Rogerio I Neves | Penn State University (original) (raw)

Papers by Rogerio I Neves

Background While the morbidity and mortality from cancer are largely attributable to its metastat... more Background While the morbidity and mortality from cancer are largely attributable to its metastatic dis-semination, the integral features of the cascade are not well understood. The widely accepted hypothesis is that the primary tumor microenvironment induces the epithelial-to-mesenchymal transition in cancer cells, facilitating their escape into the bloodstream, possi-bly accompanied by cancer stem cells. An alternative theory for metastasis involves fusion of macrophages with tumor cells (MTFs). Here we culture and characterize apparent MTFs from blood of melanoma patients. Methods We isolated enriched CTC populations from peripheral blood samples from melanoma patients, and cultured them. We interrogated these cultured cells for characteristic BRAF mutations, and used confocal microscopy for immunophenotyping, motility, DNA content and chromatin texture analyses, and then conducted xenograft studies using nude mice.

Plastic & Reconstructive Surgery, 2019

Plastic & Reconstructive Surgery

Supplemental Digital Content is available in the text. Summary: A multi-disciplinary work group i... more Supplemental Digital Content is available in the text. Summary: A multi-disciplinary work group involving stakeholders from various backgrounds and societies was convened to develop guidelines for the management of reconstruction after skin cancer resection. The goal was to identify areas of common ground and provide evidence-based recommendations to improve patient care. Given the heterogeneity of reconstructive techniques and clinical scenarios, investigation centered around common elements in the process. In some cases, a distinction was made between treatment options in the office-based setting as opposed to those in the facility setting. A systematic literature review was performed, and an established appraisal process was used to rate the quality of relevant scientific research (Grading of Recommendations Assessment, Development, and Evaluation methodology). Final recommendations are related to concepts concerning the timing of reconstruction, management of anticoagulation, use of antibiotics, methods of pain control, and follow-up assessment. At times, there was insufficient evidence to make high-level recommendations. The literature analysis highlights the need for additional methodologically robust studies in this area, to help guide clinical practice.

Clinical Cancer Research

Purpose: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operab... more Purpose: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma. Patients and Methods: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery. Results: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively). Conclusions: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator. See related commentary by Menzies et al., p. 4133

Journal for ImmunoTherapy of Cancer

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on th... more Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in...

Clinics in Plastic Surgery

Great strides in immunotherapy and targeted therapy have revolutionized the management of previou... more Great strides in immunotherapy and targeted therapy have revolutionized the management of previously devastating, advanced melanomas. Although these subfields continue to progress, novel approaches in intratumoral oncolytic therapy, adoptive cell therapy, and vaccine therapies are being developed as adjuncts or alternatives. Cytokines, meanwhile, are seeing a resurgence as a viable option as well. The array of effective agents will, in the next few years, provide options for therapy not only in the adjuvant or unresectable settings but also in the neoadjuvant settings. Perhaps, too, in earlier stage melanomas.

Journal of Clinical Oncology

9510 Background: HF10 is a bioselected replication-competent oncolytic virus derived from HSV-1. ... more 9510 Background: HF10 is a bioselected replication-competent oncolytic virus derived from HSV-1. Herein, we report the safety and efficacy data of HF10 + ipilimumab (ipi) combination treatment in a Phase II trial in melanoma. Methods: Key entry criteria: age ≥ 18 yrs, ECOG ≤ 2, Stage IIIB, IIIC, or IV unresectable melanoma, ipi naïve (IV administration) and measurable non-visceral lesion(s) suitable for injection. HF10 injected into single or multiple tumors (1 x 107 TCID50/mL/dose, up to 5mL depending on tumor size and number); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) were administered q3wk. AEs assessed per CTCAE 4.0. Tumor responses were assessed per mWHO and irRC at 12, 18, 24, 36 and 48 wks for patients (pts) continuing on HF10 monotherapy. Primary endpoint was Best Overall Response Rate (BORR) at 24 wks. Dose limiting toxicity (DLT) defined as ≥ G3 non-hematologic/hematologic toxicity, ≥ G2 neurologic toxicity, or ...

