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Background: Knowledge of the pattern of regression and distribution of residual tumor cells may assist in the selection of candidates for rectum-sparing strategies. Objective: To investigate and identify factors associated with tumor regression pattern and distribution of residual tumor cells. Methods: We conducted a prospective study of patients with T3/T4 N0/N+ adenocarcinoma of the middle and lower third of the rectum (≤10 cm) treated with radiotherapy (5×5 Gy) followed by 6 cycles of CAPOX chemotherapy. The pattern of tumor regression was classified as fragmented or solid. Microscopic intramural spread was measured. We used a model of distribution of residual tumor cells not yet applied to rectal cancer, defined as follows: type I (luminal), type II (invasive front), type III (concentric), and type IV (random). Results: Forty patients were included with a median age of 66 years; 23 (57.5%) were men. A fragmented pattern was identified in 18 patients (45.0%), and a solid pattern in 22 (55.0%). Microscopic intramural spread was identified in 25 patients (62.5%), extending from 1 to 18 mm (median, 4 mm). There were 14 cases (35.0%) of microscopic intramural spread ≥10 mm. All cases of fragmented regression pattern, except one, showed microscopic intramural spread. Within the fragmented pattern, microscopic intramural spread was 4-8 mm in 4 cases and ≥10 mm in the remaining cases. All cases of microscopic intramural spread ≥ 10 mm were within the fragmented pattern. Regarding the distribution pattern of residual tumor cells, 11 cases (31.5%) were classified as type I, 14 (40.0%) as type II, 10 (28.5%) as type III, and none as type IV. Carcinoembryonic antigen levels >5 ng/mL, downsizing <50%, residual mucosal abnormality >20 mm, and anatomopathologic lymph node involvement were significantly associated with the occurrence of fragmentation (P<0.05). Having received all 6 cycles of CAPOX chemotherapy and absence of microscopic intramural spread were significantly associated with the type I distribution pattern (P<0.05). Conclusion: The occurrence of a fragmented regression pattern is common, as is the presence of microscopic intramural spread. We could identify radiologic and clinicopathologic factors associated with the pattern of tumor regression and a type I distribution pattern.
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PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.
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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.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , América Latina , Consenso , SunitinibeAssuntos
Anilidas , Carcinoma Hepatocelular , Ipilimumab , Neoplasias Hepáticas , Nivolumabe , Piridinas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Anilidas/farmacologia , Anilidas/uso terapêutico , Ipilimumab/uso terapêutico , Ipilimumab/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaRESUMO
Hepatocellular carcinoma often develops in the context of chronic liver disease. It is the sixth most frequently diagnosed cancer and the third most common cause of cancer-related mortality worldwide. Although the mainstay of therapy is surgical resection, most patients are not eligible because of liver dysfunction or tumor extent. Sorafenib was the first tyrosine kinase inhibitor that improved the overall survival of patients who failed to respond to local therapies or had advanced disease, and for many years, it was the only treatment approved for the first-line setting. However, in recent years, trials have demonstrated an improvement in survival with treatments based on immunotherapy and new targeting agents, thereby extending the treatment options. A phase III trial showed that a combination of immunotherapy and targeted therapy, including atezolizumab plus bevacizumab, improved survival in the first-line setting, and is now considered the new standard of care. Other agents and combinations are being tested, including the combination of nivolumab plus ipilimumab and tremelimumab plus durvalumab, and they reportedly have clinical benefits. The aim of this manuscript is to review the latest approved therapeutic options in first- and second-line settings for advanced HCC and discuss future perspectives.
