Targeted Therapeutic Approaches in Vulvar Squamous Cell Cancer (VSCC): Case Series and Review of the Literature.

Therapeutic options in recurrent or metastasized vulvar squamous cell cancer (VSCC) not amenable to radiotherapy or radical surgery are limited. Evidence for the use of targeted therapies is sparse. All patients with VSCC treated at the Gynecological Cancer Center Hamburg-Eppendorf 20132019 were retrospectively evaluated for targeted therapeutic approaches. Furthermore, a MEDLINE, EMBASE, Web of Science, Scopus, and OVID database search was performed using the terms: vulvar cancer AND targeted therapy, erlotinib, EGFR, bevacizumab, VEGF, pembrolizumab, or immunotherapy. Twelve of 291 patients (4.1%) with VSCC received at least one targeted therapy at our institution. Previously, one or more platinum-based chemotherapy was applied to all patients [median 3.5 previous lines (range 25)]. In the erlotinib subgroup, two of five patients (40%) achieved stable disease (SD), while two patients (2/5, 40%) experienced partial response (PR). Treatment was given as monotherapy in second/third line for a median of 3.4 months (range 26 months). Bevacizumab (n=9) was given as maintenance therapy after platinum-based first-line chemotherapy (9/9); best response was complete response (CR) (n=2/9 22.2%). Median duration of treatment was 7 months (range 413 months) with two patients still under ongoing treatment. Best response in the pembrolizumab (n=3) subset was SD (n=1/3 33%). Treatment was given as monotherapy in second/third line for a median of 3.3 months (range 34 months). Nine of 12 patients (75%) experienced treatment-related adverse events (TRAEs), most commonly grade 1/2. Rapidly evolving antibody treatments have proven clinical benefit especially in HPV-driven tumor entities; however, clinical investigations in VSCC are still limited. These reported cases provide evidence for the clinical utility and feasibility while ensuring an acceptable safety profile.

Superficially invasive stage IA vulvar squamous cell carcinoma-therapy and prognosis.

OBJECTIVES: Superficially invasive stage IA squamous vulvar cancer (VSCC) is defined as a single lesion measuring ≤2 cm with a depth of invasion of ≤1.0 mm (FIGO stage IA). This article examines the natural course and prognosis of superficially invasive VSCC. METHODS: This is a retrospective case series of 46 patients (median age 58 years) with superficially invasive stage IA VSCC receiving wide local excision between January 1996 and November 2014 in the University Medical Center Hamburg-Eppendorf. RESULTS: Median tumor size was 4 mm. In 39/46 (84.8%) patients peri-tumoral high-grade intraepithelial neoplasia (HSIL) and/or lichen sclerosus (LS) of the vulva were histologically detected: 34 (74.0%) usual type high-grade vulvar intraepithelial neoplasia (uVIN, HSIL), 4 (8.7%) LS with simultaneous VIN (3 uVIN, 1 differentiated VIN (dVIN)), 1 (2.2%) with LS only. 37/46 (80.4%) patients had a R0 resection; in 2 (4.3%) a high-grade VIN was detected in the margin and in 7 (15.2%) the resection status was unknown. The mean follow-up was 58 (range 10-185) months. Four patients (8.7%) suffered from an invasive recurrence after 4, 17, 40, and 54 months, three in the vulva and one in the groin. All local recurrences occurred in women with LS in a combination with high-grade VIN (3 uVIN, 1 dVIN). Two were treated surgically again including inguino-femoral lymphadenectomy (ifLAE) (no regional lymph node metastasis histologically) as invasion depth exceeded 1 mm. The third patient refused treatment. Inguinal recurrence was treated with a bilateral ifLAE, revealing one positive lymph node, followed by adjuvant radiotherapy (groins, pelvis). None of these patients had experienced further recurrences at last follow-up. CONCLUSIONS: Superficially invasive VSCC is characterized by having a very good prognosis. Sole surgical therapy is highly effective. Patients with LS might benefit additionally from intensified surveillance and adequate maintenance therapy in specialized centers.

Correlation of Isotope Count With Sentinel Node Positivity in Vulvar Cancer.

OBJECTIVE: Sentinel node biopsy (SNB) has become standard of care in early stage vulvar cancer. As the correlation of isotope count with the presence of metastases remains unclear, often several active nodes are excised per groin. This can result in increased morbidity in node-negative disease despite of SNB. In the current analysis, we assess whether resection of the hottest node could be sufficient to detect sentinel lymph node (SLN) metastasis. METHODS: Patients with primary vulvar cancer receiving an SNB with radioactive tracer at the University Medical Center Hamburg-Eppendorf between 2008 and 2015 were evaluated. RESULTS: A total of 145 patients with SNB were analyzed; thereof, 144 underwent bilateral SNB, resulting in 289 analyzed groins. A median of 2 SLNs (range, 1-7) per groin were removed. From 94 (32.5%) of 289 groins, more than 2 SLNs were excised. Median overall SLN isotope count was 1400 cps. In 50 groins, a positive SLN was detected (unilateral in 38 patients, bilateral in 6). The median number of positive SLN per groin was 1 (range, 1-4). The SLN with the highest isotope count carried metastases in 36 (78.3%) of 46 groins (in 4 cases, the highest count was unknown). In 10 (21.7%) of 46 positive groins, the SLN with the highest count was not the metastatic SLN (9/10 second highest count). Median count of these 10 SLN was 60% of the highest count with a range from 11.0% to 74.0%. CONCLUSIONS: The highest isotope count does not reliably detect the positive SLN in vulvar cancer. To prevent mostly fatal groin recurrences, surgeons should continue to remove all SLN accumulating relevant radioactive tracer over background activity.

