Sarfraz Ahmad

Robotic sentinel lymph node (SLN) mapping in endometrial cancer: SLN symmetry and implications of mapping failure

To establish the bilateral pelvic concordance rate of the sentinel lymph node (SLN) and determine the likelihood of lymph node metastasis in cases of mapping failure. A database analysis was performed on 414 patients with clinical stage I endometrial cancer who underwent SLN mapping followed by robotic hysterectomy and completion pelvic (n=414, 100%) and aortic (n=186, 44.9%) lymphadenectomy from March 2011 to August 2016. Stage, histology, SLN sites, and surgico-pathologic findings were analyzed. The bilateral concordance rate of SLN location, successful unilateral and bilateral mapping rates, false negative rate, and non-SLN metastasis associated with mapping failure were calculated. Histologies included 354 (85.5%) endometrioid, 39 (9.4%) serous, 16 (3.9%) carcinosarcoma, 4 (1.0%) clear cell, and 1 (0.2%) undifferentiated. Final stages included 262 (63.3%) IA, 36 (8.7%) IB, 15 (3.6%) II, 6 (1.4%) IIIA, 68 (16.4%) IIIC1, and 27 (6.5%) IIIC2. Bilateral SLN mapping was successful in 355 (85.7%) patients, and 266 (74.9%) demonstrated mapping to the symmetrical lymphatic group contralaterally. The mapping failure rate was 13.5% (56/414) unilaterally and 0.7% (3/414) bilaterally. SLN locations were external iliac (69.1%), obturator (25.1%), internal iliac (2.2%), common iliac (1.9%), pre-sacral (0.9%), aortic (0.4%), parametrial (0.3%), and para-rectal (0.1%). Lymph node metastases were identified in 95 (22.9%) pelvic and 27 (6.5%) aortic nodes. 10 (16.9%) cases with mapping failure had lymph node metastasis on completion lymphadenectomy, similar to the proportion of SLNs with metastases (p=0.35). However, macro-metastases were more common in mapping failure completion lymphadenectomies than in the positive SLNs (80% vs 22.3%, p<0.001). The contralateral SLN location concordance rate was 75%. Most SLNs were along the medial external iliac or obturator locations. The rate of positive lymph nodes associated with SLN mapping failure was 16.9%, similar to the overall node-positive rate. The detection of pelvic node metastasis with SLN mapping failure was largely populated with macro-metastases and confirms the necessity of completion lymphadenectomy with mapping failure.

Diabetes, Obesity, and Endometrial Cancer: A Review

Endometrial cancer is the fourth most diagnosed cancer in U.S. women. Diabetes and obesity are established independent risk factors for EC, but their combined effect is less defined. This review investigates the literature on these comorbidities as risk factors and modifiers of EC. Multiple cohort and case–control investigations have shown an increased relative risk (RR) and odds ratio (OR) when diabetes and obesity coexist. In one prospective cohort, the RR of EC in diabetic women was 1.94 [95% CI, 1.23–3.08], but increased to 6.39 [95% CI, 3.28–12.06] with obesity; with low physical activity added, RR rose to 9.61 [95% CI, 4.66–19.83]. Case–control studies similarly show an OR of 1.4 [95% CI, 0.9–2.4] for diabetes alone, vs. 5.1 [95% CI, 3.0–8.7] with BMI &gt; 30 and diabetes. Mechanistically, both conditions promote a pro-cancerous microenvironment through metabolic and inflammatory pathways. They also worsen treatment outcomes, with greater surgical complications, thromboembolic events (p &lt; 0.01), prolonged hospitalizations 6.2 days versus 4.5 days (p &lt; 0.03), and poorer survival with an elevated cancer-specific mortality (HR = 2.65, 95% CI 1.60–4.40). These findings underscore the urgent need for targeted interventions and translational research on how these comorbidities impact the pathophysiologic processes of EC.

