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BACKGROUND: Febrile neutropenia (FN) is a life-threatening complication of Docetaxel-based chemotherapy regimens (DBRs). Prophylactic granulocyte-colony stimulating factor (G-CSF) can reduce the risk of FN. This study investigated the effect of G-CSF on FN in patients receiving DBRs for breast cancer. METHODS: Patients treated between 2015 and 2017 were identified from the hospital's pharmacy database and their medical records were examined retrospectively. Data from patients' first four cycles of DBR were collected. FN rate, FN associated length of hospital stay (FN-LOS), and chemotherapy dose modification/delay due to FN were compared between patients who did (G-CSF group) or did not (non-GCSF group) receive prophylactic G-CSF. RESULTS: Of the 276 included patients, 83.3% received a DBR as adjuvant or neoadjuvant therapy, and 50% received docetaxel as combination therapy. Prophylactic G-CSF was administered with the first cycle of a DBR in 69.9% of patients who were significantly less likely to experience FN compared to the non-G-CSF group (6.2% vs. 15.7%; odds ratio: 0.36 [95% CI: 0.16-0.82]; p = 0.020). Collectively and after the 4 DBR treatment cycles, FN rate (4.8 vs. 8.5; odds ratio: 0.54 [95% CI: 0.30-0.97]; p = 0.043) and the mean FN-LOS (3.55 vs. 5.28 days; t = -2.22; p = 0.037) were reduced in the G-CSF group. There was no difference in DBR dose delay/reduction between both groups in cycles 2-4. CONCLUSION: In patients receiving DBRs for breast cancer, prophylactic G-CSF significantly reduced both the rate of FN and duration of hospitalization for FN.
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Neoplasias de la Mama , Neutropenia Febril , Humanos , Femenino , Docetaxel/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Factor Estimulante de Colonias de Granulocitos , Neutropenia Febril/inducido químicamente , Neutropenia Febril/prevención & control , Neutropenia Febril/tratamiento farmacológico , GranulocitosRESUMEN
INTRODUCTION: This study aimed to determine the frequency of human epidermal growth factor receptor 2 (HER2) over-expression in newly diagnosed breast cancer (BC) patients in Saudi Arabia and to assess the clinical characteristics and outcomes in patients with HER2-positive disease. METHODS: In the first part of the study, we retrospectively reviewed the pathology records of all patients diagnosed with BC between 2007 and 2013 at 3 hospitals in the largest 3 cities in Saudi Arabia to determine the frequency of HER2 over-expression. In the second part, a representative sample from the patients identified with HER2 over-expressed BC was selected for further investigation. Data collected included demographic and clinical characteristics such as hormone-receptor status, treatment regimens, survival data, response to treatment, and selected adverse events. RESULTS: 1867 BC records were included in the study. HER2 was overexpressed in 559 patients (29.9%); of those, 348 HER2-positive BC patients were included in subsequent analyses. In the sample of HER2-positive BC patients, median age at diagnosis was 46 years, 0.9% were male, 92.5% were Saudi, 42.4% were Hormone Receptor-negative, and 13.1% had stage IV tumors. Most patients (84.2%) underwent curative intent surgery and 71.8% received radiotherapy. Average tumor size was 3.5 ± 2.5 cm and infiltrating ductal carcinoma was the most common pathology (92.9%). As for pharmacological therapy, the most commonly used regimens were Chemotherapy + Trastuzumab combination (79.1%) in neoadjuvant setting, Hormonotherapy alone (56.2%) in adjuvant setting, and Chemotherapy + Targeted therapy combination (64.8%) as palliative treatment. At the last patient evaluation, 36.9% had complete response, while 33.2% had progressive disease. Median overall survival (OS) and progression-free survival (PFS) were not reached in patients on neoadjuvant/adjuvant pharmacotherapy. As for patients on palliative intent pharmacotherapy, median OS and PFS were 64.7 and 29.3 months respectively. CONCLUSION: This study provided updated figures regarding HER2 overexpression in BC in Saudi Arabia: HER2 overexpression rate (29.9%) was within the range reported in previous studies. Patients' demographic and clinical characteristics were also similar to those reported earlier, with a median age at diagnosis of 46 years and one third of patients having locally advanced/metastatic disease at diagnosis.
