Hedgehog components are overexpressed in a series of liver cancer cases.

Liver cancers, including hepatocellular carcinoma (HCC), are the sixth most common cancer and the third leading cause of cancer-related death worldwide, representing a global public health problem. This study evaluated nine patients with HCC. Six of the cases involved hepatic explants, and three involved hepatic segmentectomy for tumor resection. Eight out of nine tumors were HCC, with one being a combined hepatocellular-cholangiocarcinoma tumor. Conventional markers of hepatocellular differentiation (Hep Par-1, arginase, pCEA, and glutamine synthetase) were positive in all patients, while markers of hepatic precursor cells (CK19, CK7, EpCAM, and CD56) were negative in most patients, and when positive, they were detected in small, isolated foci. Based on in silico analysis of HCC tumors from The Cancer Genome Atlas database, we found that Hedgehog (HH) pathway components (GLI1, GLI2, GLI3 and GAS1) have high connectivity values (module membership > 0.7) and are strongly correlated with each other and with other genes in biologically relevant modules for HCC. We further validated this finding by analyzing the gene expression of HH components (PTCH1, GLI1, GLI2 and GLI3) in our samples through qPCR, as well as by immunohistochemical analysis. Additionally, we conducted a chemosensitivity analysis using primary HCC cultures treated with a panel of 18 drugs that affect the HH pathway and/or HCC. Most HCC samples were sensitive to sunitinib. Our results offer a comprehensive view of the molecular landscape of HCC, highlighting the significance of the HH pathway and providing insight into focused treatments for HCC.

Advanced renal cell carcinoma management: the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG) consensus update.

PURPOSE: Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS: A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS: Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION: Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.

SEOM SOGUG clinical guideline for treatment of kidney cancer (2022).

Renal cancer is the seventh most common cancer in men and the tenth in women. The aim of this article is to review the diagnosis, treatment, and follow-up of renal carcinoma accompanied by recommendations with new evidence and treatment algorithms. A new pathologic classification of RCC by the World Health Organization (WHO) was published in 2022 and this classification would be considered a "bridge" to a future molecular classification. For patients with localized disease, surgery is the treatment of choice with nephron-sparing surgery recommended when feasible. Adjuvant treatment with pembrolizumab is an option for intermediate-or high-risk cases, as well as patients after complete resection of metastatic disease. More data are needed in the future, including positive overall survival data. Clinical prognostic classification, preferably IMDC, should be used for treatment decision making in mRCC. Cytoreductive nephrectomy should not be deemed mandatory in individuals with intermediate-poor IMDC/MSKCC risk who require systemic therapy. Metastasectomy can be contemplated in selected subjects with a limited number of metastases or long metachronous disease-free interval. For the population of patients with metastatic ccRCC as a whole, the combination of pembrolizumab-axitinib, nivolumab-cabozantinib, or pembrolizumab-lenvatinib can be considered as the first option based on the benefit obtained in OS versus sunitinib. In cases that have an intermediate IMDC and poor prognosis, the combination of ipilimumab and nivolumab has demonstrated superior OS compared to sunitinib. As for individuals with advanced RCC previously treated with one or two antiangiogenic tyrosine-kinase inhibitors, nivolumab and cabozantinib are the options of choice. When there is progression following initial immunotherapy-based treatment, we recommend treatment with an antiangiogenic tyrosine-kinase inhibitor. While no clear sequence can be advocated, medical oncologists and patients should be aware of the recent advances and new strategies that improve survival and quality of life in the setting of metastatic RC.

Exploring the cell death mechanisms of cytotoxic [1,2,3]triazolylcarborane lead compounds against U87 MG human glioblastoma cells.

Moving towards high-grade glioma drug discovery, this study aimed to detect the mechanism of cellular death (apoptosis, necrosis and/or autophagy) induced by three carboranyl-based lead compounds. For that, we performed in U87 MG cells, flow cytometry experiments, as the gold standard technique, as well as confocal microscopy and 1 H-NMR experiments as non-invasive assays. We selected three hybrid leads (1-3) from the in-house-library and the corresponding parent compounds, and recognized tyrosine kinase inhibitors (lapatinib, sunitinib and erlotinib) to put to the test in these experiments. Flow cytometry with Annexin V-FITC/DAPI staining showed that leads 1 and 3 and lapatinib mainly induced necrosis in U87 MG upon a 24 h treatment at IC50 dose; meanwhile, hybrid 2, sunitinib and erlotinib seem to induce apoptosis in such cells. In general, confocal microscopy studies were in agreement with flow cytometry observing loss of cell membrane integrity in necrotic cells and features of apoptosis, that is, chromatin condensation, in apoptotic cells. Finally, NMR results showed that glioblastoma cells treated with hybrid 1, 3 or lapatinib displayed changes in CH2 /CH3 signal ratio and choline signals that could indicate necrotic cell death mechanism: meanwhile, 2-, sunitinib- or erlotinib-treated cells showed apoptotic characteristic behaviors. Additionally, carboranyl-hybrid 2 also produced autophagy in U87 MG cells.

