

OBJECTIVE: To describe the clinical outcome and tolerability of weekly ixabepilone (16-20mg/m(2) days 1, 8, 15 of a 28-day cycle)±biweekly bevacizumab (10mg/kg days 1 and 15) in patients with recurrent/persistent uterine or ovarian/primary peritoneal/fallopian tube cancers. METHODS: A single-institution retrospective review was performed inclusive of all patients who received ≥2cycles from 01/2010 to 06/2014. Progression-free (PFS) and overall (OS) survival were determined using the Kaplan-Meier method. Toxicities were graded according to CTCAEv4.0. Best response was categorized using RECIST or by CA-125 criteria. RESULTS: A total of 60 patients (24 uterine and 36 ovarian cancers) were identified. Patients had received a median of 3.5 (range:1-10) prior lines of chemotherapy. Patients completed a mean of 4.7±2.9cycles of ixabepilone; 66.7% (16/24) and 91.7% (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. For uterine cancers, objective response rate (ORR) was 41.7% (12.5% complete, 29.2% partial); median duration of response or stabilization was 7months (range:2-30). Median PFS and OS were 5.2 and 9.6months, respectively. PFS and OS were improved in the setting of concurrent bevacizumab (6.5 versus 3.0months, p=0.01, HR 0.2, 95% CI 0.05-0.77; 9.6 versus 4.2months, p=0.02, HR 0.58, 95% CI 0.04-0.74). Similar ORR was observed among ovarian cancers; median PFS/OS were not yet reached. Most toxicities were grade 1/2. CONCLUSIONS: Weekly ixabepilone with or without biweekly bevacizumab has promising activity and acceptable toxicity in patients with platinum-/taxane-resistant endometrial and ovarian cancers. This combination warrants further prospective study in these populations.

Use of Monsel solution to treat obstetrical hemorrhage: a review and comparison to other topical hemostatic agents.

Peripartum hemorrhage accounts for 8% of maternal deaths in the United States, and nearly 27% worldwide. A growing need exists for tactics to spare morbidity given a rise of abnormal placentation that contributes to excessive blood loss at the time of delivery. Approaches such as compression sutures, balloon tamponade, and pelvic artery embolization are not without side effects and potential implications for future fertility. The use of topical hemostatic agents has become widespread in gynecologic and obstetric surgery despite a paucity of distinct studies in the field, and may allow providers to increasingly avoid cesarean hysterectomy. A variety of topical hemostatic agents exist along a wide cost continuum, each characterized by specific efficacy, advantages, drawbacks, and often gaps in long-term data to support safety and impact on future fertility. Herein, we comprehensively review these agents and illustrate a nontraditional use of Monsel solution applied directly to the placental bed in a case of focal placenta accreta. This ultimately contributed to successful uterine preservation with no known adverse sequelae. Monsel solution may have a role in establishing hemostasis in the setting of abnormal placentation, and may be a particularly attractive alternative in resource-poor nations.

A series of malignant ovarian cancers arising from within a mature cystic teratoma: a single institution experience.

BACKGROUND: Mature cystic teratoma (MCT) is the most common germ cell tumor. It accounts for 10% to 20% of all ovarian masses. The likelihood of malignancy arising from within an MCT is low, and prognosis is poor. METHODS: A single-institution retrospective chart review was completed of all cases of MCT from 2004 to 2012. Multiple variables were examined including procedure performed, residual disease after surgery, surgical stage, histologic type, site of primary disease, date of recurrence, whether or not adjuvant chemotherapy was given, and whether or not there was death secondary to disease. RESULTS: During the study period, 1.2% of MCTs exhibited malignant transformation. The average age at presentation was 53.7 years. Mean follow-up time was 23 months. The most common presenting symptoms were bloating and abdominal pain. The average tumor size was 18 cm. Of note, 33% of cases were at least surgical stage IIIC at the time of presentation, whereas the remainder were stage IC or lower. Four (44.4%) of the 9 cases were identified as mucinous adenocarcinoma in addition to 1 case each of malignant melanoma, squamous cell carcinoma, and poorly differentiated adenocarcinoma. Only 1 patient experienced recurrence. One patient had a known MCT that was being managed expectantly and exhibited malignant transformation to a mucinous adenocarcinoma. CONCLUSIONS: A large ovarian mass that is suspected to be a mature teratoma should be managed more aggressively in older patients. Our data suggest that although malignancy arising from mature teratomas is rare, it is more likely when patients are older than 40 years, the mass is greater than 18 cm, and there is any suspicion for a mucinous tumor. Like most ovarian tumors, these tumors most often present at later stages and, thus, can be difficult to treat. It is unclear what role chemotherapy or radiation plays in the management of these tumors.

Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo.

