Primary chemoradiation versus neoadjuvant chemotherapy followed by surgery as treatment strategy for locally advanced vulvar carcinoma (VULCANize2).

BACKGROUND: Current treatment options for patients with locally advanced vulvar cancer are limited and associated with high morbidity. Therefore, it is important to develop new and safe treatment strategies for this vulnerable patient group. PRIMARY OBJECTIVE: To compare the efficacy and safety of neoadjuvant chemotherapy followed by surgery with definitive chemoradiation in patients with locally advanced vulvar cancer. STUDY HYPOTHESIS: Neoadjuvant chemotherapy followed by surgery is oncologically safe, potentially more effective than primary chemoradiation in establishing long lasting locoregional control, and associated with an improved quality of life. TRIAL DESIGN: This study is a multicenter, prospective, phase II randomized controlled trial. Patients will be randomized 1:1 to the standard treatment arm (primary chemoradiation, consisting of a tumor dose of 64.5 Gy in 30 fractions of external beam radiotherapy with weekly cisplatin for 6 weeks) or the experimental treatment arm (neoadjuvant chemotherapy, consisting of carboplatin and paclitaxel in a 3 weekly scheme, followed by surgery). MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have a histologically confirmed primary or recurrent locally advanced squamous cell carcinoma of the vulva (International Federation of Gynecology and Obstetrics (FIGO) stages Ib-Iva; Lesions larger than 2 cm in size or stromal invasion larger than 1 mm (T1b or higher), any status of lymph node involvement (any N), no distant metastasis including pelvic lymph nodes (M0)) with the size or localization of the tumor requiring treatment through primary chemoradiation or extensive surgery. Patients with documented metastases of the pelvic lymph nodes will be excluded from participation in this study. PRIMARY ENDPOINT: Locoregional control at 24 months. SAMPLE SIZE: 98 patients will be included in the study. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2028 with presentation of results by 2030. TRIAL REGISTRATION: ClinicalTrials.gov NCT05905315.

Prognostic value of molecular classification in stage IV endometrial cancer.

OBJECTIVES: Multiple studies have proven the prognostic value of molecular classification for stage I-III endometrial cancer patients. However, studies on the relevance of molecular classification for stage IV endometrial cancer patients are lacking. Hypothetically, poor prognostic molecular subtypes are more common in higher stages of endometrial cancer. Considering the poor prognosis of stage IV endometrial cancer patients, it is questionable whether molecular classification has additional prognostic value. Therefore, we determined which molecular subclasses are found in stage IV endometrial cancer and if there is a correlation with progression-free and overall survival. METHODS: A retrospective multicenter cohort study was conducted using data from five Dutch hospitals. Patients with stage IV endometrial cancer at diagnosis who were treated with primary cytoreductive surgery or cytoreductive surgery after induction chemotherapy between January 2000 and December 2018 were included. Exclusion criteria were age <18 years or recurrent disease. The molecular classification was performed centrally on all tumor samples according to the World Health Organization 2020 classification (including POLE and estrogen receptor status). The Kaplan-Meier method was used to calculate progression free and overall survival in the molecular subclasses, for the different histological subtypes and for estrogen receptor positive versus estrogen receptor negative tumors. Groups were compared using the log-rank test. RESULTS: 164 stage IV endometrial cancer patients were molecularly classified. Median age of the patients was 67 years (range 33-86). Most patients presented with a non-endometrioid histological subtype (58%). Intra-abdominal complete cytoreductive surgery was achieved in 60.4% of the patients. 101 tumors (61.6%) were classified as p53 abnormal, 35 (21.3%) as no specific molecular profile, 21 (12.8%) as mismatch repair deficient, and 6 (3%) as POLE mutated. Molecular classification had no significant impact on progression free (p=0.056) or overall survival (p=0.12) after cytoreductive surgery. Overall survival was affected by histologic subtype (p<0.0001) and estrogen receptor status (p=0.013). CONCLUSION: The distribution of the molecular subclasses in stage IV endometrial cancer patients differed substantially from the distribution in stage I-III endometrial cancer patients, with the unfavorable subclasses being more frequently present. Although the molecular classification was not prognostic in stage IV endometrial cancer, it could guide adjuvant treatment decisions.