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Bladder cancer is an aggressive and lethal disease. Even when presenting as localized muscle-invasive disease, the 5-year survival rate is about 70%, and the recurrence rate after radical cystectomy is approximately 50%. Neoadjuvant chemotherapy (NAC) has the potential to downstage the primary tumor and treat micrometastases, leading to a decrease in recurrence rates and an increase in cure rates. There is level 1 evidence in favor of neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy. However, data from clinical trials evaluating NAC for patients undergoing bladder-sparing treatments are less robust, so this strategy remains controversial. The response to NAC is prognostic and patients with favorable pathological response have better overall survival. Strategies to select patients based on molecular biomarkers have the potential to guide treatment decisions and even de-intensify treatment, avoiding local treatment for those with complete responses to systemic therapy. This review outlines the current literature on the use of NAC in the context of bladder preservation for muscle-invasive bladder cancer, highlights neoadjuvant studies in patients ineligible for cisplatin-based NAC, and discusses novel bladder-preservation strategies, including multimodality combinations and biomarker-driven studies of definitive chemotherapy.
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Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Bexiga Urinária/patologia , Cisplatino/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cistectomia , Terapia NeoadjuvanteRESUMO
Non-muscle-invasive bladder cancer is one of the most common malignancies. Patients with intermediate-risk or high-risk disease can be treated with intravesical Bacillus Calmette-Guerin, a vaccine against tuberculosis. However, many of these patients will experience tumor recurrence, despite appropriate treatment. 1 The standard of care in these patients is radical cystectomy (RC) with urinary diversion. 2 Patients diagnosed with muscle-invasive bladder cancer (MIBC) have traditionally faced 2 main treatment options: RC and urinary diversion, as in Bacillus Calmette-Guerin-unresponsive Non-muscle-invasive bladder cancer, or alternatively, trimodal therapy comprising maximal transurethral resection of bladder tumor plus chemoradiation. 3 For patients with MIBC and clinical (c)T2-T4a, neoadjuvant chemotherapy (NAC) preceding RC is supported by Level 1 evidence with a modest 5-year overall survival benefit of 5% with cisplatin-based regimens. 4-9 A number of factors preclude MIBC patients from standard treatment options. For example, patients with serious comorbidities might be unable to tolerate general anesthesia, while others might be unwilling to adapt to the lifestyle changes after RC. 10-12 Likewise, patients with extensive carcinoma in situ or poor bladder function might not be optimal candidates for trimodal therapy or be prepared for the ongoing risk that salvage RC might be ultimately required. Reasons for the underuse of NAC range from the fear of delaying potentially curative surgery in nonresponders to patient ineligibility to cisplatin-based NAC. 13,14 Despite best efforts, in both surgical and bladder-sparing approaches, the 5-year overall survival in treated patients with MIBC is only 35% to 50%. 3,15 Strategies to improve overall prognosis as well as to reduce the indications of RC are desperately needed. Trial results have demonstrated the unprecedented ability of immune-checkpoint inhibitors to induce durable remissions in some patients with metastatic urothelial carcinoma. 16-20 Furthermore, immune-checkpoint inhibitors have shown to be better tolerated than traditional chemotherapy. 16 These successful results have spearheaded the research on these agents in earlier curative settings, with the shared goal of improving overall outcomes, and potentially avoid surgery in patients who show complete response (pT0). Strategies to enhance the immune response by combining immunotherapy with immune sensitizers such as chemotherapy, immunotherapy, targeted therapy or radiation are on the rise.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Vacina BCG/uso terapêutico , Inibidores de Checkpoint Imunológico , Recidiva Local de Neoplasia/cirurgia , Cistectomia/métodos , Terapia Neoadjuvante , Imunoterapia , Invasividade NeoplásicaRESUMO
PURPOSE: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI). PATIENTS AND METHODS: A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability. RESULTS: Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7-33.5], median PFS was 3.6 months (95% CI, 2.1-5.5), and median OS was 10.4 months (95% CI, 5.8-19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS. CONCLUSIONS: CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Nivolumabe , Piridinas , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