Molecular pharmacology, 2018

Drug combinations acting synergistically to kill cancer cells have become increasingly important ... more Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino--[(1)-1-(4-chlorop...

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Nanomedicine : nanotechnology, biology, and medicine, 2018

Drug resistance and toxicity are major limitations of cancer treatment and frequently occurs duri... more Drug resistance and toxicity are major limitations of cancer treatment and frequently occurs during melanoma therapy. Nanotechnology can decrease drug resistance by improving drug delivery, with limited toxicity. This study details the development of nanoparticles containing arachidonyl trifluoromethyl ketone (ATK), a cytosolic phospholipase A inhibitor, which can inhibit multiple key pathways responsible for the development of recurrent resistant disease. Free ATK is toxic, limiting its efficacy as a therapeutic agent. Hence, a novel nanoliposomal delivery system called NanoATK was developed, which loads 61.7% of the compound and was stable at 4C for 12 weeks. The formulation decreased toxicity-enabling administration of higher doses, which was more effective at inhibiting melanoma cell growth compared to free-ATK. Mechanistically, NanoATK decreased cellular proliferation and triggered apoptosis to inhibit melanoma xenograft tumor growth without affecting animal weight. Functionall...

American journal of surgery, Jan 23, 2018

Infrared fluorescence imaging with indocyanine green (ICG) is a novel method for sentinel node lo... more Infrared fluorescence imaging with indocyanine green (ICG) is a novel method for sentinel node localization. Our objective was to assess ICG and fluorescence imaging for preoperative and intraoperative utility. 87 eligible patients participated in this prospective study. All patients received injection of ICG dye in addition to both methylene blue and Tc. Each sentinel node was assessed for the presence of each dye. ICG was visible prior to incision in 44% of subjects. Tc identified a mean of 1.89 SLN per patient. ICG identified a mean of 1.87 SLN while methylene blue (MB) dye identified a mean of 0.71 SLN. Tc and ICG identified the same number of sentinel nodes per patient (P = .73) while methylene blue was inferior in its ability to localize sentinel nodes (P < .001). Our findings indicate that ICG/fluorescence imaging has limited ability to identify the nodal basin preoperatively, but is equivalent to Tc for intraoperative identification of sentinel nodes and superior to MB.

Journal of Radiation Oncology

ObjectiveThere is a growing body of evidence that combining radiotherapy with ipilimumab might im... more ObjectiveThere is a growing body of evidence that combining radiotherapy with ipilimumab might improve the survival and response rates in patients with metastatic melanoma. However, the patient and treatment variables that predict for improved outcomes have not been well defined.MethodsWe conducted a retrospective analysis of 69 patients treated with ipilimumab and radiotherapy for metastatic melanoma at a single institution from May 2011 to June 2015. Demographic, clinical, and treatment factors were recorded, and end points of interest included infield and global complete response (CR) after the completion of radiation and ipilimumab based on the RECIST criteria (v1.1), and overall survival (OS). A bivariate and multivariate analysis was then performed to assess the relationship between outcomes and patient variables.ResultsIn the multivariate analysis, infield CR was significantly associated with completing a full course of ipilimumab, a higher BED, and a smaller size of metastatic area treated. Global CR was significantly associated with increased age and giving radiotherapy to all areas of disease. OS was significantly associated with completing a full course of ipilimumab and a higher BED. Interestingly, after a multivariate analysis, higher BED was associated with an improved infield CR (p = 0.0281) and was not associated with an improved global CR (p = 0.5284) but was marginally associated with improved OS (p = 0.0545).ConclusionOur findings suggest that the rate of a global CR is independent of the dose of radiation given, but the rate of infield CR and OS might improve with higher doses.

The New England journal of medicine, Jun 8, 2017

Background Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.... more Background Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. Methods In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. Results Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis o...