Therapeutic Prospects of Abemaciclib for Patients with Endometrial Cancer

Endometrial cancer (EC) is a common gynecologic malignancy with a rising incidence due to obesity, comorbid conditions, and related lifestyle factors. The standard of care for primary disease consists of surgical resection with/without chemotherapy ± radiotherapy for select patients. Recurrence is common in patients with advanced-stage disease and/or high-risk features, who primarily are treated with systemic therapy. The identification of novel targets in malignant EC has led to the development of wide-range inhibitors. Abemaciclib is an orally active unique cyclin-dependent kinase (CDK) inhibitor, selective for the CDK4 and CDK6 cell cycle pathways. This agent has potential anti-neoplastic activity and is indicated in combination with various therapies such as endocrine therapy, aromatase inhibitors, and hormone therapies, primarily in breast cancer (BC). Herein, we sought to summarize the biochemical/pharmacological properties of abemaciclib and its therapeutic potential in EC. While the therapeutic role(s) of abemaciclib was fairly established in a subset of patients with advanced/metastatic BC through the pivotal MONARCH trials, its attributes and clinical utility in EC are limited. Thus, based on some promising pre-clinical/translational insights and a recent phase II study, we highlight abemaciclib’s properties and potential clinical usefulness in patients with EC, particularly in recurrent estrogen-receptor-positive cases.

Exploratory Analysis of Candidate Gene SNPs in Relation to Cervical Cancer Susceptibility in Georgian Women

Introduction Cervical cancer (CC) is the third most prevalent malignancy among women worldwide. Candidate gene studies have identified multiple single nucleotide polymorphisms (SNPs) that are associated with an increased risk of CC. The objective of this study was to examine the relationship between 8 specific single-nucleotide polymorphisms (SNPs) and the risk of cervical cancer in the Georgian population. Methods The present study employed a prospective case-control design, with 40 patients diagnosed with CC and 45 healthy women. A total of 8 single-nucleotide polymorphisms (SNPs) were genotyped using the TaqMan genotyping assay: rs7579014, rs11263763, rs7726159, rs6897196, rs2853672, rs635634, rs231775, and rs2304204. Results Our analysis demonstrated that rs7579014 ( BCL11A, G/A), rs7726159 ( TERT , C/A), and rs6356634 ( ABO , T/A) were associated with an increased risk of cervical cancer in Georgian patients. However, following the implementation of the Benjamini–Hochberg correction, only rs6356634 ( ABO T/A) and rs7579014 ( BCL11A G/A) remained statistically significant. A lack of statistically significant correlation was identified between the genetic variants rs11263763, rs6897196, rs2853672, rs2304204, and rs231775 and susceptibility to cervical cancer. Conclusions This study represents the first attempt to investigate SNP associations in women with cervical cancer in Georgia. The findings indicate that SNP-based analysis may hold promise for the early identification of susceptibility to cervical cancer, and potentially to other cancers. Nevertheless, further research involving larger sample sizes is required to validate and strengthen these preliminary observations.

Robotic-assisted laparoscopic splenectomy for recurrent ovarian cancer

Recurrent ovarian cancer frequently involves the spleen. Our aims were to describe the technique of robotic-assisted laparoscopic splenectomy and to evaluate outcomes including progression-free and overall survival in patients who underwent this procedure for recurrent ovarian cancer. Chart reviews were performed on all consecutive patients who underwent robotic splenectomy (April 2012 to May 2019) for recurrent ovarian cancer. Patients had ≤3 sites of disease and no ascites. Extent of disease was confirmed by positron emission tomography-computed tomography (PET-CT) pre-operatively and platinum-doublet chemotherapy was initiated post-operatively. Peri- and post-operative outcomes, progression-free survival, and overall survival were assessed. Two video links are included to demonstrate variations in technique and anatomy. A total of 10 patients were included. The median age was 63.5 years (range 46-74) and median body mass index was 30 kg/m Robotic splenectomy was feasible, achieving complete cytoreduction of splenic recurrent ovarian cancer, short hospital length-of-stay, and acceptable morbidity.