Pre-clinical safety of topically administered sunitinib-loaded lipid and polymeric nanocarriers targeting corneal neovascularization.

Three different types of sunitinib-loaded (SUN-loaded) nanocarriers were compared, aiming at the topical treatment of corneal neovascularization (CNV): polymeric nanospheres (NS), liposomes (LIP), and solid lipid nanoparticles (SLN). Three out of eleven formulations prepared for an optimization study - the best SUN-loaded nanocarrier of each assessed type (NS, LIP, and SLN) - were selected, based on their size, polydispersity index (PdI), drug load (DL), and encapsulation efficiency (EE). These three optimal formulations were further characterized by nanoparticle tracking analysis (NTA), electron paramagnetic resonance (EPR) spectroscopy, and zeta potential. In vitro SUN release profiles were obtained for the optimal formulations, along with ex vivo corneal permeability/retention studies, and ocular tolerance assays, namely: the bovine corneal opacity and permeability (BCOP) assay, the HET-CAM test (hen's egg test - chorioallantoic membrane), and hemolytic potential (HP) assay. None of the optimal formulations exhibited toxicity or potential for ocular irritation. SLN showed higher surface fluidity, drug release more suitable for topical ocular applications, besides greater SUN corneal retention. Our results suggest that SLN are the best CNV-targeting SUN-loaded nanocarriers for clinical translation when compared to their NS and LIP analogues.

Effect of tyrosine kinase inhibitor sunitinib on tissue repair at tooth extraction sites.

BACKGROUND: Both zoledronic acid, a potent bisphosphonate, and the antiangiogenic drug sunitinib are included in anticancer protocols and have also been associated with jaw osteonecrosis. Our aim was to compare the effect of these drugs on tissue repair at tooth extraction sites. METHODS: Wistar rats were allocated into four groups: (1) sunitinib; (2) sunitinib/zoledronic acid; (3) zoledronic acid; (4) control group. The animals underwent tooth extractions and maxillae were macro- and microscopically analyzed. RESULTS: On macroscopic evaluation, the zoledronic acid group showed a significantly higher frequency of oral mucosal lesion; lesions in the sunitinib/zoledronic acid group were larger, albeit not significantly so. The sunitinib/zoledronic acid group had significantly less epithelium than the zoledronic acid and control group, but showed no significant difference compared to the sunitinib group. The sunitinib/zoledronic acid and zoledronic acid groups did not differ from each other, but had significantly less connective tissue and more non-vital bone and microbial colonies than sunitinib and control groups, whereas these latter two groups did not significantly differ from each other. Vital bone and inflammatory infiltrate did not significantly differ between groups. CONCLUSION: Sunitinib alone is not associated with non-vital bone, whereas the sunitinib/zoledronic acid combination and zoledronic acid alone are.

Prognostic significance of telomerase reverse transcriptase promoter gen mutations in high grade meningiomas / Importancia pronóstica de las mutaciones del gen promotor de la transcriptasa inversa de la telomerasa en los meningiomas de alto grado

Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic importance of telomerase reverse transcriptase mutations in Colombian patients with grades II and III meningioma. Materials and methods: This was a multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grades II and III meningiomas, recruited between 2011 and 2018, and treated with systemic therapy (sunitinib, everolimus ± octreotide, and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was established by PCR. Results: Forty patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), being C228T and C250T the most frequent variants with 87.5 % and 14.3 %, respectively. These were more frequent among patients with anaplastic meningiomas (p=0.18), with more than 2 recurrences (p=0.04); and in patients with parasagittal region and anterior fossa lesions (p=0.05). Subjects characterized as having punctual mutations were more frequently administered with everolimus, sunitinib and bevacizumab drug series (p=0.06). Overall survival was 23.7 months (CI95% 13.1-34.2) and 43.4 months (CI95% 37.5-49.3; p=0.0001) between subjects with and without mutations, respectively. Multivariate analysis showed that the number of recurrences and the presence of telomerase reverse transcriptase mutations were tthe only variables that negatively affected overall survival. Conclusions: Mutations in telomerase reverse transcriptase allows the identification of high-risk patients and could be useful in the selection of the best medical treatment.