BACKGROUND: The vast majority of metastatic cancers cannot be cured. Palliative treatment may relieve disease symptoms by stopping or slowing cancer growth and may prolong patients' lives, but almost all patients will inevitably develop disease progression after initial response. However, for reasons that are not fully understood, a very few patients will have extraordinary durable responses to standard anticancer treatments. MATERIALS AND METHODS: We analyzed exceptional responders treated at Fox Chase Cancer Center between September 2009 and November 2017. An exceptional response was defined as a complete response lasting more than 1 year or a partial response or stable disease for more than 2 years. Tumor samples were analyzed using an Ambry Genetics test kit with a 142-gene panel. Messenger RNA expression was evaluated using NanoString's nCounter PanCancer Pathways Panel and Immune Profiling Panel and compared with matched controls for gender, age, and cancer type. RESULTS: Twenty-six exceptional responders with metastatic bladder, kidney, breast, lung, ovarian, uterine, and colon cancers were enrolled. Mutations were identified in 45 genes. The most common mutation was an EPHA5 nonsynonymous mutation detected in 87.5% of patients. Mutations in DNA damage repair pathway genes were also frequent, suggesting increased genome instability. We also found varying expression of 73 genes in the Pathways panel and 85 genes in the Immune Profiling panel, many of them responsible for improvement in tumor recognition and antitumor immune response. CONCLUSIONS: The genomic instability detected in our exceptional responders, plus treatment with DNA damage compounds combined with favorable anticancer immunity, may have contributed to exceptional responses to standard anticancer therapies in the patients studied. IMPLICATIONS FOR PRACTICE: With recent advances in the treatment of cancer, there is increased emphasis on the importance of identifying molecular markers to predict treatment outcomes, thereby allowing precision oncology. In this study, it was hypothesized that there is a "specific biologic signature" in the biology of the cancer in long-term survivors that allows sensitivity to systemic therapy and durability of response. Results showed that DNA damage repair pathway alterations, combined with favorable anticancer immunity, may have contributed to exceptional responses. It is very likely that an in-depth examination of outlier responses will become a standard component of drug development in the future.
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Neoplasias , Humanos , Oncologia , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de PrecisãoRESUMO
PURPOSE: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urogenitais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/metabolismo , Carcinoma de Células de Transição/secundário , Colite/induzido quimicamente , Diarreia/induzido quimicamente , Molécula de Adesão da Célula Epitelial/metabolismo , Fadiga/induzido quimicamente , Feminino , Hepatite/etiologia , Humanos , Hipertensão/induzido quimicamente , Ipilimumab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/metabolismo , Nivolumabe/administração & dosagem , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridinas/administração & dosagem , Receptores CXCR4/metabolismo , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Screening protocols for colorectal cancer are broadly recommended and effective in reducing mortality. However, populations from different age groups can harbor distinct pathologic and molecular profiles that can also be influenced by screening and polyp resection, especially in older ages. PATIENTS AND METHODS: We retrospectively analyzed tumors from stage IV colorectal cancer patients from a central pathology laboratory in Brazil that is a reference for mutational profiling countrywide. Patients were classified into age groups as follows: prescreening age (PrSA; < 45 years old), screening age (SA; 45-75 years old), and postscreening age (PoSA; > 75 years old). Every tumor was centrally reviewed by the pathologist. Groups were compared regarding clinicopathologic features, and the presence of RAS (renin-angiotensin system) and BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations. RESULTS: We included 1635 patients (215 PrSA, 1213 SA, 207 PoSA). There was no difference among groups regarding sidedness (P = .65) and KRAS (Kirsten rat sarcoma viral oncogene) mutations (P = .57). Stage IV disease at diagnosis (P = .04), the presence of a signet-ring cell component (P < .001), and poorly differentiated tumors (P = .02) were most common in young patients, while BRAF and NRAS (neuroblastoma RAS viral (v-ras) oncogene homolog) mutations were significantly more common among PoSA patients (P = .002 and .03, respectively). When divided by age decade, KRAS mutations seem to have a stable frequency among all ages, while the BRAF mutation rate increased with increasing age. CONCLUSION: BRAF mutations are more frequent among PoSA patients, and this seems to be a continuous trend. PrSA and PoSA patients seem to present a distinct profile from SA, including differences in molecular and pathologic aspects. These findings could impact the frequency of screening tests among different age groups.
