Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

Intraperitoneal and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Ovarian Cancer.

OPINION STATEMENT: In our clinical practice, we have shifted away from the use of adjuvant normothermic intraperitoneal (IP) chemotherapy, particularly following the publication of GOG 252. Our decision is rooted in the accumulating evidence indicating a lack of demonstrable superiority, alongside the recognized toxicities and logistical challenges associated with its administration. This strategic departure is also influenced by the rising utilization of maintenance therapies such as bevacizumab and PARP inhibitors, which present viable alternatives for improving patient outcomes. Our utilization of hyperthermic IP chemotherapy (HIPEC) is currently reserved for a specific cohort of patients, mirroring the patient population studied in the OVHIPEC-1 trial. Specifically, our HIPEC protocol applies to patients presenting with newly diagnosed stage IIIC high-grade epithelial ovarian cancer who are deemed ineligible for primary debulking surgery. Patients must exhibit at least stable disease with neoadjuvant platinum-based chemotherapy, maintain a favorable performance status (ECOG score 0-1), possess good nutritional reserves (with no evidence of protein-calorie malnutrition and an albumin level exceeding 3.5), and not have chronic kidney disease. When HIPEC is planned, it is administered at the time of interval debulking surgery, contingent upon the attainment of optimal surgical outcomes (< 1 cm of residual disease). Our HIPEC protocol adheres to the original OVHIPEC-1 trial guidelines, employing cisplatin at a dosage of 100 mg/m2. We administer at least two antiemetics, antihistamines, and sodium thiosulfate to mitigate known side effects. Postoperatively, patients are admitted to the general surgical floor, reserving the intensive care unit for those in critical condition. We follow Enhanced Recovery After Surgery principles, incorporating early ambulation and feeding into our postoperative care strategy. We have encountered encouraging results with this approach, with most patients having largely uncomplicated postoperative courses and resuming adjuvant chemotherapy within 3 to 4 weeks of surgery.

NCCN Guidelines® Insights: Cervical Cancer, Version 1.2024.

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

Timing and duration of bevacizumab treatment and survival in patients with recurrent ovarian, fallopian tube, and peritoneal cancer: a multi-institution study.

Bevacizumab has demonstrated significant benefit in recurrent ovarian, fallopian tube and peritoneal cancer (OC), but its optimal position within the sequence of systemic therapies remains controversial. Since rebound progression after bevacizumab has been observed in other cancers, and because bevacizumab is incorporated in several regimens used in the recurrent setting, the duration of treatment may impact survival. We sought to identify whether earlier bevacizumab exposure is associated with prolonged bevacizumab therapy and survival by conducting a multi-institution retrospective study of recurrent OC patients treated with bevacizumab from 2004-2014. Multivariate logistic regression identified factors associated with receiving more than six bevacizumab cycles. Overall survival by duration and ordinal sequence of bevacizumab therapy were evaluated using logrank testing and Cox regression. In total, 318 patients were identified. 89.1% had stage III or IV disease; 36% had primary platinum resistance; 40.5% received two or fewer prior chemotherapy regimens. Multivariate logistic regression demonstrated that primary platinum sensitivity (Odds Ratio (OR) 2.34, p = 0.001) or initiating bevacizumab at the first or second recurrence (OR 2.73, p < 0.001) were independently associated with receiving more than six cycles of bevacizumab. Receiving more cycles of bevacizumab was associated with improved overall survival whether measured from time of diagnosis (logrank p < 0.001), bevacizumab initiation (logrank p < 0.001), or bevacizumab discontinuation (logrank p = 0.017). Waiting one additional recurrence to initiate bevacizumab resulted in a 27% increased hazard of death (Hazard Ratio (HR) 1.27, p < 0.001) by multivariate analysis. In conclusion, patients with primary platinum sensitive disease who received fewer prior lines of chemotherapy were able to receive more cycles of bevacizumab, which was associated with improved overall survival. Survival worsened when bevacizumab was initiated later in the ordinal sequence of therapies.

Artificial Intelligence Systems Assisting in the Assessment of the Course and Retention of Orthodontic Treatment.