First Reported Histologically and Molecularly Confirmed Bilateral High-Grade Serous Ovarian Adenocarcinoma Metastasized to Placental Decidua of the Membranes.

A 43-year-old female presented with blood loss and persistent abdominal pain at 14 weeks of gestation. Ultrasound examination and subsequent magnetic resonance imaging (MRI) revealed bilateral multicystic uterine adnexa. Exploratory laparotomy was performed at 17 weeks of gestation and bilateral serous ovarian adenocarcinoma FIGO stage IIIC was diagnosed. Complete cytoreductive surgery (CRS) was not feasible at that moment. Nine days after the exploratory laparotomy, immature rupture of membranes and contractions occurred and she delivered a premature boy after 19 weeks of gestation. Pathological examination of the placenta revealed that her ovarian cancer metastasized to the membranes. We describe the first case of ovarian cancer metastasized to the decidua of the placental membranes with histological, immunohistochemical, and molecular confirmation. This case highlights the importance of conscientious evaluation of placenta and membranes in pregnant women with ovarian cancer.

Neoadjuvant chemotherapy for patients with locally advanced vulvar cancer.

PURPOSE OF REVIEW: Studies on treatment options for patients with locally advanced vulvar cancer (LAVC) are scarce, and high-level evidence for a primary treatment choice is lacking. Furthermore, current treatment options are associated with extensive morbidity and high complication rates. More effective treatment options are urgently needed. This review describes current treatment possibilities, focusing on literature regarding neoadjuvant chemotherapy (NACT) followed by surgery. RECENT FINDINGS: Although data are heterogeneous and limited, NACT followed by surgery might be an effective and well tolerated treatment alternative associated with lower morbidity compared with current treatment options, such as excenterative surgery or definitive chemoradiation. SUMMARY: Up until now, several studies describe an overall response rate of 40-86%. Surgery turned out to be possible in 40-90% of the LAVC patients who received NACT. Prospective studies on the efficacy and safety of NACT followed by surgery with a homogeneous chemotherapy regimen are urgently awaited. NACT should, at this point, still be considered investigational.

Evaluation of treatment, prognostic factors, and survival in 198 vulvar melanoma patients: Implications for clinical practice.

OBJECTIVE: To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM). MATERIALS & METHODS: This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis. RESULTS: The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-risk clinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno- or targeted therapy. CONCLUSION: Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed.

Vulvar cancer subclassification by HPV and p53 status results in three clinically distinct subtypes.

OBJECTIVE: There is great need for better risk stratification in vulvar squamous cell carcinoma (VSCC). Our aim was to define the prognostic significance of stratifying VSCC based on p16 and p53 immunohistochemistry (IHC) as surrogate markers for HPV and TP53 mutations. METHODS: A large retrospective cohort of surgically treated women with primary VSCC was used. VSCC were classified into three subtypes: HPV-positive (HPVpos), HPV-negative/p53 mutant (HPVneg/p53mut), and HPV-negative/p53 wildtype (HPVneg/p53wt). Overall survival (OS), relative survival (RS), and recurrence-free period (RFP) were depicted using the Kaplan-Meier method and survival curves for relative survival; associations were studied using univariable and multivariable Cox proportional hazard models. RESULTS: Of the 413 VSCCs, 75 (18%) were HPVpos, 63 (15%) HPVneg/p53wt, and 275 (66%) HPVneg/p53mut VSCC. Patients with HPVneg/p53mut VSCC had worse OS and RS (HR 3.43, 95%CI 1.80-6.53, and relative excess risk (RER) of 4.02; 95%CI 1.48-10.90, respectively, and worse RFP (HR 3.76, 95%CI 2.02-7.00). HPVpos VSCC patients showed most favorable outcomes. In univariate analysis, the molecular subtype of VSCC was a prognostic marker for OS, RS and RFP (p = 0.003, p = 0.009, p < 0.001, respectively) and remained prognostic for RFP even after adjusting for known risk factors (p = 0.0002). CONCLUSIONS: Stratification of VSCC by p16- and p53-IHC has potential to be used routinely in diagnostic pathology. It results in the identification of three clinically distinct subtypes and may be used to guide treatment and follow-up, and in stratifying patients in future clinical trials.

