Lisfranc Injury: Recent Trends in Management.

Lisfranc injury refers to a group of bony or ligamentous injuries in which one or more of the metatarsals are displaced with respect to the tarsus. These injuries can occur as a result of either high-energy trauma like motor vehicle accidents and falls from height, or low-energy trauma from sports activities. A significant proportion of Lisfranc injuries are missed initially. The effects of delayed and missed diagnosed cases can be devastating as patients may develop progressive midfoot instability, collapse of arch, abduction of forefoot, and post-traumatic osteoarthritis, which can cause chronic pain, stiffness, and foot and ankle complex dysfunction. Favourable outcomes are associated with early diagnosis and prompt treatment. Open reduction and internal fixation (ORIF) with arthrodesis has better results than ORIF alone in functional outcomes. Dorsal bridge plates are currently the preferred mode of fixation due to advantages over trans-articular screws.

Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

BACKGROUND: The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose. RESULTS: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. CONCLUSIONS: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.

Doubling down on the future of gynecologic oncology: The SGO future of the profession summit report.

The original vision of the field of gynecologic oncology was to establish a multidisciplinary approach to the management of patients with gynecologic cancers. Fifty years later, scientific advances have markedly changed the overall practice of gynecologic oncology, but the profession continues to struggle to define its value-financial and otherwise. These issues were examined in full at the Society of Gynecologic Oncology (SGO) Future of the Profession Summit and the purpose of this document is to summarize the discussion, share the group's perceived strengths, weaknesses, opportunities, and threats (SWOT) for gynecologic oncologists, further educate members and others within the patient care team about the unique role of gynecologic oncologists, and plan future steps in the short- and long- term to preserve the subspecialty's critical mission of providing comprehensive, longitudinal care for people with gynecologic cancers.

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).

PURPOSE: ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo. METHODS: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS: As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION: Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

Comprehensive genomic profiling of recurrent endometrial cancer: Implications for selection of systemic therapy.

OBJECTIVES: To assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions. METHODS: Archival tissues from 74 patients diagnosed with recurrent EC were prospectively analyzed using hybrid-capture-based genomic profiling. Tumor mutational burden and microsatellite instability were measured. Clinically relevant GAs (CRGAs) were defined as GAs associated with targeted therapies available on-label or in mechanism-driven clinical trials. RESULTS: Using POLE mutational analysis, mismatch repair status, and p53 mutational analysis as surrogate for 'copy-number' status CGP segregated all cases into four TCGA molecular subgroups. While recurrent serous ECs were predominantly copy-number high, we found no clear prevalence of a specific molecular subtype in endometrioid, clear cell or undifferentiated tumors. Every tumor sample had at least one GA and 91% (67/74) had at least one CRGA. In this series 32% (24/74) of patients received a matched therapy based on the results of CGP. Objective responses to the matched therapy were seen in 25% (6/24) of patients with an additional 37.5% (9/24) achieving stable disease leading to a clinical benefit rate of 62.5% with a median treatment duration of 14.6 months (range 4.3-69 months). CONCLUSIONS: CGP allows molecular classification of EC into four TCGA categories and allows identification of potential biomarkers for matched therapy in the setting of routine clinical care.

Prognostic role of pathologic response and cytoreductive status at interval debulking surgery after neoadjuvant chemotherapy for advanced epithelial ovarian cancer.

BACKGROUND: We sought to determine if complete pathologic response (cPR) and cytoreductive status at interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT) are associated with improved clinical outcomes in ovarian cancer. METHODS: We evaluated 91 patients with advanced ovarian cancer who underwent NACT and IDS. Pathologic response, cytoreductive status, and outcomes were determined. Descriptive statistics, bivariate analysis, and Kaplan-Meier survival probabilities were calculated. RESULTS: cPR occurred in 9 (10%), microscopic pathologic response (microPR) in 18 (20%), and macroscopic pathologic response (macroPR) in 64 (70%) patients. Median progression-free survival (PFS) for patients with cPR was significantly improved compared with patients with any pathologic residual disease (microPR/macroPR; undefined vs 10.9 months, P = .01); whereas, microPR was not associated with significantly improved PFS compared with macroPR (16.3 months vs 10 months, P = .08). Cytoreduction to no gross residual disease was associated with improved PFS (undefined vs 7.5 months vs 5.5 months, P < .01) and overall survival (undefined vs 38.7 months vs 12 months, P < .01) compared with visible residual disease less than or equal to 1 cm or suboptimal. CONCLUSIONS: cPR is uncommon (10%) after NACT for advanced ovarian cancer. Better pathologic response and cytoreductive status are associated with improved PFS, emphasizing the importance of both chemotherapy response and surgical effort.