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Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Detecção Precoce de Câncer/normas , Adulto , Fatores Etários , Idoso , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Análise Mutacional de DNA/estatística & dados numéricos , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos RetrospectivosRESUMO
Advanced hepatocellular carcinoma is a prevalent and potentially aggressive disease. For more than a decade, treatment with sorafenib has been the only approved therapeutic approach. Moreover, no agent has been proven to prolong survival following the progression of disease after sorafenib treatment. However, in recent years, this scenario has changed substantially with several trials being conducted to examine the effects of immunotherapy and novel targeting agents. Several immune checkpoint inhibitors have shown promising results in early-stage clinical trials. Moreover, phase III trials with large cohorts have demonstrated remarkable improvement in survival with the use of new targeted therapies in second-line treatment. Treatment regimens involving the combination of two immune checkpoint inhibitors as well as immune checkpoint inhibitors and anti-angiogenic targeted therapies have shown potential to act synergistically in clinical trials. Recently, the combination of atezolizumab and bevacizumab evaluated in a phase III clinical trial has demonstrated survival superiority in the first-line treatment; it is the new considered standard of care. In this manuscript, we aimed to review the latest advances in the systemic treatment of advanced hepatocellular carcinoma focusing on immunotherapy and targeted therapies.
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The emergence and prevalence of cooperative behavior within a group of selfish individuals remains a puzzle for evolutionary game theory precisely because it conflicts directly with the central idea of natural selection. Accordingly, in recent years, the search for an understanding of how cooperation can be stimulated, even when it conflicts with individual interest, has intensified. We investigate the emergence of cooperation in an age-structured evolutionary spatial game. In it, players age with time and the payoff that they receive after each round depends on their age. We find that the outcome of the game is strongly influenced by the type of distribution used to modify the payoffs according to the age of each player. The results show that, under certain circumstances, cooperators may not only survive but dominate the population.
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Evolução Biológica , Comportamento Cooperativo , Teoria dos Jogos , Modelos Teóricos , Humanos , Seleção GenéticaRESUMO
The Hedgehog pathway (HhP) plays an important role in normal embryonic development and its abnormal function has been linked to a variety of neoplasms. Recently, the complex mechanisms involved in this pathway have been deciphered and the cross talks with other important pathways involved in carcinogenesis have been characterized. This knowledge has led to the development of targeted therapies against key components of HhP, which culminated in the approval of vismodegib for the treatment of advanced basal cell carcinoma in 2012. Since then, other compounds have been developed and evaluated in preclinical and clinical studies with interesting results. Today, several medications against components of the HhP have demonstrated clinical activity as monotherapies and in combination with cytotoxic treatment or other targeted therapies against mitogenic pathways that are linked to the HhP. This review aims to clarify the mechanism of the HhP and the complex crosstalk with others pathways involved in carcinogenesis and to discuss both the evidence associated with the growing number of medications and combined therapies addressing this pathway and future perspectives.