Brief Report on 3-Weekly Paclitaxel Carboplatin Efficacy in Locally Advanced or Metastatic Squamous Vulvar Cancer.

In this brief report, we present our experience with 3-weekly paclitaxel-carboplatin chemotherapy for patients with vulvar cancer. Two patients with locally advanced disease had an impressive response allowing standard vulvar cancer surgery. One patient with metastatic disease had local stable disease though it was progressive in the lymph nodes. The available literature is sparse and retrospective. Based on promising results, however, a prospective multicenter study is mandatory in order to obtain full data in a larger series of patients in order to learn the benefits of neoadjuvant paclitaxel-carboplatin and compare the results with chemoradiation.

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance.

Purpose: Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor TP53 mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers.Experimental Design: We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort).Results: Frequent recurrent mutations were identified in HPV-negative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%), and HRAS (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower (P = 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV+, HPV-/p53wt, HPV-/p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV+, 16.3% for HPV-/p53wt and 22.6% for HPV-/p53abn tumors (P = 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis (P = 0.020).Conclusions: HPV- and HPV+ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV-/p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV+ VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC. Clin Cancer Res; 23(22); 6781-9. ©2017 AACR.

Stathmin is a highly sensitive and specific biomarker for vulvar high-grade squamous intraepithelial lesions.

AIMS: Differentiating between human papilloma virus-dependent vulvar low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) remains difficult in selected cases. Stathmin, a protein involved in cell cycle progression, might be a useful additional marker for this differentiation. The aim of this study was to investigate the additional diagnostic value of stathmin expression in vulvar intraepithelial neoplastic (VIN) lesions. METHODS: Immunohistochemical analysis was used to evaluate stathmin, P16 and Ki67 expression in 91 samples, including LSILs (n=16), HSILs (n=50), differentiated VIN (dVIN; n=10), lichen sclerosis (LS; n=10) and normal vulvar tissue (n=5). RESULTS: Stathmin was expressed in more than one-third of the epithelium in all HSILs and in 20% of LSILs. P16 and Ki67 were expressed in more than one-third of the epithelium in 94% of HSILs and in 13% and 40% of LSILs, respectively. Stathmin was expressed in more than one-third of the epithelium in 10% of the dVIN and in none of the LS or normal lesions. P16 and Ki67 expression was not present in more than one-third of the epithelium in any of these lesions. The sensitivity of stathmin for differentiating between LSILs and HSILs was 100% compared with a sensitivity of 94% for both p16 and Ki67. The specificity of stathmin, p16 and Ki67 was 80%, 87% and 60%, respectively. CONCLUSIONS: Stathmin is a highly sensitive and specific biomarker for the diagnosis of vulvar HSIL. In addition to the more commonly used immunohistochemical markers p16 and Ki67, stathmin can be a useful diagnostic tool for identifying HSILs, especially in cases in which differentiating between LSIL and HSIL is difficult.

Groin surgery and risk of recurrence in lymph node positive patients with vulvar squamous cell carcinoma.