Clinical outcomes in ovarian cancer patients receiving three versus more cycles of chemotherapy after neoadjuvant treatment and interval cytoreductive surgery.

OBJECTIVES: To compare clinical outcomes for stage IIIC and IV ovarian cancer patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery followed by up to three versus more cycles of post-operative chemotherapy. METHODS: We conducted a multi-institution retrospective cohort study of patients treated from January 2005 to February 2016 with neoadjuvant platinum-based therapy followed by interval surgery and post-operative chemotherapy. The following were exclusion criteria: more than four cycles of neoadjuvant chemotherapy, bevacizumab with neoadjuvant chemotherapy, non-platinum therapy, prior chemotherapy, and elevated CA125 values after three post-operative chemotherapy cycles. Progression-free and overall survival and toxicity profiles were compared between groups receiving up to three cycles versus more that three cycles post-operatively. RESULTS: A total of 100 patients met inclusion criteria: 41 received up to three cycles and 59 received more than three cycles. The groups were similar in terms of age, body mass index, performance status, tumor histology, optimal cytoreduction rates, and median number of neoadjuvant chemotherapy cycles. Median progression-free survival was 14 vs 16.6 months in those receiving up to three cycles versus more than three cycles, respectively (HR 0.99, 95% CI 0.58 to 1.68, p=0.97). Similarly, median overall survival was not different at 47.1 vs 69.4 months, respectively (HR 1.96, 95% CI 0.87 to 4.42, p=0.10). There were no differences in grade 2 or higher chemotherapy-related toxicities. CONCLUSIONS: Extending post-operative chemotherapy beyond three cycles in patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery with normalization of CA125 levels was not associated with improved survival or greater toxicity. Future study in a larger cohort is warranted to define optimal length of cytotoxic treatment.

Optimizing exosomal RNA isolation for RNA-Seq analyses of archival sera specimens.

Exosomes are endosome-derived membrane vesicles that contain proteins, lipids, and nucleic acids. The exosomal transcriptome mediates intercellular communication, and represents an understudied reservoir of novel biomarkers for human diseases. Next-generation sequencing enables complex quantitative characterization of exosomal RNAs from diverse sources. However, detailed protocols describing exosome purification for preparation of exosomal RNA-sequence (RNA-Seq) libraries are lacking. Here we compared methods for isolation of exosomes and extraction of exosomal RNA from human cell-free serum, as well as strategies for attaining equal representation of samples within pooled RNA-Seq libraries. We compared commercial precipitation with ultracentrifugation for exosome purification and confirmed the presence of exosomes via both transmission electron microscopy and immunoblotting. Exosomal RNA extraction was compared using four different RNA purification methods. We determined the minimal starting volume of serum required for exosome preparation and showed that high quality exosomal RNA can be isolated from sera stored for over a decade. Finally, RNA-Seq libraries were successfully prepared with exosomal RNAs extracted from human cell-free serum, cataloguing both coding and non-coding exosomal transcripts. This method provides researchers with strategic options to prepare RNA-Seq libraries and compare RNA-Seq data quantitatively from minimal volumes of fresh and archival human cell-free serum for disease biomarker discovery.

Discovery of novel stroke-responsive lncRNAs in the mouse cortex using genome-wide RNA-seq.