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Proteínas Hedgehog/metabolismo , Terapia de Alvo Molecular , Neoplasias/metabolismo , Transdução de Sinais , Carcinogênese/metabolismo , Carcinogênese/patologia , HumanosRESUMO
PURPOSE: Advanced pancreatic adenocarcinoma (PA) is an aggressive disease that has poor prognosis and frequently interferes with patient's quality of life. There has been progress in first-line regimens; however, there is no standard second-line regimen. The aim of this study is to analyze second-line gemcitabine after first-line fluorouracil (FU) + leucovorin (LV) + irinotecan + oxaliplatin (FOLFIRINOX) regimen. METHODS: This study included consecutive patients with advanced PA treated at Hospital Sirio-Libanês from 2011 to 2016. The patients received FOLFIRINOX as first-line treatment and upon progression, received gemcitabine alone. Survival analysis was performed using the Kaplan-Meier method. RESULTS: A total of 54 patients were evaluated. Most patients were male (61.1%) and most had an ECOG performance status of 0 or 1 prior to the beginning of second-line treatment (66.6%). The mean number of gemcitabine cycles was 3.4. Most patients had disease progression as the best response to treatment (75.9%), 11.1% had stable disease, and 9.3% experienced a partial response. The median progression-free survival was 1.7 months, and the median overall survival was 6.8 months. CONCLUSIONS: Gemcitabine alone did not show meaningful clinical benefit as second-line treatment after FOLFIRINOX.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brasil/epidemiologia , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Estimativa de Kaplan-Meier , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Qualidade de Vida , Estudos Retrospectivos , GencitabinaRESUMO
BACKGROUND: Ameloblastoma is a slow-growing neoplasm of the jaw, for which the standard treatment is surgical removal of the lesion with high recurrence rates and elevated morbidity. Systemic therapy is not established in the literature. CASE PRESENTATION: We present a case of a 29-year-old woman diagnosed with an ameloblastoma of the left mandible who had been subjected to several surgical procedures over twenty years due to multiple local recurrences. Molecular testing revealed a BRAF V600E mutation, and vemurafenib was started. She experienced complete resolution of symptoms related to the disease, and image scans evidenced continuous shrinkage of the neoplastic lesion after eleven months of therapy. CONCLUSION: This is the first report showing clinical benefit and radiological response with vemrafenib for recurrent ameloblastoma. Targeted therapy addressing BRAF V600E mutation has the potential to change clinical practice of this rare disease.
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Ameloblastoma/tratamento farmacológico , Ameloblastoma/genética , Neoplasias Maxilomandibulares/tratamento farmacológico , Neoplasias Maxilomandibulares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Alelos , Ameloblastoma/diagnóstico , Substituição de Aminoácidos , Biomarcadores Tumorais , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Maxilomandibulares/diagnóstico , Imageamento por Ressonância Magnética , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Hepatocellular carcinoma is the fifth most common cancer globally and the second leading cause of cancer-related mortality worldwide. Despite the established efficacy of screening programs for at-risk individuals, most patients are diagnosed at later stages of disease, wherein the tumor characteristics or liver disease progressions do not allow for curative interventions. Many cytotoxic chemotherapeutic agents have been tested in patients with advanced disease with disappointing outcomes and poor tolerance; therefore, no standard systemic therapy emerged until the approval of sorafenib in 2006. CONCLUSION: Despite the toxicity and low response rate, sorafenib had shown a significant survival benefit in phase III clinical trials, thus encouraging clinical research aimed at advancing the field of molecular therapy. Disrupted signaling pathways related to hepatocellular carcinoma (HCC) include the Wnt/ß-catenin, Ras/Raf/MAPK, phosphatidyl inositol 3-kinase/Akt/mechanistic target of rapamycin, hepatocyte growth factor/c-mesenchymal-epithelial transition, IGF, vascular endothelial growth factor, and platelet-derived growth factor pathways, and a variety of agents targeting these pathways are currently under investigation. Additionally, better comprehension of the complex mechanisms underlying the ability of tumor cells to escape immune surveillance has led to impressive results with immunotherapy in many types of cancer, and this treatment strategy is currently being developed for HCC patients. Previous and ongoing targeted therapy and immunotherapy trials for HCC are discussed in this review.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Imunoterapia , Neoplasias Hepáticas/terapia , Terapia de Alvo Molecular , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Ensaios Clínicos como Assunto , Humanos , Imunoterapia/tendências , Terapia de Alvo Molecular/tendências , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Treatment of localized gastric cancer (LGC) consists of surgical resection followed by adjuvant treatment. Both chemoradiation (CRT) and chemotherapy (CT) regimens have shown benefit in survival outcomes versus observation. However, there are few data comparing these approaches. METHODS: This study included consecutive patients with LGC treated at Instituto do Cancer do Estado de Sao Paulo (ICESP) from 2012 to 2015. CRT was based on the INT-0116 regimen and CT consisted of a platinum and fluoropyrimidine doublet. Treatment choice was based on physician preference. Toxicity was evaluated for every cycle. Overall survival (OS) analysis was performed by Kaplan-Meier. A propensity score-matched analysis was performed to minimize selection bias. RESULTS: A total of 309 patients were evaluated, 227 in CRT group and 82 in CT group. The most prevalent grade 3/4 toxicities in CRT and CT groups were: nausea/vomiting (9.25 vs 4.9%), fatigue (9.3% vs 2.4%), mucositis (4.4% vs 1.2%), neutropenia (37.8% vs 20.9%), febrile neutropenia (3.9% vs 0%), anemia (4.3% vs 6.1%), thrombocytopenia (2.6% vs 4.9%), neuropathy (0 vs 2.4%) and hand-foot syndrome (0.4% vs 2.4%). Two grade 5 toxicities (febrile neutropenia and anemia) occurred in CRT group. There was no difference in the pattern of recurrence. After a median follow-up of 23.5 months (CRT) and 20.6 months (CT), there was no difference in OS between groups. CONCLUSIONS: CT and CRT present similar efficacy and tolerability as adjuvant treatment for LGC.
