Hematological and renoprotective effects of folic acid and lentil extract in diclofenac sodium exposed rats / Efeitos hematológicos e renoprotetores do ácido fólico e do extrato de lentilha em ratos expostos ao diclofenaco de sódio

Excessive intake of non-steroidal anti-inflammatory drugs such as, diclofenac sodium (DS) may lead to toxicity in the rats. In this work, we aimed to examine the protective impact of lentil extract (LE) and folic acid (FA) on the hematological markers, the kidney tissue oxidative stress and the renal function against diclofenac sodium (DS) in male albino rats. The rats (120-150 g) were divided into four equal groups randomly, the first group kept as the untreated control. The second group was administrated with DS (11.6 mg/kg b.wt. orally once/day). The third group was received DS+FA (11.6 mg/kg b.wt.+76.9 microgram/kg b.wt.) orally once/day. The fourth group was treated with DS+LE (11.6 mg/kg b.wt.+500 mg/kg b.wt.) orally once/day. After four weeks, the results revealed that DS produced a significant decrease in the values of red blood cells (RBCs), hemoglobin concentration (Hb), hematocrit (HCT) and white blood cells (WBCs). On the other hand, there was a significant increase in the platelets count. Also, DS induced a renal deterioration; this was evidenced by the significant increase in the serum levels of urea, creatinine, uric acid, Na, Ca, Mg as well as the nitric oxide (NO) level in the kidney tissue. Also, there were a significant reduction in the serum levels of potassium (K) and reduced glutathione (GSH) in the kidney homogenates. Moreover, the findings in the rats treated by DS+LE or DS+FA showed a potential protection on the hematological markers, oxidative stress in the kidney tissue and the renal function disturbed by DS. LE and FA could play a potent role for the prevention the adverse hematological, the kidney tissue oxidative stress and the renal dysfunction caused by DS via their anti-oxidative and bioactive phytochemicals.

A ingestão excessiva de anti-inflamatórios não esteroidais, como o diclofenaco de sódio (DS), pode causar toxicidade em ratos. Neste trabalho, objetivamos examinar o impacto protetor do extrato de lentilha (LE) e ácido fólico (AF) em marcadores hematológicos, no estresse oxidativo do tecido renal e na função renal contra o diclofenaco de sódio (DS) em ratos albinos machos. Os ratos (120-150 g) foram divididos em quatro grupos iguais aleatoriamente, sendo o primeiro grupo mantido como controle não tratado. O segundo grupo foi administrado com DS (11,6 mg / kg de peso corporal por via oral uma vez / dia). O terceiro grupo recebeu DS + FA (76,9 mg / kg de peso corporal por via oral uma vez / dia). O quarto grupo foi tratado com DS + LE (500 mg / kg de peso corporal por via oral uma vez / dia). Após quatro semanas, os resultados revelaram que o DS produziu uma diminuição significativa nos valores de glóbulos vermelhos (RBCs), concentração de hemoglobina (Hb), hematócrito (HCT) e glóbulos brancos (WBCs). Por outro lado, houve um aumento significativo na contagem de plaquetas. Além disso, o DS induziu uma deterioração renal; isso foi evidenciado pelo aumento significativo dos níveis séricos de ureia, creatinina, ácido úrico, Na, Ca, Mg e também do nível de óxido nítrico no tecido renal. Além disso, houve uma redução significativa nos níveis séricos de potássio (K) e glutationa reduzida (GSH) nos homogenatos renais. Além disso, os achados nos ratos tratados com DS + LE ou DS + FA mostraram uma proteção potencial sobre os marcadores hematológicos, estresse oxidativo no tecido renal e função renal perturbada pelo DS. LE e AF podem desempenhar um papel potente na prevenção do estresse hematológico adverso, do estresse oxidativo do tecido renal e da disfunção renal causada pelo DS por meio de seus fitoquímicos antioxidantes e bioativos.

Impact of baseline body mass index on the outcomes of patients with neuroendocrine neoplasms.