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Neoplasias de la Mama/epidemiología , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama Masculina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor ErbB-2/genética , Estudios Retrospectivos , Arabia Saudita/epidemiologíaRESUMEN
Aim: To analyze responses to first-line metastatic renal cell carcinoma (mRCC) treatment stratified by risk criteria. Patients & methods: Clinical trials and observational studies of patients aged ≥18 years, published January 2005-May 2019, were identified via Ovid from MEDLINE, EMBASE, the Cochrane Central Trials Register and the Cochrane Database of Systematic Reviews. Data extracted included progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Results: 47/1269 articles met eligibility criteria. Most studies stratified patients by International Metastatic RCC Database Consortium (n = 19) or Memorial Sloan Kettering Cancer Center (n = 21). PFS, OS and ORR varied according to risk group. Conclusion: Pembrolizumab + axitinib, ipilimumab + nivolumab and avelumab + axitinib were most effective across all risk groups. Favorable-risk patients benefit from sunitinib treatment.
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Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Toma de Decisiones , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Metástasis de la Neoplasia , RiesgoRESUMEN
INTRODUCTION: Bone metastases are common in patients with breast cancer and can lead to pain and skeletal-related events. Bone modifying agents are licensed to be used for these patients. We report the treatment patterns and outcome of zoledronic acid and denosumab in routine practice. METHODOLOGY: Women with bone metastases from breast cancer who have started denosumab or zoledronic acid between 2011 and 2016 were eligible. Those with history of bone modifying agent use prior to diagnosis of bone metastases or with switching treatment between zoledronic acid and denosumab were excluded. Details of patients, tumors, bone modifying agent treatment, selected bone modifying agent toxicity, time to skeletal-related event development, and overall survival were collected retrospectively. RESULTS: In total, 163 women were eligible and included in this analysis. Number of skeletal-related events prior to starting bone modifying agents was 0, 1, 2, and 3 in 91 (55.8%), 53 (32.5%), 13 (8%), and 6 (3.7%), respectively. Zoledronic acid was started for 107 (65.6%) and denosumab for 56 (34.4%) patients. The proportion of patients receiving denosumab increased from 23.1 to 54.3% in years 2011 and 2016, respectively. Dose delay, reduction, and discontinuation due to toxicity were reported more frequently in patients receiving zoledronic acid. Denosumab delayed time to first on-treatment skeletal-related event compared with zoledronic acid (hazard ratio, 0.64; 95% CI, 0.41-0.98; log rank P = 0.044). There was no significant difference in median survival (zoledronic acid: 62 and denosumab: 58 months; log rank P = 0.956). CONCLUSION: Denosumab is superior to zoledronic acid in reducing risk of skeletal-related events and in tolerance profile. However, overall survival is similar with both treatments. Our findings mirror those reported in scrutinized environment of landmark clinical trials.
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Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Adulto , Anciano , Denosumab/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Ácido Zoledrónico/uso terapéuticoRESUMEN
INTRODUCTION: The currently approved techniques for RAS mutations testing in colorectal cancer (CRC) tissue are labor-intensive and time consuming. The Idylla technology (IT) is a rapid and fully automated diagnostics system. The primary aim of this study is to compare the Idylla performance against that of conventional techniques (CT). METHODOLOGY: Archival CRC tumor samples from 2 hospitals were tested for KRAS and NRAS mutations using the IT. Results were compared to those obtained earlier by CT performed in accredited laboratories. Unexplained discordant results were verified locally by next generation sequencing (NGS) to ascertain the accuracy of IT. RESULTS: Forty five samples were processed. All samples underwent dual testing (CT & IT) for KRAS mutations. IT identified mutations in 2 samples that were not detected by CT. Primary concordance rate for KRAS was 93.3% and the accuracy rate improved to 100% after verification and explanation of discordant results. Only 18 samples underwent dual testing for NRAS. Primary concordance and accuracy rates for NRAS were 94.4%. The mean time from dispatching the specimen for RAS testing by CT until receipt of results was 12 (7-28) days compared to few hours when IT was used. CONCLUSION: IT provides a quick and reliable mean for RAS testing. In addition, it identifies mutations that are not detected by CT and thus may provide better guidance to treatment choices.