Introducción. En los meningiomas, ocurren con frecuencia mutaciones en la región promotora de la transcriptasa inversa de la telomerasa. Objetivo. Estimar la importancia pronóstica de las mutaciones de la transcriptasa inversa de la telomerasa en pacientes colombianos con meningiomas de grados II y III. Materiales y métodos. Es un estudio de cohorte, retrospectivo y multicéntrico, que incluyó pacientes con diagnóstico de meningioma persistente o recidivante, de grados II y III, según la clasificación de la OMS, reclutados entre el 2011 y el 2018, con tratamiento sistémico (sunitinib, everolimus con octreótido o sin él, y bevacizumab). El estado de la mutación del promotor de la transcriptasa inversa de la telomerasa se determinó por medio de la PCR. Resultados. Se incluyeron 40 pacientes, en 21 (52,5 %) de los cuales se encontraron mutaciones en la transcriptasa inversa de la telomerasa, siendo las variantes más frecuentes la C228T (87,5 %) y la C250T (14,3 %). Estas fueron más frecuentes entre los pacientes con meningiomas anaplásicos (p=0,18), en aquellos con más de dos recurrencias (p=0,04), y en los que presentaron lesiones en la región parasagital y la fosa anterior (p=0,05). Los sujetos caracterizados por tener alteraciones puntuales fueron tratados con mayor frecuencia con la serie de medicamentos everolimus, sunitinib y bevacizumab (p=0,06). Tras el inicio del tratamiento médico, la supervivencia global fue de 23,7 meses (IC95% 13,1-34,2) en los pacientes con mutaciones y, de 43,4 meses (IC95% 37,5-49,3), entre aquellos sin mutaciones (p=0,0001). Los resultados del análisis multivariado demostraron que, únicamente, el número de recurrencias y la presencia de mutaciones en el gen de la transcriptasa inversa de la telomerasa, fueron factores que afectaron negativamente la supervivencia global. Conclusiones. Las mutaciones en el gen promotor de la transcriptasa inversa de la telomerasa permiten identificar los pacientes con alto riesgo, cuya detección podría ser de utilidad para seleccionar el mejor esquema terapéutico.

Avances en tumores del estroma gastrointestinal: ¿hacia dónde vamos?

Gastrointestinal Stromal Sarcomas (GIST) are mesenchymal neoplasms whose incidence accounts for 1-2% of digestive tumors, being located in the stomach (55-60%) and small intestine (30%). The advances in its knowledge and management succeeded in the last years have being spectacular. This review aims to summarize the most important of them for surgeons. We identified four areas of interest: molecular oncology, laparoscopic approach, management of GIST located at unusual locations, and management of advanced GIST. Advances in the field of molecular oncology lead to the discovery of new oncogenic mutations making the term Wil Type GIST obsolete. Moreover, these advances allow for the development of 2 new drugs: Avapritinib and Ripretinib, that added to the previous 3 commercially available drugs (imatinib, sunitinib and regorafenib) make possible the management of GIST with resistant mutations. The principles of the surgical management of primary GIST are well stablished which laparoscopic approach must accomplish. This approach is limited by 2 main factors: location and size. The diagnosis of GIST in unusual locations as esophagus, duodenum, rectum of out of the gastrointestinal tract (EGIST), implies an extraordinary therapeutic challenge, being imperative to manage them by surgeons and oncologist among others in the setting of a multidisciplinary team. The management of advanced/metastatic GIST has changed in a revolutionary fashion because surgery is now part of its treatment as adjuvant to tyrosine kinase inhibitors.

Los tumores del estroma gastrointestinal (GIST) suponen el 1-2% de los tumores digestivos, siendo su localización más frecuente el estómago (55-60%) y el intestino delgado (30%). Los avances más importantes sucedidos en los últimos años se centran en cuatro áreas: biología molecular, abordaje quirúrgico laparoscópico, manejo técnico del GIST en localizaciones inusuales y tratamiento e integración de la cirugía en el manejo del GIST avanzado. Los avances en el conocimiento de la biología molecular del GIST han dado lugar a la progresiva identificación de nueva mutaciones oncogénicas que hacen del concepto wild type obsoleto. Estos avances han permitido el desarrollo de dos nuevos fármacos, avapritinib y ripretinib, lo que permite el tratamiento de pacientes con mutaciones resistentes a las tres líneas terapéuticas clásicas. El tratamiento quirúrgico del GIST se rige por unos principios técnicos bien establecidos que el abordaje laparoscópico debe cumplir, abordaje que queda limitado por dos factores clave: localización y tamaño. El GIST de localización infrecuente (esófago, duodeno o recto, o extradigestivo) supone un reto terapéutico. Estos pacientes deben ser manejados en un contexto multidisciplinario. La cirugía queda integrada en el manejo del GIST avanzado, considerándose como adyuvante a los inhibidores de la tirosina cinasa.