Cancer biology & therapy, Jan 2, 2017

There is a growing body of evidence supporting the synergistic roles of radiotherapy and immunoth... more There is a growing body of evidence supporting the synergistic roles of radiotherapy and immunotherapy in the treatment of malignancy. Published case studies of the abscopal effect have been reported with the use of ipilimumab and radiotherapy in metastatic melanoma, but evidence supporting the routine use of this combination of therapy is limited. We conducted a retrospective analysis to evaluate patients treated with ipilimumab for advanced melanoma at a single institution from May 2011 to June 2015. Patients were grouped into those who had received concurrent radiotherapy while on ipilimumab (Ipi-RT), and those who did not. We then evaluated the treatment response following completion of ipilimumab. A total of 101 patients received ipilimumab in the prespecified time frame. 70 received Ipi-RT and 31 received ipilimumab without concurrent radiotherapy. Median overall survival (OS) was significantly increased in the concurrent Ipi-RT arm at 19 months vs. 10 months for ipilimumab al...

Journal of Craniofacial Surgery, 2016

Congenital anophthalmia is a rare anomaly that results in micro-orbitism and craniofacial microso... more Congenital anophthalmia is a rare anomaly that results in micro-orbitism and craniofacial microsomia. Treatment with static conformers is labor-intensive and provides minimal stimulation for orbital growth that requires eventual reconstruction with orbital osteotomies after skeletal maturity. A protocol for the treatment of congenital anophthalmia is presented. Patients underwent a preoperative low-dose radiation computed tomography (CT) scan of the facial bones to assess orbital volume. An intraorbital expander was placed and was filled on a monthly basis. Quantitative changes in the affected and unaffected orbits were assessed by a repeat CT scan obtained 1 year postoperatively. Two patients with left unilateral congenital anophthalmia were prospectively followed. In a 4-month-old, the affected orbital width and height increased by 171.6% and 116.7% respectively compared with the unaffected orbit. In a 4-year-old, the affected orbital width increased by 36.1% but the height decreased by 35.3% compared with the unaffected orbit. At 18 months follow-up, no complications, ruptures, infections, or extrusions have been observed. Our results support that accelerated expansion can be achieved in a 4-month-old orbit reversing the effects of anophthalmia. However, in a 4-year-old, minimal growth was observed. The lack of accelerated growth in this study may be explained by synostosis of the orbital sutures. As such, expansion should be initiated at the earliest age possible. Further longitudinal study is ongoing to determine if sustained catch-up growth will obviate or reduce the complexity of a secondary correction.

The oncologist, Oct 10, 2016

Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal ce... more Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small-molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC. Adverse events (AEs) commonly observed in hedgehog pathway inhibitor (HPI)-treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue).These AEs are thought to be mechanistically related to inhibition of the hedgehog pathway in normal tissue. Although the severity of the majority of AEs associated with HPIs is grade 1-2, the long-term nature of these AEs can lead to decreased quality of life, treatment interruption, and in some cases discontinuation, all of which might affect clinical outcome.The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to HPIs in advanced BCC are described. These observations represent the first step toward the development of mechanism-based preventive and management strategies. Knowledge of these AEs will allow health care professionals to provide appropriate counseling and supportive care interventions, all of which will contribute to improved quality of life and optimal benefit from therapy.

Artigo de Revisão Resumo: A incidência do melanoma cutâneo tem aumentado mundialmente e, por trat... more Artigo de Revisão Resumo: A incidência do melanoma cutâneo tem aumentado mundialmente e, por tratar-se de neoplasia bastante agressiva e de difícil tratamento em estádios mais avançados, o diagnóstico precoce é fundamental para a cura do paciente. A dermatoscopia surgiu como exame auxiliar in vivo, que tem papel fundamental na realização do diagnóstico precoce e amplifica a acurácia diagnóstica do melanoma. Para a realização do método, é necessário utilizar o dermatoscópio, aparato que permite aumentar a lesão, no mínimo, 10 vezes. A imagem obtida é interpretada utilizando-se o método diagnóstico da preferência do examinador. O método de Análise de Padrões é atualmente o mais utilizado e o que possui maior acurácia para o diagnóstico do melanoma cutâneo, tendo-se demonstrado confiável para o ensino de residentes em dermatologia. Baseia-se em padrões globais e específicos que permitem diferenciar as lesões melanocíticas das não melanocíticas (também importantes no diagnóstico diferencial com o melanoma cutâneo), assim como identificar lesões melanocíticas consideradas benignas, suspeitas ou malignas.