Neoadjuvant chemotherapy with bevacizumab for locally advanced vulvar cancer

External beam radiation with sensitizing platinum is the recommended therapy for locally advanced vulvar cancers not amenable to curative surgery and is associated with considerable acute and chronic side effects. Radical vulvectomy post-radiation for persistent disease is often compromised with poor wound healing. We describe clinical outcomes for patients who received neoadjuvant chemotherapy plus bevacizumab followed by radical vulvectomy for locally advanced vulvar cancer. We performed retrospective analyses of all patients at our institution who underwent radical vulvectomy from January 2015 to November 2023. Of 113 patients, 13 patients underwent neoadjuvant chemotherapy. Demographics and clinicopathologic data were extracted, and descriptive statistical analyses were performed. Cases with neoadjuvant chemotherapy plus bevacizumab were further evaluated for response, adverse effects, and survival. Neoadjuvant chemotherapy was administered to 13 patients with stage II-IV disease that involved the urethra, vagina, or anus. Lesion sizes ranged from 4 to 20 cm (median 7 cm). Patients received 2-6 cycles of carboplatin or cisplatin, paclitaxel, and bevacizumab. Nine (69.2%) patients had partial pathologic responses, and four patients had complete responses. All patients had negative surgical margins. Ten (76.9%) patients had radiographic evidence of inguinal lymph node metastasis prior to neoadjuvant chemotherapy, and four had residual nodal disease. Only one patient developed a superficial groin seroma. Three patients developed recurrence, two locally and one distant, and there was one death. The median follow-up was 23 months (range 6-84 months). Neoadjuvant chemotherapy using combination platinum/paclitaxel/bevacizumab was efficacious for locally advanced vulvar cancer, resulting in complete resections, negative margins, and excellent wound healing. A multi-institutional phase II trial is warranted to validate these findings.

Carcinomatosis in Early-Stage Cervical Cancer Treated with Robotic Radical Hysterectomy: Recurrence Patterns, Risk Factors, and Survival

Minimally invasive radical hysterectomy has been associated with increased recurrence of disease and worse survival compared with open radical hysterectomy for early-stage cervical cancer. We evaluated patterns of recurrence and histopathologic risk factors in patients who underwent robotic radical hysterectomy (RRH). Patients who underwent RRH (4/2007-12/2018) were evaluated for specific locations of recurrent disease, disease-free survival, overall survival (OS), and histopathologic risk factors for recurrence. Inclusion criteria were follow-up ≥ 1 year, histology with adenocarcinoma, adenosquamous, or squamous carcinoma and clinical stage IA2 to IB ≤ 4-cm tumor size cervical cancers (FIGO-2018). A total of 140 patients underwent RRH and 112 met criteria. Median tumor size was 2.1 cm [interquartile range (IQR): 1.1-3.3]. Median follow-up was 61 months (IQR: 36-102). Fifty (45%) patients underwent adjuvant radiation ± cisplatin with either Sedlis' or Peters' risk factors. There were 11 (9.8%) recurrences with median disease-free survival of 12 (IQR 8.5) months. All patients with recurrence had measured tumor size ≥ 2 cm (median tumor size 3-cm (IQR: 2.6-4.0). Tumor size > 2 cm was associated with Sedlis' intermediate-risk factors (p  2 cm recurred. Five (4.5%) of patients had carcinomatosis representing 45% of all recurrences. Carcinomatosis was associated with reduced OS compared with other recurrence patterns (22 months vs. 7.8 years, p < 0.05). Carcinomatosis was observed in early-stage cervical cancers treated with RRH and was associated with reduced OS. All recurrences were associated with lesions ≥ 2 cm, and no recurrences were identified with negative conization margins.

Analysis of abdominal vs. robotic radical hysterectomies for patients with cervical cancer: a Bulgarian experience

To assess and compare the peri-operative, oncologic, and survival outcomes for women with cervical cancer (CC) treated with abdominal radical hysterectomy (ARH) versus robotic radical hysterectomy (RRH) approaches in Bulgaria. We retrospectively analyzed patients with histologically diagnosed CC operated via ARH or RRH methods during January-2008 to April-2019. The data analyzed include patients and tumor characteristics, peri-operative outcomes, and disease status. Kaplan-Meier method and Cox regression analysis were performed to determine disease-free survival (DFS) and overall survival (OS). There were consecutive 1347 patients (ARH = 1006, RRH = 341), which formed the basis of study analyses. Women in the RRH group had significantly shorter median hospital length-of-stay than ARH cases (7 vs. 11 days, p < 0.001), higher post-operative hemoglobin (116 vs. 108 g/L, p < 0.001), and fewer blood transfusions (7.3% vs. 21.5%, p < 0.001), respectively. The overall incidence of post-operative complications was also lower in the RRH vs. ARH group (2.1% vs. 9.4%, p < 0.001). Median follow-up time for ARH vs. RRH groups was 4.32 vs. 5.24 years, respectively (p < 0.001). Kaplan-Meier analysis demonstrated that the RRH cohort had a significantly higher survival rate compared to the ARH group (CC-specific death 8.5% vs. 16.5% respectively). Mean time to recurrence did not differ significantly in either surgical approach (p = 0.495). Cox multivariate regression showed no significant impact of surgical approach on DFS or OS. No significant difference in DFS or OS between ARH vs. RRH for CC was observed. RRH approach does not lead to inferior oncologic outcomes and is associated with better peri-operative outcomes. In regard to "all stages" of CC, we found robotic surgery safer compared to laparotomy, and thus consider RRH a better surgical treatment option for patients with CC.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer

Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. The primary endpoint is PFS in the intention-to-treat population. Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. NCT05281471.

Theranostic implications of Nectin-4 oncoprotein in gynecologic cancers: A review

Gynecologic cancers, in order of prevalence, include uterine, ovarian, cervical, vaginal, and vulvar cancers. In 2024, there will be more than 116,000 new cases of gynecologic cancers and 33,800 disease-related deaths. Therefore, a concerted effort has been made to better understand the underlying pathophysiological processes and identify novel theranostic approaches. Comprehensively examine the current peer-reviewed literature surrounding Nectin-4 and its implication in the identification and treatment of gynecologic cancers. PubMed and Google search with relevant keywords for articles published in the last 15 years. Nectin-4 as a cell adhesion molecule (CAM) promotes cell growth through intra-tumoral angiogenesis, strengthens cell-cell bonds, and creates a tight spheroid structure, which is more chemotherapy resistant. In high-grade serous ovarian cancer (HGSOC), Nectin-4 is strongly associated with the presence of peritoneal metastases and worse prognoses. When compared to CA-125, a common tumor marker for ovarian cancer, Nectin-4 showed higher specificity and sensitivity for predictive value of tumorigenesis. Regarding cervical cancer, inhibition of Nectin-4 by nanoformulated Quinacrine inhibits both cancer stem cell proliferation and DNA damage. Nectin-4 as a tumor marker can discriminate endometrial cancer from healthy adjacent tissue with a specificity of 95.4 % and sensitivity of 82.81 %. Lastly, there is scarce evidence of Nectin-4 and fallopian tube, vaginal, or vulvar cancer but given ovarian cancer cells may originate from the fallopian tube, there is plausibility of using Nectin-4 to detect fallopian and/or ovarian cancer earlier. Overall, Nectin-4 as a promoter of cancer cell growth and metastasis supports the emphasis in current peer-reviewed literature as an effective theranostic biomarker.

Development of tele-lifestyle-based multidisciplinary survivorship program for gynecologic oncology practice

Abstract We assessed the recruitment and retention of a short 8-week telemedicine-based group peri-habilitation program for gynecologic cancer survivors. Multidisciplinary team included: a gynecologic oncologist with additional board certification by the American College of Lifestyle Medicine, cancer-specific nutritionist, culinary medicine chef, physical therapist, exercise physiologists, mental health counselor, body image aesthetician, pelvic floor therapist, and sex therapist. Pre- and post-self-administered questionnaires assessed conformity to lifestyle medicine pillars and a general medical symptom questionnaire (MSQ). Recruitment was suboptimal (11.7%). Neither provider referrals nor flyers sufficiently directed patients to the program, but those that completed the program expressed meaningful impact on lifestyle behavioral change and improved quality-of-life across multiple parameters including MSQ (40.0 vs 20.75) and 85% participants reported compliance with recommendations. This pilot program suggests that a multidisciplinary tele-lifestyle-based survivorship program beyond just diet and exercise to improve quality-of-life in gynecologic cancer survivors, though novel and well received, needs physician buy-in and enhanced marketing strategies.

