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PURPOSE OF REVIEW: The purpose of this review is to look at recent advancements and treatment options of systemic therapies to treat penile squamous cell carcinoma (PSCC). PSCC is a rare cancer that remains with limited funding for research and systemic therapy development. This review aims to discuss the most recent advancements in systemic treatments and our understanding of PSCC. RECENT FINDINGS: Neoadjuvant chemotherapy (NAC) and adjuvant therapy remain integral parts of treatment in locally advanced PSCC. New potential drug regimens are being studied to expand on the availability of first-line regimen options. There has been a large development in discoveries of cellular pathways and immune system targets as potential treatment options but these therapies as of today have limited trial evidence and currently have no support to be used in a clinical setting. SUMMARY: PSCC is a rare genitourinary cancer with limited treatment options for patients with advanced disease that is refractory to chemotherapy. Although many new therapies targeting the immune system and cellular pathways are being developed for other studies, clinical and translational research for PSCC are still understudied and underfunded.
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Carcinoma de Células Escamosas , Neoplasias Penianas , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Terapia Combinada , Humanos , Imunoterapia , Masculino , Neoplasias Penianas/tratamento farmacológico , Neoplasias Penianas/patologia , Terapias em EstudoRESUMO
Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n = 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1%, 0.5%, and 1% (wt/vol) concentrations, whereas the control (Ctr; n = 8) group received a blank TMS gel. All Rx mice (0.1% [n = 4], 0.5% [n = 6], and 1% [n = 5]) were vaginally challenged with two transmitted/founder (T/F) HIV-1 strains (2.5 × 10(5) 50% tissue culture infectious doses). Rx mice were challenged at 4 h (0.1%), 24 h (0.5%), and 7 days (1%) posttreatment (p.t.) and Ctr mice were challenged at 4 h p.t. Blood was drawn weekly for 4 weeks postinoculation (p.i.) for plasma viral load (pVL) using reverse transcription-quantitative PCR. Ctr mice had positive pVL within 2 weeks p.i. Rx mice challenged at 4 h and 24 h showed 100% protection and no detectable pVL throughout the 4 weeks of follow-up (P = 0.009; Mantel-Cox test). Mice challenged at 7 days were HIV-1 positive at 14 days p.i. Further, HIV-1 viral RNA (vRNA) in vaginal and spleen tissues of Rx group mice with negative pVL were examined using an in situ hybridization (ISH) technique. The detection of vRNA was negative in all Rx mice studied. The present studies elucidate TDF-NP-TMS gel as a long-acting, coitus-independent HIV-1 vaginal protection modality.
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Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/prevenção & controle , Prevenção Primária/métodos , RNA Viral/antagonistas & inibidores , Tenofovir/administração & dosagem , Cremes, Espumas e Géis Vaginais/administração & dosagem , Administração Intravaginal , Animais , Modelos Animais de Doenças , Emulsificantes/química , Feminino , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Humanos , Ácido Láctico/química , Camundongos , Camundongos Transgênicos , Nanopartículas/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , RNA Viral/genética , Temperatura , Fatores de Tempo , Vagina/efeitos dos fármacos , Vagina/virologia , Cremes, Espumas e Géis Vaginais/química , Carga Viral/efeitos dos fármacosRESUMO
INTRODUCTION: This study investigated the efficacy and safety of neoadjuvant chemotherapy for locally advance penile squamous cell carcinoma for which current evidence is lacking. METHODS: Included patients had locally advanced penile squamous cell carcinoma with clinical lymph node metastasis treated with at least 1 dose of neoadjuvant chemotherapy prior to planned consolidative lymphadenectomy. Objective response rates were assessed using Response Evaluation Criteria in Solid Tumors v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan-Meier method. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events v5.0. RESULTS: A total of 209 patients received neoadjuvant chemotherapy for locally advanced and clinically node-positive penile squamous cell carcinoma. The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 treatment-related adverse events occurred in 35 (17%) patients, and no treatment-related mortality was observed. Of the patients, 201 (97%) completed planned consolidative lymphadenectomy. During follow-up, 106 (52.7%) patients expired, with a median overall survival of 37.0 months (95% confidence interval [CI] = 23.8 to 50.1 months) and median progression-free survival of 26.0 months (95% CI = 11.7 to 40.2 months). Objective response rate was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to neoadjuvant chemotherapy had a longer median overall survival (73.0 vs 17.0 months, P < .01) compared with those who did not. The lymph node pathologic complete response rate was 24.8% in the cohort. CONCLUSION: Neoadjuvant chemotherapy with lymphadenectomy for locally advanced penile squamous cell carcinoma is well tolerated and active to reduce the disease burden and improve long-term survival outcomes.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Escamosas , Excisão de Linfonodo , Terapia Neoadjuvante , Neoplasias Penianas , Humanos , Masculino , Neoplasias Penianas/tratamento farmacológico , Neoplasias Penianas/patologia , Neoplasias Penianas/mortalidade , Neoplasias Penianas/cirurgia , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Adulto , Estadiamento de Neoplasias , Metástase Linfática , Estudos Retrospectivos , Quimioterapia Adjuvante , Idoso de 80 Anos ou maisRESUMO
OBJECTIVES: To improve outcomes in infants with neonatal opioid withdrawal syndrome (NOWS) admitted to NICU by implementing a quality improvement (QI) initiative incorporating "eat, sleep, console" (ESC) as a withdrawal evaluation tool and promotion of nonpharmacological interventions. Secondarily, we evaluated the impact of the coronavirus disease 2019 pandemic on QI initiative and outcomes. METHODS: We included infants born ≥ 36 weeks gestation and admitted to NICU with a primary diagnosis of NOWS between December 2017 and February 2021. (preintervention; December 2017-January 2019, postintervention; February 2019-February 2021). We compared cumulative dose, duration of opioid treatment, and length of stay (LOS) as our primary outcomes. RESULTS: The average duration of opioid treatment decreased from 18.6 days in the preimplementation cohort (n = 36) to 1.5 days in the first-year postimplementation (n = 44) with a reduction in cumulative opioid dose from 5.8 mg/kg to 0.6 mg/kg and decrease in the proportion of infants treated with opioids from 94.2% to 41.1%. Similarly, the average LOS decreased from 26.6 to 7.6 days. In the second-year postimplementation during the coronavirus disease 2019 pandemic (n = 24), there was an increase in average opioid treatment duration and LOS to 5.1 and 12.3 days respectively, but cumulative opioid dose (0.8 mg/kg) remained significantly lower than the preimplementation cohort. CONCLUSIONS: ESC-based quality improvement initiative led to a significant decrease in LOS and opioid pharmacotherapy in infants with NOWS in NICU setting. Despite the impact of the pandemic, some of the gains were sustained with adaptation to ESC QI initiative.
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COVID-19 , Síndrome de Abstinência Neonatal , Recém-Nascido , Lactente , Humanos , Analgésicos Opioides/uso terapêutico , Melhoria de Qualidade , Pandemias , COVID-19/epidemiologia , Síndrome de Abstinência Neonatal/tratamento farmacológico , SonoRESUMO
Penile Squamous Cell Carcinoma (PSCC) is associated with high-risk human papillomavirus (HR-HPV). The immunohistochemical (IHC) test for p16INK4a (p16) is highly correlated with HR-HPV expression in other SCCs. To investigate whether the expression of p16 IHC or HR-HPV is associated with survival in PSCC, we conducted a single institution analysis of 143 patients with a diagnosis of PSCC and, available tissue were tested for p16 IHC staining patterns, histological subtype, tumor grade, and lymphovascular invasion (LVI) by an experienced pathologist. HR-HPV status using the Cobas PCR Assay or the RNAScope high-risk HPV in situ hybridization kit were also assessed. Patient characteristics were summarized using descriptive statistics of clinico-pathologic variables. Kaplan-Meier was used to estimate median overall survival (OS), cancer specific survival (CSS) and correlated with HPV, p16, and other study variables. Patients with p16+ tumors had a significantly longer median CSS in comparison to the p16- group (p = 0.004), with respective 5-year CSS probability of 88% (95% CI; 0.84, 1) versus 58% (95% CI; 0.55, 0.76; p = 0.004). HPV status did not predict survival outcomes. Multivariable analysis with respect to OS and CSS, showed that p16+ status was associated with a lower risk of death (HR = 0.36, 95%CI; 0.20-0.67, p = 0.001), and improved CSS (HR = 0.20, 95% CI; 0.07-0.54, p = 0.002) after adjusting for covariates. In conclusion, tumor p16 status via IHC was an easy to perform independent prognostic factor for OS and CSS that correlates with HR-HPV expression.