Sunitinib induced resistance of endothelial cells by up-regulating P-glycoprotein and PI3K/Akt pathway

Abstract Drug resistance is a crucial obstacle to achieve satisfactory chemotherapeutic effects. Numerous studies have shown that the PI3K/Akt signaling pathway plays a significant role in various processes of cellular events and tumor progression, while few studies have focused on the PI3K/Akt signaling pathway in drug resistance of endothelial cells. The present study aims to explore the relationship of PI3K/Akt signaling and cellular resistance to anticancer drugs in human microvessel endothelial cells (HMEC-1). We established stable sunitinib-resiatant human microvessel endothelial cells (HMEC-su) after long-term exposure to sunitinib (a small-molecule tyrosine kinase receptor inhibitor) for 12 months. HMEC-su showed significant alternations of cell morphology and exhibited a 2.32-fold higher IC50 of sunitinib than parental HMEC-1 cells. Expression of P-glycoprotein (P-gp) and breast cancer-resistance protein (ABCG2) which mediates drug efflux, increased significantly in HMEC-su lines compared with HMEC-1 cells by western blots assay. Our study further demonstrates that LY294002 (blocking the PI3K/Akt pathway) enhances the sensibility of HMEC-su to suntinib and inhibits the gene transcription and protein expression of P-gp, ABCG2 in HMEC-su cells. In conclusion, these results indicate that LY294002 could reverse P-gp and ABCG2 mediated-drug resistance to sunitinib in HMEC-su cells by inhibiting PI3K/Akt signaling.

Influence of treatment access on survival of metastatic renal cell carcinoma in brazilian cancer center

ABSTRACT Background: Tyrosine kinase inhibitors (TKI) and immunotherapy improved survival in metastatic renal cell carcinoma (mRCC). Disparities in treatment access are present in healthcare systems globally. The aim of this study was to analyze survival outcomes of mRCC patients treated with first-line TKIs in the public (PHS) and private (PrS) health system in a Brazilian Cancer Center. Materials and Methods: Records from all mRCC patients treated with first-line TKIs from 2007-2018 were reviewed retrospectively. Categorial variables were compared by Fisher's exact test. Survival was estimated by Kaplan-Maier method and survival curves were compared using the log-rank test. Prognostic factors were adjusted by Cox regression model. Results: Of the 171 eligible patients, 37 (21.6%) were PHS patients and 134 (78.4%) were PrS patients. There were no difference in age, gender, or sites of metastasis. PHS patients had worse performance status (ECOG ≥2, 35.1% vs. 13.5%, p=0.007), poorer risk score (IMDC poor risk, 32.4% vs. 16.4%, p=0.09), and less nephrectomies (73% vs. 92.5%, p=0.003) than PrS patients. Median lines of therapy was one for PHS versus two for PrS patients (p=0.03). Median overall survival (OS) was 16.5 versus 26.5 months (p=0.002) and progression-free survival (PFS), 8.4 versus 11 months (p=0.01) for PHS and PrS patients, respectively. After adjusting for known prognostic factors on multivariate analysis, PHS patients still had a higher risk of death (HR: 1.61, 95% CI: 1.01-2.56, p=0.047). Conclusion: Patients with mRCC treated via the PHS had worse overall survival, possibly due to poorer prognosis at presentation and less drug access.

Hand-Foot Skin Reaction Secondary to Sunitinib in a Patient With Metastatic Clear Cell Renal Cell Carcinoma.

A man, age 45 years, was diagnosed with intermediate-risk stage IV clear cell renal carcinoma (lung and lymph node metastases). He was prescribed first-line systemic treatment with sunitinib (Sutent) 50 mg per day (each cycle: 4 weeks on, 2 weeks off). Upon day 22 of his second sunitinib cycle, he came to the oncology clinic complaining of difficulty walking due to bilateral sole pain. He described initial tingling sensations, which then became burning and painful, with symmetrical erythema and edema of the soles, without blisters. These turned into painful plaques with yellowish discoloration and hyperkeratosis on pressure-bearing areas. He denied fever or other symptoms. The pain limited his instrumental activities of daily living, but not his self-care activities of daily living. Total body skin examination disclosed hyperkeratotic plaques on the undersurface of the great toes and heels of both feet, predominantly at sites of pressure; no blisters, crusts, ulcers, or fissures were found. No relevant findings were found upon physical examination of his hands, mucosae, and scalp. A diagnosis of grade 2 hand-foot skin reaction (HFSR) was made.

Do we need skin toxicity? Association of immune checkpoint inhibitor and tyrosine kinase inhibitor-related cutaneous adverse events with outcomes in metastatic renal cell carcinoma.

INTRODUCTION: Skin toxicity is a common, expected side effect of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) used for metastatic renal cell carcinoma (mRCC). We evaluated the association between skin toxicity and clinical efficacy outcomes of these agents in mRCC patients. METHODS AND MATERIALS: Data were obtained from patients with mRCC treated with TKIs and/or ICIs from 2016-2019 at a referral hospital in Mexico City. Clinical outcomes were compared among patients who developed treatment-related cutaneous adverse events (AEs) and those without skin toxicity. RESULTS: Thirty-five patients with mRCC were identified who were treated with sunitinib (51.4%), nivolumab plus cabozantinib (28.6%), nivolumab monotherapy (17.1%), or ipilimumab plus nivolumab plus cabozantinib (2.9%). Any grade skin toxicity was seen in 65.7% of patients. With a median follow-up of 14 months, radiological responses were as follows: 48.6% stable disease, 25.7% partial response, and 2.8% complete response. Compared to subjects without skin toxicity, patients who developed cutaneous AEs had higher disease control rate 91.3% vs. 50.0% (P = 0.019) and superior 12-month overall survival rate 91% vs. 67% (P = 0.01), respectively. There was a trend toward improved median progression-free survival (16 months vs. 5 months, P = 0.13). Grade 1-2 cutaneous toxicity was found to be predictive for disease control, with HR 2.72 (95% CI 1.1-6.71, P = 0.030), and all grade cutaneous toxicity was prognostic of overall survival, with HR 0.18 (95% CI 0.04-0.91, P = 0.039). CONCLUSION: Cutaneous AEs are associated with improved overall survival and response in patients with mRCC treated with immunotherapy and/or TKIs.

