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Paracoccidioidomycosis is endemic in subtropical rainforests of Latin America. Acute/subacute presentations involve an aggressive dissemination throughout the lymphatic system, while chronic forms (more frequent) arise as differential diagnosis for other conditions involving lung, oropharynx, skin, and eventually the brain. We present the case of a man referred for evaluation and treatment of a possible lung tumor with brain metastasis. The finding of multibudded yeasts and the microbiological isolation of a dimorphic fungus identified as Paracoccidioides sp. from a brain biopsy prompted a cardinal change in prognosis and treatment. This case alerts on the importance of considering systemic fungal diseases as differential diagnosis of compatible clinical presentations in patients who had lived in, or visited, endemic areas.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Paracoccidioidomicosis/diagnóstico , Biopsia , Diagnóstico Diferencial , Humanos , Inmunocompetencia , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
INTRODUCTION: Systemic and local therapies for patients with metastatic renal cell carcinoma (mRCC) are often challenging despite the evolution of multimodal cancer therapies in the last decade. In this review, we will focus on recent multidisciplinary approaches for patients with mRCC. AREAS COVERED: Systemic therapies for patients with mRCC have been garnering attention particularly after the approval of immuno-oncology (IO) agents, including anti-programmed death 1/programmed death-ligand 1. IO combinations have significantly prolonged overall survival in patients with mRCC in the first-line setting. Regarding local therapies, cytoreductive nephrectomy (CN) has become less common in the post-Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques (CARMENA) trial era, even though CN may still benefit selected patients with mRCC. In addition, metastasis-directed local therapies, namely metastasectomy or stereotactic radiotherapy, particularly for oligo-metastatic lesions or brain metastases, may have a prognostic impact. Several ablative techniques are also evolving while maintaining high local control rates with acceptable safety. EXPERT OPINION: Multimodal cancer therapies are essential for conquering complex cases of mRCC. Modern systemic therapies including IO-based combination therapy as well as local therapies including CN, metastasectomy, stereotactic radiotherapy, and ablative techniques appear to improve oncologic outcomes of patients with mRCC, although appropriate patient selection is indispensable.
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Carcinoma de Células Renales , Neoplasias Renales , Nefrectomía , Humanos , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/terapia , Neoplasias Renales/tratamiento farmacológico , Terapia Combinada , Nefrectomía/métodos , Tasa de Supervivencia , Pronóstico , Metástasis de la Neoplasia , Procedimientos Quirúrgicos de Citorreducción/métodos , Selección de Paciente , Radiocirugia/métodos , Metastasectomía/métodos , Inmunoterapia/métodosRESUMEN
BACKGROUND AND OBJECTIVE: Adjuvant pembrolizumab significantly improved overall survival (OS) in renal cell carcinoma (RCC), but real-world data on sequential treatment are scarce. We sought to evaluate the clinical outcomes of first-line (1L) systemic therapy following adjuvant immune oncology (IO)-based regimens. METHODS: A retrospective study including patients with recurrent RCC following adjuvant IO across 29 international institutions was conducted. The primary endpoint was progression-free survival (PFS) on 1L systemic therapy estimated using the Kaplan-Meier method. Preplanned subanalyses of clinical outcomes by type of 1L systemic therapy, recurrence timing, and International Metastatic RCC Database Consortium (IMDC) risk groups were performed. Treatment-related adverse events leading to treatment discontinuation, dose reduction, or corticosteroid use were assessed. KEY FINDINGS AND LIMITATIONS: A total of 94 patients were included. Most received adjuvant pembrolizumab (n = 37, 39%), atezolizumab (n = 28, 30%), or nivolumab + ipilimumab (n = 15, 16%). The cohort included 49 (52%) patients who had recurrence within 3 mo of the last adjuvant IO dose, whereas 45 (48%) recurred beyond 3 mo. Bone metastases were significantly higher in tumors recurring at <3 mo (10/49, 20%) than those recurring at >3 mo (1/45, 2.2%; p = 0.008). Most patients received 1L vascular endothelial growth factor-targeted therapy (VEGF-TT; n = 37, 39%), IO + VEGF-TT (n = 26, 28%), or IO + IO (n = 12, 13%). The remaining underwent local therapy. The median follow-up for the 1L systemic therapy cohort was 15 mo. The 18-mo PFS and OS rates were 45% (95% confidence interval [CI]: 34-60) and 85% (95% CI: 75-95), respectively. Treatment-related adverse events occurred in 32 (42%) patients and included skin toxicity (n = 7, 9.2%), fatigue (n = 6, 7.9%), and diarrhea/colitis (n = 4, 5.3%). Limitations included selecting patients from large academic centers and the short follow-up period. CONCLUSIONS AND CLINICAL IMPLICATIONS: A subset of patients with recurrent RCC following adjuvant IO respond to systemic therapies, including VEGF-TT and IO-based regimens. Notably, patients with favorable-risk disease may derive more benefit from VEGF-TT than from IO therapies in this setting. Future approaches utilizing radiographic tools and biomarker-based liquid biopsies are warranted to detect occult metastatic disease and identify candidate patients for adjuvant IO therapy. PATIENT SUMMARY: Adjuvant pembrolizumab significantly improved overall survival in renal cell carcinoma (RCC). There are limited data on clinical outcomes after the recurrence of RCC tumors following adjuvant immunotherapy. In this study, we find that patients respond to subsequent systemic therapies across different treatment options.