OBJECTIVE: To assess the impact of baseline body mass index (BMI) on the outcomes of patients with neuroendocrine neoplasms (NENs) in a population-based setting. METHODS: Linked provincial administrative databases (within the province of Alberta, Canada), 2004-2019, were accessed, and patients with NENs and complete information about BMI near the time of diagnosis were reviewed. The impact of BMI on overall survival was evaluated through the use of Kaplan-Meier survival estimates and multivariable Cox regression modeling. RESULTS: A total of 1010 patients with NENs and BMI information were included. Using Kaplan-Meier survival estimates, survival outcomes were best with individuals with obesity and were worst with underweight individuals (P < 0.0001). The following factors were associated with worse overall survival, older age (HR: 1.02; 95% CI: 1.01-1.03), male sex (HR: 1.60; 95% CI: 1.32-1.93), higher Charlson comorbidity index (HR: 1.22; 95% CI: 1.13-1.31), non-small intestinal primary (HR for gastric primary versus small intestinal primary: 2.36; 95% CI: 1.44-3.85), stage 4 disease (HR: 2.67; 95% CI: 2.16-3.31), neuroendocrine carcinoma histology (HR: 1.76; 95% CI: 1.43-2.17), and underweight BMI (HR versus normal BMI: 1.74; 95% CI: 1.11-2.73). When the model was repeated using BMI as a continuous variable (rather than as a categorical variable), increasing BMI was associated with better overall survival (HR with increasing BMI: 0.97; 95% CI: 0.95-0.98). CONCLUSIONS: Lower BMI is associated with worse overall survival among patients with NENs. This finding was demonstrable regardless of the tumor's stage or histology.

Revisiting the AJCC staging system of adrenocortical carcinoma.

OBJECTIVE: To evaluate the performance characteristics of AJCC 7th and 8th staging systems among patients with adrenal cortical carcinoma. METHODS: Surveillance, Epidemiology, and End Results (SEER) 18-registry was accessed and patients with adrenocortical carcinoma who were diagnosed 2010-2015 with complete information about AJCC 7th staging system were included. AJCC 8th staging system information was then reconstructed for each patient using available TNM staging variables. Kaplan-Meier overall survival estimates, multivariable Cox regression analysis, and concordance index (C-statistic) were used to examine the performance characteristics of both staging systems. RESULTS: A total of 574 patients with a diagnosis of adrenocortical carcinoma were included in the current analysis. Using Kaplan-Meier survival estimates, overall survival was compared among different AJCC stages for both versions; and the P value was significant (< 0.001) for both comparisons. C-statistic was then calculated for both staging systems and the results were as follows: for AJCC 7th version: 0.726 (95% CI 0.683-0.769); and for AJCC 8th version: 0.745 (95% CI 0.704-0.786). Patients with M1 disease (stage IV according to AJCC 8th edition) were then divided according to the extent of distant metastases into single versus multiple sites of metastases. Using Kaplan-Meier survival estimates, patients with a single site of metastases have better overall survival (P = 0.006). A C-statistic for a hypothetical modification of AJCC 8th staging system subdividing stage IV patients into IVA and IVB based on the number of metastatic sites was: 0.753 (95% CI 0.713-0.794). CONCLUSIONS: There is a minimal difference in the prognostic performance between both versions of the AJCC staging system. Subdivision of stage IV cancer into stage IVA and IVB (according to the number of organs with metastatic deposits) should be considered in subsequent versions of adrenocortical carcinoma staging.

Subtype-specific risk factors for postmenopausal breast cancer: findings from the PLCO trial.

OBJECTIVE: The aim of this analysis is to evaluate the relative weight of different epidemiological risk factors on the development of different breast cancer subtypes (i.e. luminal, Her2+ overexpressed or triple negative). METHODS: De-identified datasets of female participants recruited within the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial were accessed. Multivariate Cox regression analysis was utilized to assess factors affecting the development of breast cancer (regardless of subtype). Additional multivariate analyses were conducted to assess factors affecting the development of the three principal subtypes of breast cancer (ER+/Her2- breast cancer; Her2 overexpressed breast cancer and ER-/Her2- breast cancer). RESULTS: A total of 73,570 eligible participants were evaluated in the current analysis of which 2370 participants subsequently developed breast cancer. The following factors were associated with a higher risk of ER+/Her2- breast cancer: white race (P < 0.001), nulliparity (P < 0.001), higher body mass index (P = 0.003), prior exposure to hormone treatment (P = 0.004) and breast cancer in first-degree female relatives (P < 0.001). The following factors were associated with a higher risk of Her2 overexpressed breast cancer: prior exposure to hormone treatment (P = 0.002) and breast cancer in first-degree female relatives (P = 0.001). The following factors were associated with a higher risk of ER-/Her2- breast cancer: black race (P = 0.013), younger age (P = 0.017) and breast cancer in first-degree female relatives (P 0.023). CONCLUSIONS: There is considerable heterogeneity in risk factors among patients with different subtypes of breast cancer. In particular, factors associated with high estrogen levels seem to be associated with luminal breast cancer rather than other breast cancer subtypes.