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Neoplasias Colorrectales/genética , Análisis Mutacional de ADN/métodos , GTP Fosfohidrolasas/genética , Proteínas de la Membrana/genética , Técnicas de Diagnóstico Molecular/métodos , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Colorrectales/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Cancer can escape the immune system through different mechanisms. One of which is the expression of program death ligand-1 (PD-L1). This ligand binds to programmed cell death 1 receptor on activated T cells, subsequently leading to inhibition of the immune response. Nivolumab is a novel antibody that binds to programmed cell death 1 and prevents such immune tolerance. Several recently published clinical trials confirmed the clinical efficacy of single agent nivolumab in pretreated patients with different cancer types. Publications on nivolumab in Hodgkin lymphoma are very scarce. We report on a 30-year-old man with stage IVB Hodgkin lymphoma, who failed nine lines of treatments including high-dose chemotherapy and autologous stem cell transplantation and brentuximab vedotin. He reached a major response after four cycles of nivolumab and got married. The available literature is being reviewed. Pre-treated Hodgkin lymphoma is amenable to novel immunotherapy. Nivolumab induces clinically meaningful responses with excellent tolerance. The drug enriches our treatment options by reviving the immune system response against cancer. Further clinical studies are needed to determine the effectiveness on a large patients' cohort.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adulto , Humanos , Masculino , Nivolumab , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , RetratamientoRESUMEN
Rituximab, a chimeric monoclonal antibody is licensed for the treatment of CD20 positive lymphomas. Previous studies have found rituximab, in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone alone in the treatment of diffuse large B-cell lymphoma and many other B-cell lymphomas. Acute hypersensitivity reactions have been reported in patients receiving rituximab infusion and usually manifesting as headache, fever, chills, sweats, skin rash, dyspnea, mild hypotension, and nausea. Acute major venous thrombosis and seizures have not been reported as manifestation of acute hypersensitivity reaction. We report on a 22-year-old woman, who was diagnosed with stage III B CD20 positive B-cell diffuse large B-cell lymphoma. During the first cycle of treatment, she developed grand-mal seizure while receiving rituximab infusion without any other features of acute hypersensitivity reaction. Imaging confirmed new onset jugular vein thrombosis with normal coagulation parameters. These events were managed by anticonvulsants and anticoagulation therapy. The patient completed eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone without rituximab and achieved complete remission. No further complications were noted. To our knowledge, this is the first case in the literature describing grand-mal seizures and acute thrombosis while on rituximab treatment. Clinicians should be aware of this rare side effect, as stopping rituximab can prevent recurrence of these complications.