Long noncoding RNAs (lncRNAs) play major roles in regulating gene expression in mammals, but are poorly understood in ischemic stroke. Using a mouse model of transient focal ischemia, we applied RNA-seq to evaluate for the first time the unbiased, genome-wide expression of lncRNAs as a function of reperfusion time in the cerebral cortex. Focal ischemia was induced in adult male C57BL/6 mice followed by reperfusion for 6, 12 or 24h. Total RNA from ipsilateral cortices was used for Illumina sequencing and reads were mapped to the mouse reference genome (GRCm38). Annotated and novel transcript isoforms were identified and differential expression between the groups was estimated. We observed that the baseline expression of lncRNAs in the healthy cortex was low, but many were highly altered after stroke. Very few of these altered lncRNAs were previously annotated. A total of 259 lncRNA isoforms at 6h, 378 isoforms at 12h, and 217 isoforms at 24h of reperfusion were differentially expressed versus sham controls. Of these, 213, 322 and 171 isoforms at 6, 12 and 24h of reperfusion, respectively, were novel lncRNAs. Reperfusion time-point-specific analyses revealed that the lncRNAs reached peak expression levels at 6h of reperfusion. Positional analysis of ischemia-responsive lncRNAs with respect to ischemia-responsive protein-coding genes identified potential gene-regulatory relationships. Overall, this work shows that transient focal ischemia induces widespread changes in the expression of lncRNAs in the mouse cortex with distinct reperfusion time-point-dependent expression characteristics that may underlie progression of the ischemic pathophysiology. The detection of hundreds of novel ischemia-responsive lncRNAs marks the discovery of new disease-related genomic regions in the adult cortex and may help identify novel opportunities for therapeutic targeting.

Evaluation of venous thrombosis and tissue factor in epithelial ovarian cancer.

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) and high grade serous ovarian cancer (HGSOC) are associated with the highest risk of VTE among patients with epithelial ovarian cancer (EOC). Tissue factor (TF) is a transmembrane glycoprotein which can trigger thrombosis. We sought to evaluate if there is an association between VTE and tumor expression of tissue factor (TF), plasma TF, and microvesicle TF (MV TF) activity in this high-risk population. METHODS: We performed a case-control study of OCCC and HGSOC patients with and without VTE. 105 patients who underwent surgery at a tertiary care center between January 1995 and October 2013 were included. Plasma TF was measured with an enzyme-linked immunosorbent assay. A TF-dependent Factor Xa generation assay was used to measure MV TF activity. Immunohistochemical (IHC) analysis was performed to evaluate tumor expression of TF. RESULTS: 35 women with OCCC or HGSOC diagnosed with VTE within 9months of surgery were included in the case group. Those with VTE had a worse OS, p<0.0001, with a greater than three-fold increase in risk of death, HR 3.33 (CI 1.75-6.35). There was no significant difference in median plasma TF level or MV TF activity level between patients with and without VTE. OCCC patients had greater expression of TF in their tumors than patients with HGSOC, p<0.0001. CONCLUSIONS: TFMV activity and plasma TF level were not predictive of VTE in this patient population. Given the extensive expression of TF in OCCC tumors, it is unlikely IHC expression will be useful in risk stratification for VTE in this population.

Genomic profiling of gynecologic cancers and implications for clinical practice.

PURPOSE OF REVIEW: This article summarizes advances in the application of next-generation sequencing (NGS) to the personalized treatment of gynecologic malignancies. RECENT FINDINGS: Many recurrent genomic alterations (GA) in gynecologic malignancies have been identified by studies applying NGS to tumor tissue, which can provide insights into tumor biology, diagnostic or prognostic information, and potential targeted therapy options. NGS can be used to assay single genes, portions of multiple genes ("hot-spot" panels), or the complete coding sequence of a broad range of cancer-associated genes [i.e. comprehensive genomic profiling (CGP)]. CGP of a patient's tumor reveals to practitioners clinically relevant GA (CRGA) and associated biomarker-matched treatments, with a goal of improving therapeutic response while limiting cumulative chemotherapeutic toxicities. Although the use of precision medicine for gynecologic cancers holds much promise, the data detailing impact on survival and quality of life is still accumulating, lagging behind other areas of oncology. Enrolling gynecologic oncology patients in genotype-matched trials remains challenging and highlights the need for more molecular-based basket trials for reproductive tract malignancies. SUMMARY: Identification of molecular subsets with distinct clinical attributes, prognostic significance, and targeted therapy directed options is now feasible in clinical gynecologic oncology practice.

Three versus six cycles of adjuvant platinum-based chemotherapy in early stage clear cell ovarian carcinoma - A multi-institutional cohort.