This scoping review examines the contemporary applications of advanced artificial intelligence (AI) software in orthodontics, focusing on its potential to improve daily working protocols, but also highlighting its limitations. The aim of the review was to evaluate the accuracy and efficiency of current AI-based systems compared to conventional methods in diagnosing, assessing the progress of patients' treatment and follow-up stability. The researchers used various online databases and identified diagnostic software and dental monitoring software as the most studied software in contemporary orthodontics. The former can accurately identify anatomical landmarks used for cephalometric analysis, while the latter enables orthodontists to thoroughly monitor each patient, determine specific desired outcomes, track progress, and warn of potential changes in pre-existing pathology. However, there is limited evidence to assess the stability of treatment outcomes and relapse detection. The study concludes that AI is an effective tool for managing orthodontic treatment from diagnosis to retention, benefiting both patients and clinicians. Patients find the software easy to use and feel better cared for, while clinicians can make diagnoses more easily and assess compliance and damage to braces or aligners more quickly and frequently.

Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org.

Molecular testing for endometrial cancer: An SGO clinical practice statement.

The Cancer Genome Atlas publication first described the genomic landscape of endometrial cancer and characterized these cancers into four molecular subtypes with different prognoses. The Proactive Molecular Classifier for Endometrial Cancer was developed to more easily and inexpensively classify endometrial cancers into four similar molecular subtypes which are termed POLE, mismatch repair deficient, p53 abnormal and no specific molecular profile. Beyond these four subtypes, other molecular biomarkers may influence clinical behavior and response to targeted therapies and include beta-catenin, Her2 amplification, PI3K/mTOR/AKT alterations, L1CAM, hormone receptor expression, tumor mutational burden, and ARID1A. There are numerous clinical trials exploring treatment escalation and de-escalation within the four molecular subtypes as well as matching targeted therapies to specific mutational or biomarker profiles. All endometrial cancers should undergo basic molecular classification that includes assessment of mismatch repair status. POLE and p53 status are prognostic and may become actionable in the future. Clinicians who treat patients with endometrial cancer should understand the role of molecular classification in guiding treatment. The goal of this practice statement is to guide appropriate testing, interpretation, and application of molecular information in endometrial cancer.

Fabrication and In Vitro Characterization of Novel Hydroxyapatite Scaffolds 3D Printed Using Polyvinyl Alcohol as a Thermoplastic Binder.

This paper presents a proof-of-concept study on the biocolonization of 3D-printed hydroxyapatite scaffolds with mesenchymal stem cells (MSCs). Three-dimensional (3D) printed biomimetic bone structure made of calcium deficient hydroxyapatite (CDHA) intended as a future bone graft was made from newly developed composite material for FDM printing. The biopolymer polyvinyl alcohol serves in this material as a thermoplastic binder for 3D molding of the printed object with a passive function and is completely removed during sintering. The study presents the material, the process of fused deposition modeling (FDM) of CDHA scaffolds, and its post-processing at three temperatures (1200, 1300, and 1400 °C), as well it evaluates the cytotoxicity and biocompatibility of scaffolds with MTT and LDH release assays after 14 days. The study also includes a morphological evaluation of cellular colonization with scanning electron microscopy (SEM) in two different filament orientations (rectilinear and gyroid). The results of the MTT assay showed that the tested material was not toxic, and cells were preserved in both orientations, with most cells present on the material fired at 1300 °C. Results of the LDH release assay showed a slight increase in LDH leakage from all samples. Visual evaluation of SEM confirmed the ideal post-processing temperature of the 3D-printed FDM framework for samples fired at 1300 °C and 1400 °C, with a porosity of 0.3 mm between filaments. In conclusion, the presented fabrication and colonization of CDHA scaffolds have great potential to be used in the tissue engineering of bones.

Society of Gynecologic Oncology Journal Club: Controversial conversations in gynecologic cancer - Navigating maintenance therapy for homologous recombinant proficient ovarian cancer.

The Society of Gynecologic Oncology (SGO) Journal Club is an open forum to review pertinent studies relevant to controversial topics in the management of gynecologic cancers. On August 3rd, 2022, SGO hosted a Journal Club focused on the role of maintenance therapy for homologous recombinant proficient (HRP) patients with ovarian cancer. Navigating optimal therapies has become more complex with the emergence of new clinical trial data and the evolving understanding of how to classify ovarian cancers as HRP. Our speakers, Drs. Susan Modesitt, Barbara Norquist and Rodney Rocconi presented Gynecologic Oncology Group (GOG) 218 (Burger et al., 2011), the VITAL Trial (Rocconi et al., 2021), and the PRIMA study (Gonzalez-Martin et al., 2019). We asked our experts to discuss their opinions and interpretations on the application of these data to current clinical practice. Poll questions were presented to the audience for a pre- and post-webinar comparison (Table 1). Results of the poll questions are shown in Table 1.