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Antineoplásicos/efectos adversos , Rituximab/efectos adversos , Trombosis/inducido químicamente , Adulto , Antineoplásicos/uso terapéutico , Femenino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Rituximab/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND/AIMS: Lymph node ratio (LNR) defined as the number of lymph nodes (LNs) involved with metastases divided by number of LNs examined, has been shown to be an independent prognostic factor in breast, stomach and various other solid tumors. Its significance as a prognostic determinant in colorectal cancer (CRC) is still under investigation. This study investigated the prognostic value of LNR in patients with resected CRC. METHODOLOGY: We retrospectively ex- amined 145 patients with stage II & III CRC diagnosed and treated at a single institution during 9 years pe- riod. Patients were grouped according to LNR in three groups. Group 1; LNR < 0.05, Group 2; LNR = 0.05-0.19 & Group 3 > 0.19. Chi square, life table analysis and multivariate Cox regression were used for statistical analysis. RESULTS: On multivariate analysis, number of involved LNs (NILN) (HR = 1.15, 95% CI 1.055-1.245; P = 0.001) and pathological T stage (P = 0.002) were statistically significant predictors of relapse free survival (RFS). LNR as a continuous variable (but not as a categorical variable) was statistically significant predictor of RFS (P = 0.02). LNR was also a statistically significant predictor of overall survival (OS) (P = 0.02). CONCLUSION: LNR may predict RFS and OS in patients with resected stage II & III CRC. Studies with larger cohorts and longer follow up are needed to further examine and validate theprognostic value of LNR.
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Carcinoma/secundario , Neoplasias Colorrectales/patología , Ganglios Linfáticos/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/mortalidad , Carcinoma/cirugía , Distribución de Chi-Cuadrado , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/cirugía , Supervivencia sin Enfermedad , Egipto , Femenino , Humanos , Ganglios Linfáticos/cirugía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: There is lack of consensus on how nutritional screening and intervention should be provided to cancer patients. Nutritional screening and support of cancer patients are not well established in the Middle East. We report our systematic and practical experience led by a qualified specialist dietician in a cancer inpatient setting, using a novel nutritional screening tool. METHODS: Ninety-seven consecutive inpatients underwent nutritional screening and categorised into three nutritional risk groups based on oral intake, gastrointestinal symptoms, body mass index (BMI) and weight loss. Nutritional support was introduced accordingly. Statistical tests used included ANOVA, Bonferroni post hoc, chi-square and log rank tests. RESULTS: Median age was 48 (19-87)years. Patients were categorised into three nutritional risk groups: 55 % low, 37 % intermediate and 8 % high. Nutritional intervention was introduced for 36 % of these patients. Individually, weight, BMI, oral intake, serum albumin on admission and weight loss significantly affected nutritional risk and nutritional intervention (all significant P values). Eighty-seven, 60 and 55 % of patients admitted for chemotherapy, febrile neutropenia and other reasons, respectively, did not require specific nutritional intervention. There was a statistically significant relationship between nutritional risk and nutritional intervention (P=0.005). Significantly more patients were alive at 3 months in low (91 %) than intermediate (75 %) than high (37 %)-risk groups. CONCLUSIONS: About a third of cancer inpatients require nutritional intervention. The adopted nutritional risk assessment tool is simple and practical. The validity of this tool is supported by its significant relation with known individual nutritional risk factors. This should be confirmed in larger prospective study and comparing this new tool with other established ones.
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Neoplasias/terapia , Evaluación Nutricional , Apoyo Nutricional/métodos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Humanos , Pacientes Internos , Masculino , Persona de Mediana Edad , Medio Oriente , Neoplasias/metabolismo , Proyectos Piloto , Estudios Prospectivos , Factores de Riesgo , Pérdida de Peso , Adulto JovenRESUMEN