Pembrolizumab plus axitinib and nivolumab plus ipilimumab as first-line treatments of advanced intermediate- or poor-risk renal-cell carcinoma: a number needed to treat analysis from the Brazilian private perspective.

BACKGROUND: Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. METHODS: Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. RESULTS: Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,773,865 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,773,865 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. CONCLUSION: At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.

Influence of treatment access on survival of metastatic renal cell carcinoma in brazilian cancer center.

BACKGROUND: Tyrosine kinase inhibitors (TKI) and immunotherapy improved survival in metastatic renal cell carcinoma (mRCC). Disparities in treatment access are present in healthcare systems globally. The aim of this study was to analyze survival outcomes of mRCC patients treated with first-line TKIs in the public (PHS) and private (PrS) health system in a Brazilian Cancer Center. MATERIALS AND METHODS: Records from all mRCC patients treated with first-line TKIs from 2007-2018 were reviewed retrospectively. Categorial variables were compared by Fisher's exact test. Survival was estimated by Kaplan-Maier method and survival curves were compared using the log-rank test. Prognostic factors were adjusted by Cox regression model. RESULTS: Of the 171 eligible patients, 37 (21.6%) were PHS patients and 134 (78.4%) were PrS patients. There were no difference in age, gender, or sites of metastasis. PHS patients had worse performance status (ECOG ≥2, 35.1% vs. 13.5%, p=0.007), poorer risk score (IMDC poor risk, 32.4% vs. 16.4%, p=0.09), and less nephrectomies (73% vs. 92.5%, p=0.003) than PrS patients. Median lines of therapy was one for PHS versus two for PrS patients (p=0.03). Median overall survival (OS) was 16.5 versus 26.5 months (p=0.002) and progression-free survival (PFS), 8.4 versus 11 months (p=0.01) for PHS and PrS patients, respectively. After adjusting for known prognostic factors on multivariate analysis, PHS patients still had a higher risk of death (HR: 1.61, 95% CI: 1.01-2.56, p=0.047). CONCLUSION: Patients with mRCC treated via the PHS had worse overall survival, possibly due to poorer prognosis at presentation and less drug access.

Eficacia y seguridad de pazopanib para el tratamiento de pacientes adultos con carcinoma renal de células claras recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea / Efficacy and safety of pazopanib for the treatment of adult patients with recurrent/metastatic clear cell renal cell carcinoma intolerant to sunitinib as first-line treatment