OBJECTIVES: Treatment of groin metastasis in vulvar squamous cell carcinoma (VSCC) patients consists of surgery, often combined with (chemo)radiotherapy, and is associated with significant morbidity. Our aim was to compare the risk of groin recurrence and morbidity in patients with lymph node positive VSCC after standard full inguinofemoral lymphadenectomy (IFL) versus less radical debulking of clinically involved lymph nodes or removal of sentinel nodes only followed by radiotherapy. METHODS: A retrospective cohort study of 68 patients with primary VSCC and proven lymph node metastasis to the groin(s) was conducted. Patients were divided into three subgroups by type of initial groin surgery (84 groins): sentinel node (SN), IFL, and debulking of clinically involved nodes. Most patients (82%) received adjuvant radiotherapy. Overall survival was analyzed using time dependent cox regression. Analysis of morbidity and groin recurrence-free time was performed per groin with the generalized estimating equation model and Kaplan Meier method. RESULTS: There was no significant difference in the risk of developing a groin recurrence (SN 25%, debulking 16%, IFL 13%, p=0.495). Despite the fact that more patients received radiotherapy after debulking (90% vs 67%), the complication rate was significantly lower (p=0.003) compared to IFL, especially regarding lymphocysts and lymphedema (p=0.032 and p=0.002 respectively). CONCLUSIONS: The risk of groin recurrence was similar in all treatment groups. Debulking of clinically involved lymph nodes was related to a significant lower risk of complications compared to IFL. These findings support that the preferred treatment of patients with clinically involved lymph nodes is debulking followed by radiotherapy.

Genetic and epigenetic changes in vulvar squamous cell carcinoma and its precursor lesions: a review of the current literature.

Vulvar cancer is a relatively rare gynecologic malignancy with an annual incidence in developed countries of approximately 2 per 100,000 women. Vulvar squamous cell carcinoma (VSCC) has two etiological pathways: a high risk human papillomavirus (HPV)-dependent route, which has usual vulvar intraepithelial neoplasia (uVIN) as a precursor lesion, and an HPV-independent route, which is associated with differentiated VIN (dVIN), lichen sclerosus, and genetic alterations, such as TP53 mutations. Research on the molecular etiology of vulvar cancer has increased in the past years, not only regarding genetic alterations, but also epigenetic changes. In genetic alterations, a mutation irreversibly changes the nucleotide sequence of the DNA, or the number of copies of chromosomes per cell is altered. In epigenetics, the nucleotide sequence remains the same but genes can be 'switched' on or off by, for example, DNA methylation or histone modification. We searched the current literature on genetic and epigenetic alterations in VSCC and its precursor lesions. Many studies have reported a higher incidence of somatic mutations in HPV-negative tumors compared to HPV-positive tumors, with TP53 mutations being the most frequent. Allelic imbalances or loss of heterozygosity are more frequently found in higher stages of dysplasia and in invasive carcinomas, but it is not exclusive to HPV-negative tumors. A limited number of studies are available on epigenetic changes in vulvar lesions, with hypermethylation of CDKN2A being the most frequently investigated change. For most genes, hypermethylation occurs more frequently in vulvar squamous cell carcinomas than in precursor lesions. As most studies have focused on HPV infection and TP53 mutations, we suggest that more research should be performed using whole genome or next generation sequencing to determine the true landscape of genetic and epigenetic alterations in vulvar squamous cell carcinoma.

The optimal treatment of severe hypertension in pregnancy: update of the role of nicardipine.

OBJECTIVE: Hypertensive disorders in pregnancy remain a major cause of maternal morbidity and mortality. Blood pressure control is essential for maternal and neonatal outcome. Therefore, we analyzed the potency and side effects of two treatment options (nicardipine compared to labetalol) in order to gain insight in improved treatment of severe hypertension during pregnancy and to evaluate the feasibility of a randomised controlled trial. STUDY DESIGN: A nested case control study in an inner city teaching hospital alongside a meta-analysis. Data from women who received nicardipine were compared with patients who received labetalol during pregnancy. Primary outcome measure was successful control of severe hypertension. Secondary outcome measures were maternal and neonatal side effects. These results were included in a meta-analysis. RESULTS: Only one previous study described nicardipine in comparison to labetalol during pregnancy. The combined results indicate a similar success-rate of treatment with nicardipine compared to labetalol during pregnancy. Women treated with nicardipine had more often tachycardia, headache and nausea compared to women treated with labetalol. Hypotension resulting in fetal distress was found more often in the labetalol group. CONCLUSION: Nicardipine is a potent drug to control hypertension during pregnancy with side effects including maternal headaches, nausea and tachycardia. Labetalol had more neonatal side effects including hypotension compared with nicardipine. These results support the justification and prove that it is safe to perform a randomized controlled trial comparing nicardipine to labetalol in the treatment of severe hypertension in pregnancy.