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Background: Previous studies with bipolar androgen therapy (BAT) have shown clinical activity in metastatic Castration Resistant Prostate Cancer (mCRPC) as well as the potential to re-sensitise prostate cancer cells to prior androgen receptor-targeted agents. None of these studies had tested BAT after chemotherapy. In this study, we gathered real-world evidence from three centres in Argentina where BAT is being used in castration-resistant prostate cancer (CRPC), not only prior to chemotherapy but also after several lines of treatment. Materials and methods: This retro-prospective nonrandomised multicentre cohort study included patients with mCRPC, who received BAT in different scenarios defined by the treating physician at three centres in Argentina. Results: A total of 21 asymptomatic patients with mCRPC were included. There was a median of two lines before BAT, with nine patients (42.8%) receiving three or more lines, and 13 patients (61.9%) receiving chemotherapy previously. Previous lines included next-generation hormonal agents (NHA) in 100% (abiraterone 33.3% and enzalutamide 71.4%), chemotherapy in 61.9%, Radium-223 in 47.6% and others in 4.8%. The progression free survival (PFS) after BAT was 3.5 months (95% CI: 3.06-7.97). PSA50 response rate (RR) was 28.5% and the overall RR was 14.3%. Of the 17 patients who had disease progression, 9 had a rechallenge to NHA, achieving a 55% RR, 6 received other treatment (chemotherapy in 5 and 177Lu-PSMA in 1) with a 66% RR and 2 best supportive care. The PFS2, calculated after the initiation of BAT in the 15 patients who received further therapy, was 7.93 months (95% CI: 6.73-NR). Treatment was overall well tolerated, with only two patients requiring hospitalisation and treatment interruption due to worsening pain. Conclusion: To the authors' knowledge, this is the first publication of BAT in later lines of therapy in mCRPC. BAT showed clinical activity in this scenario. Our data supports that BAT may play a role in CRPC re-sensitisation after multiple treatment lines.
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PURPOSE: In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair-related genes. PATIENTS AND METHODS: We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair-related genes (gBRCA1/2-ATM-CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS: Among the total population (n = 217), 15 (6.9%) patients carried gBRCA1/2 (n = 10)-ATM (n = 4)-CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger (P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group (P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival (P = .020) and overall survival (P = .012). CONCLUSION: In this retrospective real-world study, gBRCA1/2-ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.
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Neoplasias de la Mama , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/genética , Reparación del ADN/genética , Femenino , Células Germinativas/metabolismo , Humanos , Estudios RetrospectivosRESUMEN
Poly (ADP-ribose) polymerase (PARP) inhibitors (iPARPs) have shown efficacy in homologous recombination (HR) deficiency patients with advanced castration resistant prostate cancer and have shown a radiosensitizing effect in preclinical and early clinical trials. Preclinical data in prostate cancer cells suggest a similar cytotoxic effect with half the radiation dose under the effect of Olaparib or Rucaparib irrespective of HR status. Due to the biologic synergy of radiotherapy (RT) and iPARPs, the risk of recurrence of high-risk prostate cancer and the morbidity associated with prostate cancer local treatment, this interesting strategy seems promising, and a better understanding of the clinical implications remains to be elucidated.