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de pazopanib comparado con interferón alfa 2a (IFNα 2a) para el tratamiento de pacientes adultos con carcinoma renal de células claras recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea. El carcinoma de células renales (CCR) es el tipo más frecuente de cáncer renal y se origina en el revestimiento de los túbulos del riñón dentro de la corteza renal. Representa un 80-85 % de todos los tumores malignos renales. El CCR de células claras (CCRCC) es el subtipo histológico más frecuente (80 %), generalmente tiene una deleción del cromosoma 3p y surgen del túbulo proximal. Los pacientes con CCRCC metastásico, se encuentran en la etapa más avanzada de la enfermedad y la sobrevida a 5 años es menor al 10 %. Por otro lado, en los pacientes con CCRCC recurrente, la neoplasia puede reaparecer en el riñón o en otras partes del cuerpo incluso años después del tratamiento inicial. Aproximadamente, en el 20-30 % de los pacientes con tumores localizados se produce recurrencia/metástasis luego del tratamiento quirúrgico. El tratamiento de los pacientes con CCRCC recurrente/metastásico es principalmente la terapia sistémica; cuya finalidad es conseguir remisión o impedir la progresión de la enfermedad. La terapia sistémica incluye el tratamiento con medicamentos biológicos (inmunoterapia) y/o inhibidores de puntos de control (IPC) específicos. Los IPC específicos son el IPC del ligando 1 de muerte celular (PD-L1) y el inhibidor del factor de crecimiento endotelial vascular (VEGF, por sus siglas en inglés). Actualmente, la terapia sistémica con interleucina 2 (IL-2) e interferón alfa 2a (IFNα2a) se usa con menos frecuencia. En el contexto de EsSalud, a la fecha, los pacientes con CCRCC recurrente/metastásico tienen a su disposición medicamentos para terapia sistémica tales como sunitinib e IFNα2a. Sunitinib es un inhibidor de los receptores de VEGF y del factor de crecimiento derivado de plaquetas en las células cancerígenas, células endoteliales vasculares y pericitos, inhibiendo la proliferación de células tumorales y el desarrollo de vasos sanguíneos tumorales. Sunitinib tiene autorización de uso en el Perú desde el 2008 y ha sido aprobado por Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) - EsSalud en el 2015 como tratamiento de primera línea en pacientes con CCR metastásico. Sin embargo, algunos pacientes con CCRCC recurrente/metastásico presentan intolerancia a la terapia con sunitinib, por lo que los especialistas de la institución sugieren el uso de pazopanib como opción de tratamiento a fin de lograr el control de la enfermedad. Los especialistas sugieren que pazopanib sería la opción de tratamiento más adecuada en términos de eficacia y seguridad, comparado con IFNα2a (la otra alternativa de tratamiento disponible en EsSalud). METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con el objetivo de identificar la mejor evidencia sobre eficacia y seguridad de pazopanib comparado con IFNα 2a para el tratamiento de pacientes adultos con CCRCC recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea. Se utilizaron las bases de datos The Cochrane Library, PubMed, LILACS y el metabuscador TRIP Database, priorizando evidencia proveniente de ensayos clínicos controlados aleatorizados. La búsqueda sistemática se basó en una metodología escalonada, la cual consistió en la búsqueda inicial de estudios secundarios (de tipo revisiones sistemáticas de ensayos clínicos) que respondan a la pregunta PICO, seguido de la búsqueda de estudios primarios (de tipo ensayos clínicos aleatorizados). Asimismo, se realizó una búsqueda manual dentro de las bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias y guías de práctica clínica (GPC) incluyendo la National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Institute for Clinical and Economic Review (ICER), The Institute for Quality and Efficiency in Healthcare (IQWiG por sus siglas en alemán), Base regional de informes de evaluación de tecnologías en salud de las Américas (BRISA) y páginas web de organizaciones especializadas en el manejo de CCR. Se realizó una búsqueda adicional en la página web de clinicaltrial.gov para poder identificar ensayos clínicos en curso, corroborar los resultados y eventos adversos (EA) reportados en las publicaciones. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de pazopanib como tratamiento de pacientes adultos con CCRCC recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea. La presente sinopsis describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS con o sin metaanálisis o metaanálisis en red y estudios primarios). CONCLUSIONES: Previamente, IETSI aprobó el uso de sunitinib como tratamiento de primera línea para pacientes con CCRCC recurrente/metastásico, concluyendo que sunitinib presenta mayor eficacia y similar perfil seguridad que IFNα2a. Asimismo, evaluó pazopanib vs sunitinib, concluyendo que ambos medicamentos tendrían similar eficacia y seguridad, por lo que teniendo aprobado a sunitinib como medicamento fuera de petitorio, no se aprobó el uso de pazopanib. Actualmente, en el contexto de EsSalud, se tiene la necesidad de una alternativa de tratamiento para aquellos pacientes con intolerancia a sunitinib. Así, considerando que sunitinib es superior a IFNα2a y que pazopanib sería similar a sunitinib, los especialistas consideran a pazopanib como una alternativa de tratamiento para aquellos pacientes con intolerancia a sunitinib. El presente dictamen evaluó la mejor evidencia disponible en torno a la eficacia y seguridad de pazopanib, comparado con IFNα2a, para el tratamiento de pacientes adultos con CCRCC recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea. Se identificaron tres GPC elaboradas por NCCN, EUA y ESMO que formularon recomendaciones sobre el tratamiento de pacientes con CCRCC recurrente/metastásico en el contexto de primera línea de tratamiento; una ETS, desarrollada por CADTH, que comparó pazopanib con sunitinib en pacientes CCRCC metastásico en el contexto de primera línea y una RSNWMA. Así, considerando: i) todas las GPC recomiendan el uso de pazopanib, especialmente para aquellos con mejor nivel pronóstico, pero no presentan a IFNα2a como parte de las alternativas de tratamiento, ii) la evidencia procedente de una RSNWMA sugiere que pazopanib tiene mayor eficacia y similar perfil de seguridad que IFNα2a, iii) todas las GPC recomendaron pazopanib y sunitinib (actual primera línea tratamiento disponible en EsSalud) en el mismo grado de recomendación, iv) el antecedente de evaluación de medicamentos para el tratamiento de CCRCC recurrente/metastásico realizados por el IETSI refiere que pazopanib es no inferior a sunitinib en términos de eficacia y seguridad; v) la necesidad de tratamiento para los pacientes con CCRCC recurrente/metastásico e intolerantes a sunitinib y vi) los costos del tratamiento a un año con pazopanib serían similares o incluso menores al costo de la terapia con sunitinib (actual primera línea tratamiento disponible en EsSalud), podemos concluir que pazopanib podría considerarse como una alternativa de tratamiento para el control de los pacientes con CCRCC recurrente/metastásico intolerante a sunitinib. Por lo expuesto, el IETSI aprueba el uso de pazopanib en pacientes con CCRCC recurrente/metastásico con intolerancia a sunitinib, según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Sorafenib as a second-line treatment in metastatic renal cell carcinoma in Mexico: a prospective cohort study.