Outcomes of metastatic colorectal cancer patients in relationship to prior and concurrent antibiotics use; individual patient data analysis of three clinical trials.

BACKGROUND: Antibiotic use at the time of chemotherapy has been linked with inferior outcomes among a number of solid tumors. The current study aims at further assessing this observation among metastatic colorectal cancer patients treated with first-line systemic chemotherapy. METHODS: This is a pooled analysis of three clinical trial datasets (NCT00384176; NCT00272051; NCT00305188) that were accessed from the Project Data Sphere platform. Kaplan-Meier survival estimates were used to evaluate the impact of antibiotic use on overall and progression-free survival and multivariable Cox regression models were employed to further assess this impact. RESULTS: A total of 1446 patients were included in the current analysis. These include 108 patients who received antibiotics before the start of chemotherapy, 499 patients who received antibiotics after the start of chemotherapy, and 839 patients who did not receive antibiotics. Using Kaplan-Meier survival estimates, the use of antibiotics prior to the start of chemotherapy was associated with worse progression-free (P = 0.001) and overall survival (P < 0.001). Likewise, when multivariable Cox regression analyses were conducted, prior antibiotic use is associated with worse progression-free (HR for antibiotic use during chemotherapy versus antibiotic use prior to chemotherapy = 0.764; 95% CI 0.604-0.966; P = 0.024) and overall survival (HR for antibiotic use during chemotherapy versus antibiotic use prior to chemotherapy = 0.710; 95% CI 0.537-0.940; P = 0.017). CONCLUSION: Antibiotic use before (but not following) the start of 5FU-based chemotherapy is associated with worse progression-free and overall survival among patients with metastatic colorectal cancer.

Prognostic value of HPV status among patients with hypopharyngeal carcinoma: a population-based study.

OBJECTIVE: To clarify the prognostic role of human papilloma virus (HPV) status among patients with hypopharyngeal carcinoma. METHODS: Surveillance, Epidemiology and End Results (SEER) HPV head and neck cancer database has been accessed and cases with hypopharyngeal squamous cell carcinoma with known HPV status were retrieved. Kaplan-Meier survival estimates were used to evaluate the impact of HPV status on overall survival outcomes of included patients and multivariable cox regression analysis was used to assess the impact of HPV status on overall and head and neck cancer-specific survival. RESULTS: A total of 1157 patients' records with hypopharyngeal carcinoma were included in the current analysis. Using Kaplan-Meier survival estimates, patients with HPV positive status seem to have better overall survival compared to patients with HPV negative status (P < 0.01). When stratified by stage, patients with HPV positive regional and distant disease have better overall survival compared to patients with HPV negative regional and distant disease (P < 0.01 for both categories). The same observation cannot be confirmed for patients with localized disease (P = 0.15). Using multivariable Cox regression analysis, HPV positive status seems to be associated with better overall survival (HR for HPV negative versus HPV positive status: 1.76; 95% CI 1.39-2.24; P < 0.01) and cancer-specific survival (HR for HPV negative versus HPV positive status: 1.54; 95% CI 1.12-2.11; P < 0.01). CONCLUSIONS: Patients with HPV positive hypopharyngeal carcinoma seem to have better overall and cancer-specific survival compared to patients with HPV negative hypopharyngeal carcinoma.

Generalisability of Common Oncology Clinical Trial Eligibility Criteria in the Real World.