OBJECTIVES: Uterine serous carcinoma (USC) represents an aggressive variant of endometrial cancer and accounts for a large proportion of deaths annually. HER2/neu amplification is associated with USC in approximately 30-35% of cases. The objective of this study was to determine the sensitivity of a panel of primary USC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 and HER2 inhibitor, both in vitro and in vivo. METHODS: HER2/neu amplification was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine the effects of neratinib on cell viability, cell cycle distribution and signaling in vitro. Mice harboring HER2/neu amplified xenografts were treated with neratinib to assess the efficacy of the drug in vivo. RESULTS: HER2/neu amplification was noted in 8/24 primary cell lines. Data regarding the efficacy of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified cell lines with similar growth rates. Data revealed that cell lines with HER2/neu amplification were exquisitely more sensitive to neratinib compared to non-amplified cell lines (mean ± SEM IC50: 0.011µM ± 0.0008 vs. 0.312µM ± 0.0456 p<0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor growth and improved overall survival compared to vehicle (p=0.0019). CONCLUSIONS: Neratinib may be a potential treatment option for patients harboring HER2/neu amplified USC. Clinical trials for this subset of endometrial cancer patients are warranted.

Taxanes: their impact on gynecologic malignancy.

The use of taxanes in the treatment of gynecologic malignancies has expanded tremendously over the past 30 years. Both paclitaxel and docetaxel have unique microtubule stabilizing, antiangiogenic and radiation sensitizing properties that endow them with remarkable activity as chemotherapeutic agents. As research into the appropriate dose, timing, treatment interval, and response rates have been studied, they have emerged as one of the most active agents available in the treatment of gynecologic cancer. The body of research on taxanes continues to expand especially with regard to the use of taxanes in alternative formulations and in combination with newer treatments or routes of treatment. This review focuses on the development of taxanes as an effective therapy in the treatment of gynecologic cancers and data currently available in the literature regarding their efficacy. Future directions of taxane-based chemotherapy with regards to ovarian, uterine, and cervical cancers are also addressed. There is little doubt that taxane-based chemotherapy will remain an integral part of the treatment of gynecologic cancer for the foreseeable future.

Co-Packaged PARP inhibitor and photosensitizer for targeted photo-chemotherapy of 3D ovarian cancer spheroids.

BACKGROUND: Within the last decade, poly(ADP-ribose) polymerase inhibitors (PARPi) have emerged in the clinic as an effective treatment for numerous malignancies. Preclinical data have demonstrated powerful combination effects of PARPi paired with photodynamic therapy (PDT), which involves light-activation of specialized dyes (photosensitizers) to stimulate cancer cell death through reactive oxygen species generation. RESULTS: In this report, the most potent clinical PARP inhibitor, talazoparib, is loaded into the core of a polymeric nanoparticle (NP-Tal), which is interfaced with antibody-photosensitizer conjugates (photoimmunoconjugates, PICs) to form PIC-NP-Tal. In parallel, a new 3D fluorescent coculture model is developed using the parental OVCAR-8-DsRed2 and the chemo-resistant subline, NCI/ADR-RES-EGFP. This model enables quantification of trends in the evolutionary dynamics of acquired chemoresistance in response to various treatment regimes. Results reveal that at a low dosage (0.01 µM), NP-Tal kills the parental cells while sparing the chemo-resistant subline, thereby driving chemoresistance. Next, PIC-NP-Tal and relevant controls are evaluated in the 3D coculture model at multiple irradiation doses to characterize effects on total spheroid ablation and relative changes in parental and subline cell population dynamics. Total spheroid ablation data shows potent combination effects when PIC and NP-Tal are co-administered, but decreased efficacy with the conjugated formulation (PIC-NP-Tal). Analysis of cell population dynamics reveals that PIC, BPD + NP-Tal, PIC + NP-Tal, and PIC-NP-Tal demonstrate selection pressures towards chemoresistance. CONCLUSIONS: This study provides key insights into manufacturing parameters for PARPi-loaded nanoparticles, as well as the potential role of PDT-based combination therapies in the context of acquired drug resistance.

Early Implementation of Robotic Training in Surgical and Surgical Subspecialty Residency.

BACKGROUND: Robotic surgery has emerged as an operative tool for many elective and urgent surgical procedures. The purpose of this study was to evaluate early surgical trainees' experiences and opinions of robotic surgery. METHODS: An introductory robotic training course consisting of online da Vinci Xi/X training and in-person, hands on training was implemented for residents and medical students across surgical subspecialties at a single institution. A voluntary survey evaluating perceptions of and interest in robotic surgery and prior robotic surgery experience, as well as a basics of robotics quiz, was distributed to participants prior to the start of the in-person session. Descriptive statistics were used to evaluate the cohort. RESULTS: 85 trainees participated in the course between 2020 and 2023, including 58 first- and second-year surgical residents (general surgery, urology, OB/GYN, and thoracic surgery) and 27 fourth-year medical students. 9.4% of participants reported any formal robotic surgery training prior to the session, with only 19% of participants reporting robotic operative experience. 52% of the participants knew of and/or had completed the da Vinci online course modules prior to the scheduled training session. Participants unanimously (100%) agreed that robotic surgery should be implemented into surgical training. CONCLUSIONS: There is rising enthusiasm for robotic surgery, yet early exposure and training remain infrequent and inconsistent amongst medical students and new surgical residents. A standardized introduction of multi-disciplinary robotic surgery training should be incorporated into medical school and/or early residency education to ensure surgical residents receive appropriate exposure and training to achieve competency.