Uterine lavage identifies cancer mutations and increased TP53 somatic mutation burden in individuals with ovarian cancer.

Current screening methods for ovarian cancer (OC) have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultra-deep sequencing for the detection of disseminated OC cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with OC (6 non-serous and 14 high grade serous-like (serous)). Ultra-deep duplex sequencing (~3000x) with a panel of common OC genes identified the tumor mutation in 33% of non-serous (all early stage) and in 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without OC, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with OC, suggesting that TP53-specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential OC risk factor.

Smartphone-Based Facial Scanning as a Viable Tool for Facially Driven Orthodontics?

The current paradigm shift in orthodontic treatment planning is based on facially driven diagnostics. This requires an affordable, convenient, and non-invasive solution for face scanning. Therefore, utilization of smartphones' TrueDepth sensors is very tempting. TrueDepth refers to front-facing cameras with a dot projector in Apple devices that provide real-time depth data in addition to visual information. There are several applications that tout themselves as accurate solutions for 3D scanning of the face in dentistry. Their clinical accuracy has been uncertain. This study focuses on evaluating the accuracy of the Bellus3D Dental Pro app, which uses Apple's TrueDepth sensor. The app reconstructs a virtual, high-resolution version of the face, which is available for download as a 3D object. In this paper, sixty TrueDepth scans of the face were compared to sixty corresponding facial surfaces segmented from CBCT. Difference maps were created for each pair and evaluated in specific facial regions. The results confirmed statistically significant differences in some facial regions with amplitudes greater than 3 mm, suggesting that current technology has limited applicability for clinical use. The clinical utilization of facial scanning for orthodontic evaluation, which does not require accuracy in the lip region below 3 mm, can be considered.

Cervical cancer - times they are a changing: A report from the Society of Gynecologic Oncology journal club.

In January 2021, the Society of Gynecologic Oncology (SGO) Clinical Practice and Education Committees launched a "Journal Club" webinar series to invite national experts to discuss literature pertaining to common clinical scenarios encountered by the members of SGO. On December 13, 2021, SGO hosted its third journal club focused on the use of immunotherapy in cervical cancer. Charles A. Leath, III from the O'Neal Comprehensive Cancer at the University of Alabama and Leslie M. Randall from Massey Cancer Center at Virginia Commonwealth University discussed the recently published KEYNOTE-826 trial (Colombo et al., 2021) and Jyoti Mayadev from the University of California, San Diego Moores Cancer Center discussed GOG-9929 (Mayadev et al., 2020). Renata Urban from the University of Washington and Christine S. Walsh from the University of Colorado served as moderators. The following is a report of the journal club presentation.

The optimal management of brain metastases from gestational trophoblastic neoplasia.

INTRODUCTION: Gestational trophoblastic diseases and neoplasias (GTDs and GTNs) comprise a spectrum of diseases arising from abnormally proliferating placental/trophoblastic tissue following an antecedent molar or non-molar pregnancy. These can spread to the brain hematogenously in about 10% of patients, mostly in high-risk disease. The optimal management of patients with brain metastases from GTN is unclear, with multiple systemic regimens under use and an uncertain role for radiotherapy. AREAS COVERED: Here, we review the epidemiology, workup, and treatment of GTN with central nervous system (CNS) involvement. Literature searches in PubMed and Google Scholar were conducted using combinations of keywords such as 'gestational trophoblastic disease,' 'gestational trophoblastic neoplasia,' 'choriocarcinoma,' and 'brain metastases.' EXPERT OPINION: Systemic therapy is the frontline treatment for GTN with brain metastases, and radiotherapy should only be considered in the context of a clinical trial or for resistant/recurrent disease. Surgery has a limited role in palliating symptoms or relieving intracranial pressure/bleeding. Given the highly specialized care these patients require, treatment at a high-volume referral center with multidisciplinary collaboration likely leads to better outcomes. Randomized trials should be conducted to determine the best systemic therapy option for GTN.

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates.

BACKGROUND: Anti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer. PATIENTS AND METHODS: This phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67. RESULTS: The most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53). CONCLUSIONS: Pembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy. TRIAL REGISTRATION NUMBER: NCT03029598.

NCCN Guidelines® Insights: Uterine Neoplasms, Version 3.2021.