OBJECTIVES: To determine if 6 versus 3cycles of adjuvant platinum-based chemotherapy with or without taxane impacts survival in early stage ovarian clear cell carcinoma (OCCC). METHODS: We retrospectively identified all cases of stage I and II OCCC treated at 5 institutions from January 1994 through December 2011. Patients were divided into 2 groups: those who received 3 versus 6cycles of adjuvant chemotherapy. Our cohort consisted of 210 patients with stage IA-II disease, 116 of whom underwent full surgical staging. Cox proportional hazards regression and Kaplan-Meier analyses were performed to evaluate progression-free (PFS) and overall survival (OS) between groups. RESULTS: Among 210 eligible patients, the median age was 53years (range 30-88). The majority of patients were Caucasian (83.8%). All patients received adjuvant chemotherapy with 90% receiving carboplatin and paclitaxel. Thirty-eight (18.1%) patients received 3cycles, and 172 (81.9%) patients received 6cycles of adjuvant treatment. Recurrence rate was comparable between groups (18.4% vs. 27.3% for 3 vs. 6cycles, p=0.4). There was no impact of 3 versus 6cycles of chemotherapy on PFS (hazard ratio [HR] 1.4; 95% confidence interval [CI] 0.63-3.12, p=0.4) or OS (HR 1.65; 95% CI 0.59-4.65, p=0.3) on univariate analysis. There was no benefit to more chemotherapy in stratified analysis by stage nor on multivariate analysis adjusting for the impact of stage. Subgroup analysis of surgically staged patients also showed no difference in survival between 3 versus 6cycles of chemotherapy. CONCLUSIONS: Three cycles of platinum with or without taxane adjuvant chemotherapy were comparable to 6cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. CONDENSATION: Three cycles of platinum with or without taxane adjuvant chemotherapy are comparable to 6 cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort.

Anatomic Outcomes of Robotic Assisted Supracervical Hysterectomy and Concurrent Sacrocolpopexy at a Tertiary Care Institution at Initial Adaptation of the Procedure.

OBJECTIVE: The aim of the study was to review anatomic and surgical outcomes of robotic-assisted supracervical hysterectomy (RASCH) with concurrent sacrocolpopexy in the treatment of primary pelvic organ prolapse (POP) on initial adaption of this procedure. STUDY DESIGN: A retrospective chart review of patients undergoing RASCH with concurrent sacrocolpopexy between 2009 and 2012 was performed at a tertiary care academic institution, after initial adaption of this procedure. The primary outcome was change in vaginal support (assessed with the pelvic organ prolapse quantification [POP-Q]) at 3 months and 1 year postoperatively. Secondary measures assessed included estimated blood loss, operative times, hospital length of stay, and operative complications. RESULTS: Forty patients (N = 40) underwent RASCH with concurrent sacrocolpopexy. Twenty-six patients (65%) had preoperative stage II POP, and 35% had stage III POP. Three months after undergoing the procedure, 55% had achieved stage 0 POP. An additional 35% were categorized as stage I POP. At 1 year, 72.7% were stage I POP or lower. The mean (SD) operating time was 275 (82.3) minutes. Estimated blood loss and mean (SD) length of hospital stay were 163 (114.9) mL and 1.3 (0.8) days, respectively. There were no intensive care unit admissions. The most common postoperative complication was immediate urinary retention in 10% of patients; all cases resolved with time-limited intermittent self-catheterization. CONCLUSIONS: Even with initial adaptation of the procedure, RASCH with concurrent sacrocolpopexy for the repair of primary POP is effective in restoring anatomic support in the short term. Operative complications are minimal.

Nested PCR for specific diagnosis of Taenia solium taeniasis.

Taeniasis due to Taenia solium is a disease with important public health consequences, since the larval stage is not exclusive to the animal intermediate, the pig, but also infects humans, causing neurocysticercosis. Early diagnosis and treatment of T. solium tapeworm carriers is important to prevent human cysticercosis. Current diagnosis based on microscopic observation of eggs lacks both sensitivity and specificity. In the present study, a nested-PCR assay targeting the Tso31 gene was developed for the specific diagnosis of taeniasis due to T. solium. Initial specificity and sensitivity testing was performed using stored known T. solium-positive and -negative samples. The assay was further analyzed under field conditions by conducting a case-control study of pretreatment stool samples collected from a population in an area of endemicity. Using the archived samples, the assay showed 97% (31/32) sensitivity and 100% (123/123) specificity. Under field conditions, the assay had 100% sensitivity and specificity using microscopy/enzyme-linked immunosorbent assay coproantigen testing as the gold standards. The Tso31 nested PCR described here might be a useful tool for the early diagnosis and prevention of taeniasis/cysticercosis.