Given that colorectal cancer is one of the leading causes of mortality, mucinous adenocarcinoma is one of the subtypes and is characterized by the presence of mucin-producing tumor cells with mucin components and is more challenging to manage. In Saudi Arabia, it represents approximately 10-15% of all colorectal carcinoma. The main etiological cause of mucinous adenocarcinoma is yet not well understood. The main goal of our study is to discuss the histopathology and the molecular background of mucinous colorectal adenocarcinoma and also to provide an update on its prognosis and therapeutics from recent published literature. It is a retrospective cohort study that was conducted at King Faisal Specialist Hospital, Jeddah, Saudi Arabia. The study included 68 adult patients diagnosed with mucinous colon cancer, who did surgical resection alone or with or without adjuvant chemotherapy following from January 2011 to December 2020. The mucinous subtypes are found more commonly in the proximal colon. In our study, 26 patients (38.2% of the cases) were right-sided and 35 patients (51.5%) were from the left side, but these included the rectum as well and this reflects the higher incidence of diagnosis of rectal cancer in the region. Most tumors were classified as Grade II in 56 patients (82.4%), consistent with the intermediate differentiation status often associated with the mucinous subtypes. The most common symptom at presentation was abdominal pain in 38 patients (55.9%) followed by per rectal bleeding and abdominal mass. The management in our study was in line with the standard established practice and surgical resection as expected was the primary potentially curative approach. Notably of patients presenting with locally advanced rectal cancer, six patients underwent concomitant chemoradiotherapy followed by surgery and four patients had upfront surgery. The duration of the median follow-up was 32 months. At the time of analysis, 30 patients (44.1%) were alive and remained on regular follow-up, 17 patients (25%) had succumbed to the disease, and 21 patients (30.9%) were lost to follow-up. The median overall survival was not reached, and notably, 49 patients (71.6%) remained alive at the four-year mark. Whilst our study contributes to the current understanding of mucinous adenocarcinomas of the colon, further research in molecular profiling and genomic testing and larger clinical trials with tailored treatments is necessary to refine treatment strategies and improve outcomes.
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Metastatic bone disease complicates the course of malignancy in a substantial proportion of patients with advanced cancer. Bisphosphonates are now widely used to improve skeleton-related outcomes of patients with metastatic cancer to the bone. Most studies evaluating the efficacy of bisphosphonates and other bone-targeted agents have been performed in patients with metastatic breast and prostate cancer. Only a few studies have evaluated the role of bisphosphonates in other tumor types involving the skeletal system. We present a review of the clinical literature focusing on the current and potential roles of bisphosphonates (particularly zoledronic acid) and newer bone-targeted therapies in patients with metastasis to bone arising from solid tumors other than breast and prostate cancer.
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Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Difosfonatos/uso terapéutico , Biomarcadores , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Neoplasias Óseas/metabolismo , Neoplasias Óseas/mortalidad , Difosfonatos/administración & dosificación , Difosfonatos/efectos adversos , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND: There is no reliable prognostic and predictive biomarkers for clear cell renal cell carcinoma (cc-RCC). METHODS: DNA from 47 cc-RCC tissue samples were sequenced using next generation sequencing and a customized gene panel testing for tumor-driver genes including 19 Mucin genes. RESULTS: Distinctive variants in 12 Mucin genes were present in all samples. These genes are: MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC12, MUC16, MUC17, MUC19, and MUC22. The numbers of distinctive and non-distinctive variants were counted for each sample. The median number of variants was 455. High variant number (HVN) (>455) was associated with shorter overall survival compared to low variant number (≤455) [Median 50 months vs. not reached; P=0.041]. In the 11 patients who received anti-angiogenic tyrosine kinase inhibitors (TKIs), HVN was associated with a trend of shorter progression free survival. CONCLUSION: Alterations in Mucin family genes are common in ccRCC. HVN is associated with worse prognosis and may predict decreased benefit from anti-angiogenic TKIs. KEY WORDS: Mucin; Variants; Renal cell carcinoma; Biomarker; Tyrosine kinase inhibitors.