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer or uterine sarcoma. These NCCN Guidelines Insights focus on the recent addition of molecular profiling information to aid in accurate diagnosis, classification, and treatment of uterine sarcomas.

Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations, part II.

In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. This manuscript, Part II in a two-part series, includes specific recommendations on treatment of recurrent disease, post treatment surveillance and survivorship, considerations for younger women, and special situations. Part I covered histopathology and molecular pathology, risk factors, presentation and diagnostic approach, surgical approach and adjuvant therapy.

Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations.

INTRODUCTION: In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. Despite these advances, the incidence of endometrial cancer as well as the deaths attributable to the disease have continued to rise; from 1987 to 2014 there has been a 75% increase in cases and almost 300% increase in endometrial cancer deaths. Fortunately, since then, there has been progress in the treatment of patients with endometrial cancer with increased utilization of molecular pathology, greater understanding of genetic predisposition, enhanced methods for lymph node assessment, a broader understanding of the efficacy of radiation and chemotherapy, and a more efficient approach to survivorship and surveillance. The purpose of this document is to present a comprehensive review of this progress. MANUSCRIPT DEVELOPMENT PROCESS: The authors reviewed the available evidence, contributed to the development of this manuscript, provided critical review of the guidelines, and finalized the manuscript recommendations. The review was also presented to and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Publications Committee, and the SGO board members prior to submission for publication. The recommendations for this manuscript were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current uterine cancer literature. The terminology used in these guidelines was adopted from the ASCCP management guidelines [1] using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses.

Society of Gynecologic Oncology recommendations for fellowship education during the COVID-19 pandemic and beyond: Innovating programs to optimize trainee success.

In approximately ten months' time, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 34 million people and caused over one million deaths worldwide. The impact of this virus on our health, relationships, and careers is difficult to overstate. As the economic realities for academic medical centers come into focus, we must recommit to our core missions of patient care, education, and research. Fellowship education programs in gynecologic oncology have quickly adapted to the "new normal" of social distancing using video conferencing platforms to continue clinical and didactic teaching. United in a time of crisis, we have embraced systemic change by developing and delivering collaborative educational content, overcoming the limitations imposed by institutional silos. Additional innovations are needed in order to overcome the losses in program surgical volume and research opportunities. With the end of the viral pandemic nowhere in sight, program directors can rethink how education is best delivered and potentially overhaul aspects of fellowship curriculum and content. Similarly, restrictions on travel and the need for social distancing has transformed the 2020 fellowship interview season from an in-person to a virtual experience. During this time of unprecedented and rapid change, program directors should be particularly mindful of the needs and health of their trainees and consider tailoring their educational experiences accordingly.

A multicenter open-label randomized phase II trial of paclitaxel plus EP-100, a novel LHRH receptor-targeted, membrane-disrupting peptide, versus paclitaxel alone for refractory or recurrent ovarian cancer.

OBJECTIVE: This randomized open-label phase II study evaluated the safety and clinical activity of EP-100 plus weekly paclitaxel in patients with recurrent ovarian cancer expressing positive LHRH receptor. METHODS: In a limited "run-in" dose escalation phase for EP-100, six patients were treated with ascending dose levels (13 mg/m2, 20 mg/m2, 30 mg/m2). In the randomized phase, patients received weekly paclitaxel (80 mg/m2 intravenously) plus twice weekly EP-100 (30 mg/m2 intravenously; combination arm) or weekly paclitaxel alone (80 mg/m2 intravenously; paclitaxel arm). The primary study endpoint was overall response rate (ORR). RESULTS: Forty-four patients were then randomized to either the experimental combination arm (n = 23) or the standard of care paclitaxel monotherapy arm (n = 21). The ORR was 35% (95%CI 16%-57%) for the combination arm and 33% (95% CI 15%-57%) for the paclitaxel arm. An interesting observation from an unplanned analysis was that a subset of patients with target liver lesions showed a greater overall response rate to the combination (69%) compared to paclitaxel alone (16%). The frequency of treatment-related grade 3-4 adverse events was similar between treatment arms: 48% vs 43% for the combination and paclitaxel arms, respectively. CONCLUSIONS: ORR in the EP-100 combination arm was similar to that in the group treated with paclitaxel alone; however, a subset of patients with liver metastases appeared to benefit from the combination. The addition of EP-100 did not appear to augment the adverse event profile of paclitaxel and was well tolerated.