Platelet-derived growth factor receptor beta serum concentrations during first-line therapy in ovarian cancer.

OBJECTIVES: Angiogenesis plays an important role in ovarian cancer. The interaction of platelet-derived growth factor receptor-beta (PDGFR-ß) with vascular endothelial growth factor (VEGF) in the process of angiogenesis may represent an essential feature in the progression of the disease. METHODS: Patients with epithelial ovarian cancer, who underwent primary surgery and platinum-based first-line chemotherapy, were included. A total of 133 serum samples from 39 patients were analyzed. Samples were prospectively collected at 4 time points: (1) before surgery, (2) after surgery and before chemotherapy, (3) during chemotherapy and (4) after chemotherapy. Serum PDGFR-ß was quantified by ELISA. We analyzed the correlation of serum levels to chemotherapy response, progression-free and overall survival (PFS and OS) and the serum markers CA-125 and VEGF-165. RESULTS: Serum concentration of PDGFR-ß ranged between 4 and 72 ng/ml and increased significantly during first-line chemotherapy (p = 0.019). PDGFR-ß serum concentrations showed an inverse correlation with CA-125 and VEGF-165 after chemotherapy (r = -0.495, p = 0.003 and r = -0.345, p = 0.04, respectively). Increased PDGFR-ß serum levels after chemotherapy were significantly correlated with better PFS (p = 0.026) and OS (p = 0.013) in a univariate analysis. CONCLUSION: PDGFR-ß might be a useful biomarker in terms of prognosis and could be important as antiangiogenic agents become a component of standard treatment in ovarian cancer.

Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis.

Podocyte foot process retraction is a hallmark of proteinuric glomerulonephritis. Cytoskeletal rearrangement causes a redistribution of slit membrane proteins from the glomerular filtration barrier towards the cell body. However, the underlying signaling mechanisms are presently unknown. Recently, we have developed a new experimental model of immune-mediated podocyte injury in mice, the antipodocyte nephritis (APN). Podocytes were targeted with a polyclonal antipodocyte antibody causing massive proteinuria around day 10. Rho-kinases play a central role in the organization of the actin cytoskeleton of podocytes. We therefore investigated whether inhibition of Rho-kinases would prevent podocyte disruption. C57/BL6 mice received antipodocyte serum with or without daily treatment with the specific Rho-kinase inhibitor HA-1077 (5 mg/kg). Immunoblot analysis demonstrated activation of Rho-kinase in glomeruli of antipodocyte serum-treated mice, which was prevented by HA-1077. Increased Rho-kinase activity was localized to podocytes in APN mice by immunostainings against the phosphorylated forms of Rho-kinase substrates. Rho-kinase inhibition significantly reduced podocyte loss from the glomerular tuft. Periodic acid staining demonstrated less podocyte hypertrophy in Rho-kinase-inhibited APN mice, despite similar amounts of immune complex deposition. Electron microscopy revealed reduced foot process effacement compared with untreated APN mice. Internalization of the podocyte slit membrane proteins nephrin and synaptopodin was prevented by Rho-kinase inhibition. Functionally, Rho-kinase inhibition significantly reduced proteinuria without influencing blood pressure. In rats with passive Heymann nephritis and human kidney biopsies from patients with membranous nephropathy, Rho-kinase was activated in podocytes. Together, these data suggest that increased Rho-kinase activity in the podocyte may be a mechanism for in vivo podocyte foot process retraction.

Nephrotic syndrome and subepithelial deposits in a mouse model of immune-mediated anti-podocyte glomerulonephritis.

Subepithelial immune complex deposition in glomerular disease causes local inflammation and proteinuria by podocyte disruption. A rat model of membranous nephropathy, the passive Heymann nephritis, suggests that Abs against specific podocyte Ags cause subepithelial deposit formation and podocyte foot process disruption. In this study, we present a mouse model in which a polyclonal sheep anti-mouse podocyte Ab caused subepithelial immune complex formation. Mice developed a nephrotic syndrome with severe edema, proteinuria, hypoalbuminemia, and elevated cholesterol and triglycerides. Development of proteinuria was biphasic: an initial protein loss was followed by a second massive increase of protein loss beginning at approximately day 10. By histology, podocytes were swollen. Electron microscopy revealed 60-80% podocyte foot process effacement and subepithelial deposits, but no disruption of the glomerular basement membrane. Nephrin and synaptopodin staining was severely disrupted, and podocyte number was reduced in anti-podocyte serum-treated mice, indicating severe podocyte damage. Immunohistochemistry detected the injected anti-podocyte Ab exclusively along the glomerular filtration barrier. Immunoelectron microscopy localized the Ab to podocyte foot processes and the glomerular basement membrane. Similarly, immunohistochemistry localized mouse IgG to the subepithelial space. The third complement component (C3) was detected in a linear staining pattern along the glomerular basement membrane and in the mesangial hinge region. However, C3-deficient mice were not protected from podocyte damage, indicating a complement-independent mechanism. Twenty proteins were identified as possible Ags to the sheep anti-podocyte serum by mass spectrometry. Together, these data establish a reproducible model of immune-mediated podocyte injury in mice with subepithelial immune complex formation.