BACKGROUND: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a second-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI). METHODS: A prospective observational cohort in Mexico (2012-2019). We included 132 subjects with metastatic RCC and who had progression despite treatment with sunitinib. The primary end-point was time to disease progression as evaluated every 12-16 weeks. RESULTS: The mean age of the cohort was 59 years (interquartile range [IQR] 50-72), 96 (73%) were men, and 48 (36%) had a favorable prognosis according to the IMDC (International Metastatic RCC Database Consortium) prognostic model. The median progression-free survival (PFS) and overall-survival after the introduction of sorafenib treatment was 8.6 months (95% confidence interval [CI]: 6.7-10.5) and 40 months (95% CI: 34.5-45.4) respectively. The median overall survival from RCC diagnosis to death was 71 months (95% CI: 58.2-83.8). On multivariable analyses, age > 65 years was associated with a longer PFS (HR 0.51; 95% CI: 0.31-0.86; p = 0.018). The median PFS in subjects aged > 65 years was longer compared to subjects ≤65 years (14.0 [95% CI: 9.2-18.8] vs. 7.2 months [95% CI: 5.3-9.1]; p = 0.012). Adverse events grade ≥ 3 associated with sorafenib occurred in 38 (29%) patients. CONCLUSION: Sequential inhibition of VEGF with sorafenib as a second-line treatment may benefit patients with metastatic RCC, especially in subjects > 65 years old.

Actualización de medicamentos asociados a necrosis avascular de los maxilares: perspectiva y revisión de literatura / Update of medications associated with avascular necrosis of the jaws: a perspective and literature review

La osteonecrosis de los maxilares está definida como la exposición de hueso necrótico en la región maxilofacial al menos por ocho semanas en pacientes que están recibiendo medicamentos antirresortivos para el tratamiento del cáncer primario o metastásico hacia el hueso, osteoporosis o enfermedad de Paget, sin historia previa de radiación. Desde el año 2003, la terminología utilizada estaba en relación con los bifosfonatos, en la actualidad ha sido introducido el término osteonecrosis de los maxilares relacionada por medicamentos (OMAM). La cirugía oral (implantología o cirugía periapical) incrementa el riesgo de OMAM, así como los desbalances concomitantes de la salud oral (inflamación dental y formación de abscesos). Las estrategias conservadoras en el tratamiento varían desde el cuidado local conservador hasta la resección quirúrgica radical del hueso necrótico. En el presente artículo se expone un análisis sistemático retrospectivo de la literatura en páginas como PubMed, ScienceDirect y Springer, Cochrane Library. Con el objetivo de resaltar el aumento de la incidencia de OMAM a nivel mundial con el uso de antirresortivos y otros medicamentos asociados en su patogenia en el Hospital Regional «General Ignacio Zaragoza¼ del ISSSTE, UNAM, en la Ciudad de México (AU)

Osteonecrosis of the jaws is defined as the exposure of necrotic bone in the maxillofacial region for at least 8 weeks in patients receiving antiresorptive medications for the treatment of primary or metastatic cancer towards the bone, osteoporosis, or Paget's disease, without previous history of radiation. Since 2003, the terminology used was related to bisphosphonates, the term medication-related osteonecrosis of the jaws has now been introduced. Oral surgery (implantology or periapical surgery) increases the risk of avascular necrosis, as well as concomitant imbalances in oral health (dental inflammation and abscess formation). Conservative strategies in treatment vary from conservative local care to radical surgical resection of the necrotic bone. In this article, a systematic retrospective analysis of the literature is presented on pages such as PubMed, Science Direct and Springer, Cochrane Library. And in which the objective is to highlight the increase in the incidence of medication related osteonecrosis of the jaws worldwide with the use of antiresorptive, and other associated medications in its pathogenesis at the Hospital Regional «General Ignacio Zaragoza¼ ISSSTE, UNAM in Mexico City (AU)

Prognostic Value of Systemic Inflammatory Biomarkers in Patients with Metastatic Renal Cell Carcinoma.