The long-term immune response after HPV16 peptide vaccination in women with low-grade pre-malignant disorders of the uterine cervix: a placebo-controlled phase II study.

The capacity of a low-dose HPV16 synthetic long-peptide vaccine (HPV16-SLP) to induce an HPV16-specific T-cell response as well as to establish long-term immunologic memory in patients with low-grade abnormalities of the cervix was determined in a placebo-controlled, double-blinded phase II study. In addition, the effect of a booster vaccination after 1 year was evaluated. Patients received either the HPV16-SLP or a placebo at the start of the study. After 1 year, the vaccinated patients were again randomized to receive the HPV16-SLP or a placebo. Patients were followed for 2 years. HPV16-specific T-cell responses were determined in pre- and post-vaccination blood samples by ELISPOT, proliferation assay and cytokine assays. We show that the HPV16-specific T-cell responses detected after vaccination are clearly due to vaccination and that reactivity was maintained for at least 2 years. Interestingly, a booster vaccination after 1 year especially augmented the HPV16-specific Th2 response. Furthermore, pre-existing immunity to HPV16 was associated with a stronger response to vaccination and with more side effects, reflected by flu-like symptoms. We conclude that two low-dose injections of HPV16-SLP can induce a strong and stable HPV16-specific T-cell response that lasts for at least 1 year. If booster vaccination is required, then polarizing adjuvant should be added to maintain the Th1 focus of the vaccine-induced T-cell response.

The reliability of methionine challenge test is not affected by a deficiency in pyridoxal phosphate, folic acid, or cobalamin.

UNLABELLED: Abnormal methionine challenge test results cannot be explained by a deficiency in pyridoxal phosphate, folic acid, or cobalamin. The methionine challenge test is reliable for demonstrating hyperhomocysteinemia. OBJECTIVE: To research the status of pyridoxal phosphate, folic acid, and cobalamin as part of an examination for hyperhomocysteinemia and to establish their relationship to the results of methionine challenge tests in women, who were tested at least 3 months after they had ended a pregnancy which was complicated by preeclampsia or other vascular-related pregnancy complications. METHODS: In the Isala clinics in Zwolle, women with vascular-related complications of pregnancy were tested at least 3 months postpartum for hyperhomocysteinemia, by performing a methionine challenge test, as well as tests to measure their vitamin status. The diagnosis of hyperhomocysteinemia was made after two abnormal test results. The χ(2) test was used to compare the vitamin status of the group with normal results to those with an abnormal result of methionine challenge tests. RESULTS: No statistically significant differences in the vitamin status were found between the group of women with an abnormal and the group with normal results of the methionine challenge tests. CONCLUSION: Abnormal methionine challenge test results cannot be explained by a deficiency in pyridoxal phosphate, folic acid, or cobalamin. We demonstrate that, when women are tested 3 months postpartum, the methionine challenge test is reliable for demonstrating hyperhomocysteinemia as a risk factor for vascular-related complications of pregnancy.

Trapezius aplasia: indications for a dual developmental origin of the trapezius muscle.

Aplasia of the trapezius muscle is a rarely encountered, mostly asymptomatic anomaly. We report a case of isolated unilateral complete trapezius aplasia that was noticed during a dissection course. Apart from isolated cases, trapezius aplasia may occur in different combinations with other muscle aplasias. We suggest that the patterns of concomitant muscle involvement are indicative of a combined occipital and cervical somitogenic origin.