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Carcinoma de Células Renales , Carcinoma , Neoplasias Renales , Humanos , Mucinas/genética , Carcinoma de Células Renales/genética , Pronóstico , Neoplasias Renales/genéticaRESUMEN
BACKGROUND: Chemotherapy regimens containing a combination of anti-Her2 antibodies are effective but can be associated with cardiac toxicity. OBJECTIVES: We evaluate the outcome with a particular focus on the cardiac function of patients with Her2 over-expressed breast cancer receiving Chemotherapy regimens combined with Trastuzumab and Pertuzumab in routine clinical practice settings. DESIGN AND METHODS: The initial cohort of patients who started Chemotherapy regimens in combination with Trastuzumab and Pertuzumab before September 2019 in four cancer units were reviewed retrospectively. All patients had regular measurements of left ventricular ejection fraction by Doppler ultrasound. RESULTS: Sixty-seven patients were identified. Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment were administered in the neoadjuvant and palliative settings in 28 (41.8%) and 39 (58.2%) patients, respectively. All patients underwent left ventricular ejection fraction assessment prior to starting Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment and at 3 and 6 months later. Subsequently, left ventricular ejection fraction was measured at 9, 12, 15, 18, 21, and 24 months as long as patients are still receiving any of the treatment components. Compared to baseline, the mean left ventricular ejection fraction was not significantly different at any of the subsequent time points (range; decrease by 0.936% to increase by 1.087%: T-test P value not statistically significant for all comparisons). Trastuzumab and Pertuzumab administration was withheld temporarily for two patients due to clinically suspected cardiac toxicity which was excluded upon further investigations. In the neoadjuvant cohort, 82.3% of patients were relapse free at 3 years. The median progression-free survival was 20 months, and the median overall survival was 41 months in the palliative cohort. CONCLUSION: In this cohort describing our limited initial experience, dual anti-Her2 antibodies (Trastuzumab and Pertuzumab) combined with chemotherapy is effective and not associated with significant cardiac toxicity when the left ventricular ejection fraction is measured every 3 months. This may suggest that previous concerns about cardiotoxicity may have been overemphasized. Further studies investigating less frequent left ventricular ejection fraction monitoring may be warranted.
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Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama , Trastuzumab , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cardiotoxicidad/etiología , Cardiotoxicidad/tratamiento farmacológico , Receptor ErbB-2 , Estudios Retrospectivos , Trastuzumab/efectos adversos , Trastuzumab/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
Background: Oral capecitabine in combination with intravenous oxaliplatin (XELOX) or irinotecan (XELIRI) are acceptable substitutions to fully intravenous regimens. Biweekly (as opposed to weekly) cetuximab is more convenient when combined with biweekly chemotherapy. Here, we report the tolerability and efficacy of biweekly cetuximab in combination with biweekly XELOX or XELIRI in patients with RAS wild-type metastatic colorectal cancer (RAS-WT mCRC). Methods: Clinical data of consecutive patients with mCRC who received biweekly cetuximab (500 mg/m2) in combination with XELOX or XELIRI between January 2009 and May 2019 in the first- or second-line settings was extracted. Dosage of XEL (Capecitabine/XELODA) was 1,000 mg/m2 twice daily for 9 days, plus on day 1 oxaliplatin 85 mg/m2 or irinotecan 180 mg/m2. Treatment dose reduction and delay for ≥7 days was analysed as surrogates for toxicity. Extended RAS testing was performed in the context of this study for patients who received treatment based on limited KRAS-WT genotype. Results: Sixty one patients with RAS-WT mCRC fulfilled the eligibility criteria. XELOX was administered to 26 (42.6%) and XELIRI to 35 (57.4%) of patients. For all patients in the first-line setting, the objective response rate (ORR), median progression free survival (PFS) and median overall survival (OS) were 54%, 8 months and 25 months, respectively. The corresponding outcomes for the subgroup of patients who received first-line XELOX were 68%, 10 months and not reached, respectively. For all patients in the second-line setting, the ORR, PFS and OS were 50%, 7 months and 20 months, respectively. Chemotherapy components dose reduction and delays were observed in 18 (29.5%) and 25 (41%) patients, respectively. The corresponding frequencies for cetuximab were 3 (5%) and 31 (50.8%). Conclusion: Biweekly cetuximab in combination with XELOX or XELIRI is tolerable and effective. The addition of cetuximab to capecitabine and oxaliplatin is associated with favourable outcome.