A Phase Ib Study of Indirect Immunization with Oregovomab and Toll-like-Receptor-3 Stimulation with Hiltonol® in Patients with Recurrent Platinum-Resistant Ovarian Cancer

Objectives: This phase Ib study assessed the safety and compatibility of indirect oregovomab immunization and Toll-like-receptor-3 (TLR3) stimulation with immune adjuvant Hiltonol® (poly-ICLC) and induced clinically relevant CA125-specific anti-tumor immunity in heavily pretreated patients with progressive platinum-resistant ovarian cancer (PROC). Methods: Patients with elevated serum CA125 level &gt;50 U/mL received four intravenous infusions with 2 mg oregovomab followed by 2 mg Hiltonol® intramuscular 30 min and 48 h post-oregovomab at weeks 0, 3, 6, and 9. At week 12, imaging was performed, and salvage chemotherapy was allowed post-progression per the investigator’s discretion. The Fifth/final oregovomab with Hiltonol® infusion was given at week 16. Results: Fifteen enrolled patients were analyzed for safety and efficacy. Thirteen (87%) patients completed at least three Hiltonol® infusions with oregovomab, specifically, two cycles (n = 2), three cycles (n = 2), four cycles (n = 3), and five cycles (n = 8). Adverse events included mild fatigue, flu-like symptoms, chills, axillary pain, and injection site discomfort in 13 (87%) patients. Serious adverse events were reported in seven (47%) patients, including Grade 3 hypertension (n = 2), thrombocytopenia (n = 1), and Grade 3 events attributed to underlying disease (n = 4). Ten (67%) patients had disease progression, three (20%) had stable disease, and two were unevaluable. Early humoral response by week 6 was observed in seven of nine (77%) patients, median progression-free survival was 2.7 months (95% confidence interval [CI]: 2.2, 3.3), and median overall survival was 15.0 months (95% CI: 8.2–23.9). Conclusions: The safety and compatibility of combining oregovomab with Hiltonol® have been demonstrated in this study. The potential to enhance activity of chemotherapy using oregovomab indirect immunization and Hiltonol® stimulation is proposed.

An Overview of Endometrial Cancer with Novel Therapeutic Strategies

Endometrial cancer (EC) stands as the most prevalent gynecologic malignancy. In the past, it was classified based on its hormone sensitivity. However, The Cancer Genome Atlas has categorized EC into four groups, which offers a more objective and reproducible classification and has been shown to have prognostic and therapeutic implications. Hormonally driven EC arises from a precursor lesion known as endometrial hyperplasia, resulting from unopposed estrogen. EC is usually diagnosed through biopsy, followed by surgical staging unless advanced disease is expected. The typical staging consists of a hysterectomy with bilateral salpingo-oophorectomy and sentinel lymph node biopsies, with a preference placed on a minimally invasive approach. The stage of the disease is the most significant prognostic marker. However, factors such as age, histology, grade, myometrial invasion, lymphovascular space invasion, tumor size, peritoneal cytology, hormone receptor status, ploidy and markers, body mass index, and the therapy received all contribute to the prognosis. Treatment is tailored based on the stage and the risk of recurrence. Radiotherapy is primarily used in the early stages, and chemotherapy can be added if high-grade histology or advanced-stage disease is present. The risk of EC recurrence increases with advances in stage. Among the recurrences, vaginal cases exhibit the most favorable response to treatment, typically for radiotherapy. Conversely, the treatment of widespread recurrence is currently palliative and is best managed with chemotherapy or hormonal agents. Most recently, immunotherapy has emerged as a promising treatment for advanced and recurrent EC.

Efficacy & Safety of Olvi-Vec and Platinum-doublet + Bevacizumab Compared to Physician's Choice of Chemotherapy and Bevacizumab in Platinum-Resistant/Refractory Ovarian Cancer (PRROC) (OnPrime, GOG-3076)

The OnPrime study is a multi-center, randomized open-label phase 3 study evaluating the safety and efficacy of Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab compared to the Active Comparator Arm with Physician's Choice of chemotherapy and bevacizumab in women diagnosed with platinum-resistant/refractory ovarian cancer (includes fallopian tube cancer and primary peritoneal cancer). This Phase III trial builds on the efficacy and safety data reported in the previous Phase II VIRO-15 trial with promising objective response rate and progression-free survival observed in heavily pre-treated patients with platinum-resistant/refractory ovarian cancer. The phase II results also showed that the intra-peritoneal route of delivery was efficient in generating tumor cell killing and immune activation, and led to clinical reversal of platinum-resistance or refractoriness in this difficult-to-treat patient population.