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INTRODUCTION: We characterize patient perceptions of telemedicine (video-enabled) and telephonic (audio-only) visits conducted during the COVID-19 pandemic. METHODS: A single-center cohort of 76 patients who underwent remote ambulatory visits from March 2020 to July 2020 was evaluated. Patients responded to a questionnaire assessing perception of timeliness, efficiency, overall satisfaction and willingness to have a remote appointment after the pandemic. Responses were compared for telephonic (audio-only) vs telemedicine (video) visits. RESULTS: High satisfaction scores were reported for both telephonic and telemedicine appointments, with a mean score of 6.61 out of 7 (SD 1.0) for overall satisfaction. Telephonic visits demonstrated higher scores regarding timeliness and efficiency of the visit (6.58 vs 5.92, p=0.017) and willingness to have a remote encounter with a urology resident (6.58 vs 5.61, p=0.001) or advanced practice provider (6.21 vs 5.51, p=0.015). No difference in perception of confidentiality or overall satisfaction was observed between both groups. In all, 91% of participants desired the option of a virtual visit with their provider after the pandemic. CONCLUSIONS: Patients undergoing remote urology appointments during the COVID-19 pandemic report high satisfaction rates, though telephonic encounters were more favorable for patients in regard to timeliness and efficiency. Importantly, most patients desired the option of telephonic and telemedicine calls after the pandemic. Further analysis on safety, efficacy, provider perceptions, outcomes and economic impact is needed to assess the feasibility of continuing regular telephonic and telemedicine visits after the COVID-19 pandemic is over.
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HIV continues to be one of the greatest challenges facing the global health community. More than 36 million people currently live with HIV and, in 2015 2.1 million new infections were reported globally. Pre-Exposure Prophylaxis (PrEP) prevents HIV infection by inhibiting viral entry, replication, or integration at the primary site of pathogenic contraction. Failures of large antiretroviral drug (ARV) PrEP clinical trials indicate the current insufficiencies of PrEP for women in high-risk areas, such as sub-Saharan Africa. A combination of social, adherence, and drug barriers create these insufficiencies and limit the efficacy of ARV. Nanotechnology offers the promise of extended drug release and enhances bioavailability of ARVs when encapsulated in polymeric nano-particles. Nanoparticle encapsulation has been evaluated in vitro in comparative studies to drug solutions and exhibit higher efficacy and lower cytotoxicity profiles. Delivery systems for nanoparticle PrEP facilitate administration of nano-encapsulated ARVs to high-risk tissues. In this mini-review, we summarize the comparative nanoparticle and drug solution studies and the potential of two delivery methods: thermosensitive gels and polymeric nanoparticle films for direct prophylactic applications.
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To adequately reduce new HIV infections, development of highly effective pre-exposure prophylaxis (PrEP) against HIV infection in women is necessary. Cellulose acetate phthalate (CAP) is a pH sensitive polymer with HIV-1 entry inhibitory properties. Dolutegravir (DTG) is an integrase strand transfer inhibitor with potent antiretroviral activity. DTG delivered in combination with CAP may significantly improve current PrEP against HIV. In the present study the development of DTG-loaded CAP nanoparticles incorporated in thermosensitive (TMS) gel at vaginal pH 4.2 and seminal fluid pH 7.4 is presented as proof-of-concept for improved PrEP. Water-oil-in-water homogenization was used to fabricate DTG-loaded CAP nanoparticles (DTG-CAP-NPs). Size, polydispersity, and morphological analyses illustrate that DTG-CAP-NPs were smooth and spherical, ≤200 nm in size, and monodispersed with a polydispersity index PDI ≤ 0.2. The drug encapsulation (EE%) and release profile of DTG-CAP-NPs was determined by HPLC analysis. The EE% of DTG in DTG-CAP-NPs was evaluated to be â¼70%. The thermal sensitivity of the TMS gel was optimized and the pH dependency was evaluated by rheological analysis. DTG release studies in TMS gel revealed that DTG-CAP-NPs were stable in TMS gel at pH 4.2 while DTG-CAP-NPs in TMS gel at pH 7.4 rapidly release DTG (≥80% release within 1 h). Cytotoxicity studies using vaginal cell lines revealed that DTG-CAP-NPs were relatively non-cytotoxic at concentration <1 µg/mL. Confocal microscopic studies illustrate that ≥98% cells retained DTG-CAP-NPs intracellularly over seven days. Antiretroviral drug loaded nanocellulose fabrications in TMS gel delivered intravaginally may enhance both microbicidal and antiretroviral drug efficacy and may present a novel option for female PrEP against HIV.