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This study explored the roles of activins and follistatin in colorectal cancers. Paired malignant and normal colonic tissues were collected from archived paraffin-embedded (n = 90 patients) alongside fresh (n = 40 patients) specimen cohorts. Activin ß-subunits, follistatin and Smad4 mRNAs and proteins were measured by real-time PCR and immunohistochemistry (IHC). Mature activin-A, -B, -AB and follistatin proteins were measured by ELISA. Cancer tissues having ≤ the 20th percentile of the Smad4 IHC score were considered as low (L-S4) group. The Smad4-intact SW480 and Smad4-null HT29 colon cancer cell lines were treated with activins and follistatin, and cell cycle was analysed by flow cytometry. The cell cycle inducing (CCND1/CCND3) and inhibitory (p21/p27) proteins alongside the survival (survivin/BCL2) and pro-apoptosis (Casp-8/Casp-3) markers were measured by immunofluorescence. Thirty-nine patients had right-sided cancers (30%) and showed higher rates of L-S4 tumours (n = 17; 13.1%) alongside worse clinicopathological characteristics relative to left-sided cancers. The ßA-subunit and activin-A increased, whilst ßB-subunit and activin-AB decreased, in malignant sites and the late-stage cancers revealed the greatest abnormalities. Interestingly, follistatin declined markedly in early-stage malignant tissues, whilst increased significantly in the advanced stages. All activin molecules were comparable between the early stage right- and left-sided tumours, whereas the late-stage right-sided cancers and L-S4 tumours showed more profound deregulations. In vitro, activin-A increased the numbers of the SW480 cells in sub-G1 and G0/G1-phases, whereas reduced the HT29 cell numbers in the sub-G1 phase with simultaneous increases in the G0/G1 and S phases. The p21/p27/Casp-8/Casp-3 proteins escalated, whilst CCND1/CCND3/BCL2/survivin declined in the SW480 cells following activin-A, whereas activin-A only promoted p21 and p27 alongside reduced CCND3 in the HT29 cells. By contrast, activin-AB increased the numbers of SW480 and HT29 cells in Sub-G1 and G0/G1-phases and promoted the anti-cancer and reduced the oncogenic proteins in both cell lines. In conclusion, activins and follistatin displayed stage-dependent dysregulations and were markedly altered during the advanced stages of right-sided and L-S4 cancers. Moreover, the activin-A actions in CRC could be Smad4-dependent, whereas activin-AB may act as a Smad4-independent tumour suppressor protein.
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Activinas/metabolismo , Neoplasias Colorrectales/metabolismo , Folistatina/metabolismo , Proteína Smad4/metabolismo , Activinas/genética , Activinas/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Femenino , Folistatina/genética , Folistatina/farmacología , Humanos , Subunidades beta de Inhibinas/metabolismo , Masculino , ARN Mensajero/genética , Proteína Smad4/genéticaRESUMEN
BACKGROUND: Cetuximab has a favorable effect on patients with metastatic colorectal cancer harboring wild K-ras gene. This meta-analysis was planned to quantify the benefit. METHODS: A meta-analysis of clinical studies that have used cetuximab-based therapy (CBT) for patients with known K-ras status. RESULTS: There were four randomized studies (RS) that compared CBT versus non-cetuximab control (NCC) in 2,292 patients, and six non-randomized studies (NRS) included patients received cetuximab after failure of prior chemotherapy (411 patients). Patients in RS with wild K-ras tumor gained more benefit from CBT vs. NCC. For response rate (RR), the odds ratio was 2.10 (p = 0.0002), while the hazard ratio (HR) for progression-free survival (PFS) was 0.64 (p = 0.04). On the other hand, CBT was associated with an adverse effect on RR and no effect on PFS in mutated K-ras. In all patients who received CBT in RS and NRS, those with wild vs. mutated K-ras demonstrated higher RR (odds ratio 3.72; p < 0.0001). Compared with NCC in three RS, CBT showed significant overall survival (OS) advantage in patients with wild K-ras (HR = 0.68; p = 0.01). CONCLUSIONS: The significant clinical benefit of CBT concerning RR, PFS, and OS was restricted to patients with wild-type K-ras. There is a need to better define potential responders to CBT.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Mutación/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Anticuerpos Monoclonales Humanizados , Cetuximab , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Humanos , Metástasis de la Neoplasia , Oportunidad Relativa , Proteínas Proto-Oncogénicas p21(ras) , Resultado del TratamientoRESUMEN