Metastatic renal cell carcinoma (mRCC) encompasses a heterogeneous group of neoplasms with distinct clinical behavior and prognoses. As a result of the increasing number of therapeutic options in the metastatic setting, it is crucial to improve prognostic stratification ability. We aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and combination platelet count and neutrophil lymphocyte ratio (COP-NLR) in patients with mRCC. We evaluated a cohort of mRCC patients treated with first-line pazopanib or sunitinib. Levels of NLR, PLR and COP-NLR were measured prior to systemic treatment and evaluated as prognostic predictors. Primary endpoint was overall survival (OS). Data from 276 patients were included, of which 54.7% received first-line pazopanib and 45.3%, sunitinib. Memorial Sloan-Kettering Cancer Center risk classification was intermediate and poor in 50% and 42.6% of patients, respectively. High NLR (> 3.5) was associated with inferior OS (median 9.6 vs 17.8 months, P < 0.001). A high PLR (> 200) was associated with inferior OS (median 10.3 vs 17 months, P = 0.002). The median OS in the COP-NLR 1, 2 and 3 groups were 19.0 months (95% CI 15.3-26.0), 13.1 months (95% CI 9.8-17.0) and 7.4 months (95% CI 3.6-11.9), respectively (P < 0.001). In the multivariate analysis, high NLR and high COP-NLR were associated with inferior OS. Both high NLR and high COP-NLR were associated with poorer OS in our cohort of patients with mRCC treated with first-line pazopanib or sunitinib.

[Cost-effectiveness between pazopanib and sunitinib for metastatic renal cancer from the perspective of the Brazilian Unified National Health System]. / Custo-efetividade do pazopanibe comparado ao sunitinibe para câncer renal metastático na perspectiva de um hospital do Sistema Único de Saúde.

Renal cancer is the 13th most frequent neoplasm in the world. From 2010 to 2014, renal cancer accounted for 1.43% of cancer deaths in Brazil. The treatment of choice for metastatic renal cancer is tyrosine kinase inhibitors (TKI) sunitinib and pazopanib. This article assesses cost-effectiveness between pazopanib and sunitinib in the treatment of metastatic renal cancer. A cost-effectiveness study was performed from the perspective of a federal hospital under the Brazilian Unified National Health System (SUS). TKI effectiveness and safety outcomes were applied to the decision tree model. Clinical data were extracted from patient charts, and direct costs were consulted from official Ministry of Health sources. The cost of 10 months of treatment, including the costs of the TKI, procedures and management of adverse events, was BRL 98,677.19 for pazopanib and BRL 155,227.11 for sunitinib. The drugs displayed statistically equivalent effectiveness and statistically different safety outcomes, with pazopanib displaying better results. In this setting, pazopanib is the dominant technology when the treatment costs are analyzed together with the costs of managing adverse events.

O câncer renal é a 13ª neoplasia mais frequente no mundo. Entre 2012 e 2016, representou 1,48% das mortes por câncer no Brasil. A terapia de escolha para o tratamento de câncer renal metastático são os inibidores de tirosina quinase (ITK), sunitinibe e pazopanibe. Este artigo avalia o custo-efetividade do pazopanibe comparado ao sunitinibe no tratamento de câncer renal metastático. Foi realizada uma análise de custo-efetividade sob a perspectiva de um hospital federal do Sistema Único de Saúde. No modelo de árvore de decisão foram aplicados os desfechos de efetividade e segurança dos ITK. Os dados clínicos foram extraídos de prontuários e os custos diretos consultados em fontes oficiais do Ministério da Saúde. O custo de 10 meses de tratamento, englobando o valor dos ITK, procedimentos e manejo de eventos adversos, foi de R$ 98.677,19 para o pazopanibe e R$ 155.227,11 para o sunitinibe. Os medicamentos apresentaram efetividade estatisticamente equivalente e diferença estatisticamente significativa para o desfecho de segurança, no qual o pazopanibe obteve o melhor resultado. O pazopanibe, nesse contexto, é a tecnologia dominante quando os custos de tratamento são associados aos de manejo de eventos adversos.

El cáncer renal es la 13ª neoplasia más frecuente en el mundo. Entre 2010 y 2014, representó un 1,43% de las muertes por cáncer en Brasil. La terapia de elección para el tratamiento de cáncer renal metastásico son los inhibidores de tirosina quinasa (ITK), sunitinib y pazopanib. Este artículo evalúa el costo-efectividad entre pazopanib y sunitinib en el tratamiento de cáncer renal metastásico. Se realizó un análisis de costo-efectividad desde la perspectiva de un hospital federal del Sistema Único de Salud. En el modelo de árbol de decisión se aplicaron los desenlaces de efectividad y seguridad de los ITK. Los datos clínicos se extrajeron de registros médicos, y los costos directos consultados en fuentes oficiales del Ministerio de Salud. El costo de 10 meses de tratamiento, englobando el valor de los ITK, procedimientos y gestión de eventos adversos, fue de BRL 98.677,19 con el pazopanib y BRL 155.227,11 con el sunitinib. Los medicamentos presentaron efectividad estadísticamente equivalente y diferencia estadísticamente significativa para el desenlace de seguridad, en el que el pazopanib obtuvo el mejor resultado. El pazopanib, en este contexto, es la tecnología dominante cuando los costes de tratamiento están asociados a los de la gestión de eventos adversos.