Assuntos
Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia Adjuvante/efeitos adversos , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pontuação de Propensão , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Resultado do TratamentoRESUMO
PURPOSE: Our objective was to evaluate the benefit of re-exposing patients with refractory metastatic colorectal cancer (mCRC) to a combination of oxaliplatin, irinotecan and 5-fluorouracil treatment. METHODS: We retrospectively analysed patients with mCRC who received a combination of oxaliplatin, irinotecan and fluorouracil as a rechallenge regimen after progressing on the same drugs. Both FOLFOXIRI and FOLFIRINOX were used. Toxicity was evaluated for each treatment cycle, and survival analysis was performed using the Kaplan-Meier method. RESULTS: A total of 21 patients who were treated between January 2011 and December 2013 were selected for this study. Most of the patients (95.2%) had an ECOG status of 0-1. The median age at diagnosis was 52.1 years (range 36-77 years), and 14 (66.6%) patients had wild-type KRAS. Thirteen patients received FOLFIRINOX, and eight received FOLFOXIRI. Most patients had previously received at least three regimens, with 80% receiving anti-VEGF and 66% anti-EGFR antibodies. The response rate was 38%, and 24% patients had stable disease. The median time to disease progression was 4.0 months (range 1.0-9.1 months), and the median overall survival duration was 8.6 months (range 6.3-11.5 months). Most patients required dose adjustment and treatment delays. One patient experienced grade 5 neutropenic sepsis. CONCLUSIONS: Both FOLFIRINOX and FOLFOXIRI are active and potentially feasible rechallenge treatment options for heavily pretreated patients with good performance status. With dose reduction and close monitoring for toxicity, the risk of serious adverse events can be minimised.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Compostos Organometálicos/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/etiologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Combinação de Medicamentos , Feminino , Fluoruracila/farmacologia , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Leucovorina/farmacologia , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/farmacologia , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Retratamento/efeitos adversos , Retratamento/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Metastatic gastric cancer (GC) is an incurable and aggressive disease with a poor prognosis. Immunotherapy is an attractive approach for treating patients with cancer, and studies using immunotherapy have shown promising results in melanoma, kidney and non-small cell lung cancers, among others. CASE PRESENTATION: We present a case of a 50-year-old woman with metastatic GC whose cancer had progressed after first-line chemotherapy and who received pembrolizumab as an experimental treatment. Molecular analyses showed that her tumor was negative for PD-L1 expression, contained microsatellite stability and several focal somatic copy number alterations. The patient experienced an almost complete response after eleven cycles of treatment. Her symptoms related to the disease disappeared, and the medication was well tolerated. CONCLUSIONS: Despite reports of promising responses in some patients, immunotherapy is not suitable for all patients; therefore, we explored the molecular characteristics that could explain the exceptional response and clinical benefits observed in our patient.