INTRODUCTION: Oncotype DX assay recurrence score (ODX-RS) cut-off values have recently changed after the publication of the TAILOR-X trial results. We aim to explore decisions for adjuvant chemotherapy (ACT) based on physicians' clinical assessment and the evolving ODX-RS. METHODOLOGY: Patients who underwent ODX testing after curative surgical resection of estrogen receptor positive (ER+), Her2 non-overexpressed (Her2-) and lymph node-negative (LN-) breast cancer (BC) were eligible. Management of these patients was guided by the results of the old ODX-RS-1 (<18, 18-30, and ≥31) risk grouping. For the purpose of this study, treatment decisions were also assumed according to TAILOR-X results (ODX-RS-2). Decisions of 3 medical oncologists on ACT were solicited by blinding them to the RS to investigate concordance with ODXA RS-1 and 2 recommendations. RESULTS: Sixty-six consecutive patients were included. Median age was 50.5 (range: 21-73) years. There was 1 male patient, and 37/65 females (56.9%) were premenopausal. Among the 3 oncologists, recommendations for ACT based on clinical assessment were discrepant in 29 (43.9%) patients. Based on majority consensus (≥2 oncologists), ACT would have been recommended to 22/41 (53.7%) and 22/46 (47.82%) patients with low-risk tumors according to ODX-RS-1 and ODX-RS-2, respectively. Compared to ODX-RS-1, ODX-RS-2 identifies 12% (46 vs. 41) more low-risk patients and 66% (20 vs. 12 patients) more high-risk patients. CONCLUSION: Overtreatment and discrepancies in the management of patients with ER+/Her2-/LN- early BC can be minimized by the implementation of ODX genomic assay. Some differences in ACT recommendations exist between ODX-RS-1 and ODX-RS-2.
RESUMEN
Breast cancer is a heterogeneous disease that encompasses several distinct entities with different biological characteristics and clinical behavior. Basal subtype is considered as a prognostically unfavorable subset. The purpose of this study is to compare the clinico-pathological characteristics and outcome of basal vs. luminal A subtype, as approximated by ER, PR, and HER-2. Sixty-four patients with basal breast cancer were matched for age, stage, and year of diagnosis with 64 patients having luminal A disease. Basal tumors were immunohistochemically defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and HER-2, while luminal A cancers were ER+ or PR+, and HER-2-. As compared with luminal A, basal subtype patients had significantly larger primary tumor size, higher percentage of grade III tumor, more tumor that showed lymphovascular invasion, less presence of non-invasive disease, and higher proportion of extranodal extension. There was no statistically significant difference in metastatic sites, pathology type, or in the axillary lymph nodal status. A few patients received neoadjuvant chemotherapy--13 and 9 patients in basal and luminal A groups, respectively). The complete pathological response was 20% and 14%, respectively (not significant). At a median follow-up of approximately 2 years, there was no statistically significant difference in the overall survival rate between basal and luminal A patients. Analysis of disease-free survival (DFS) for stage I-III (53 patients in each group) showed that the median DFS for basal patients was 41.4 months (95% CI, 26.5-55.3 months), whereas the DFS for the luminal A patients was not reached (P = 0.014). After adjusting for several significant prognostics variables identified in a univariate analysis, a multivariate conditional logistic regression analysis identified the negative effect of lymphovascular invasion and the favorable influence of the use of neoadjuvant and/or adjuvant chemotherapy. This matched case-control study confirmed the poor clinical and pathological characteristics of patients with basal subtype and their unfavorable outcome compared with luminal A disease. Management of basal tumors remains a challenging task, and new therapeutic strategies are warranted.