AIMS: Strict oncology clinical trial eligibility criteria can contribute to low accrual and result in poorly generalisable study findings. Using common eligibility criteria, we sought to (i) determine how many patients would be eligible versus ineligible and (ii) describe real-world patterns of treatments and outcomes between those considered trial eligible and ineligible. MATERIALS AND METHODS: The Alberta Cancer Registry was used to assemble a population-based cohort of patients diagnosed with 11 common malignancies between 2004 and 2015. We considered age >75 years, anaemia, comorbid conditions (heart disease, uncontrolled diabetes, kidney disease, liver disease) and history of a prior malignancy or immunosuppression to be exclusion criteria. Logistic regression was used to characterise the likelihood of receiving treatment. Cox regression models were constructed to determine cancer-specific and overall survival. RESULTS: We identified 125 316 cancer patients, of whom 53% were men; the median age was 66 (interquartile range 48-84) years. Approximately 38% of patients were considered trial ineligible. The most common reasons for ineligibility were advanced age (24%) and heart disease (16%). In this ineligible group, 12, 47 and 19% still underwent chemotherapy, surgery and radiotherapy, respectively. Compared with ineligible patients, eligible patients were more likely to undergo chemotherapy (odds ratio 1.98, 95% confidence interval 1.89-2.07, P < 0.0001), surgery (odds ratio 1.39, 95% confidence interval 1.32-1.46, P < 0.0001) and radiotherapy (odds ratio 1.46, 95% confidence interval 1.4-1.52, P < 0.0001). Compared with ineligible patients who did not receive treatment, those considered ineligible but who still received treatment experienced improved cancer-specific survival (hazard ratio 0.75, 95% confidence interval 0.74-0.77, P < 0.0001) and overall survival (hazard ratio 0.89, 95% confidence interval 0.87-0.90, P < 0.0001). CONCLUSIONS: A significant proportion of real-world patients are unable to participate in clinical trials due to stringent exclusion criteria, but many still receive treatment in routine practice. The eligibility criteria of oncology clinical trials should be broadened.

Outcomes of clinically localized prostate cancer patients managed with initial monitoring approach versus upfront local treatment: a North American population-based study.

OBJECTIVE: To assess the outcomes of active monitoring (active surveillance or watchful waiting) as an initial management approach compared to upfront definitive local treatments (prostatectomy or radiation therapy) in a cohort of clinically localized prostate cancer patients. METHODS: Patients with clinically localized prostate cancer registered within the Surveillance, Epidemiology and End Results (SEER) watchful waiting database from 2010-2015 were reviewed. Kaplan-Meier analysis was used to compare overall survival outcomes between patients treated with different initial therapeutic approaches. Multivariate Cox regression analysis (stratified by the risk group) was used to assess potential factors affecting prostate cancer-specific survival. RESULTS: Using Kaplan-Meier analysis, prostatectomy was associated with better overall survival compared to radiation therapy and active monitoring (P < 0.001). Multivariate Cox regression analysis was then employed to evaluate different factors affecting prostate cancer-specific survival. Among patients with low-risk disease, the following factors were predictive of better prostate cancer-specific survival: younger age (hazard ratio for patients ≥ 70 years versus patients 40-69 years: 2.081; 95% CI 1.277-3.390; P = 0.003), white race (hazard ratio for black race versus white race: 2.575; 95% CI 1.538-4.311; P < 0.001), non-Hispanic ethnicity (hazard ratio versus Hispanic ethnicity: 0.472; 95% CI 0.244-0.910; P = 0.025), and initial treatment with prostatectomy (hazard ratio for prostatectomy versus active monitoring: 0.551; 95% CI 0.371-0.818; P = 0.003). CONCLUSIONS: Active monitoring seems to be at least as effective as upfront radiation therapy in the management of low-risk disease. Radical prostatectomy is associated with better overall and prostate cancer-specific survival compared to either radiation therapy or active monitoring.

Outcomes of early-stage breast cancer patients treated with sequential anthracyclines-taxanes in relationship to relative dosing intensity: a secondary analysis of a randomized controlled trial.

PURPOSE: To assess the impact of relative dosing intensity (RDI) on the outcomes of breast cancer patients referred for adjuvant anthracycline-taxane chemotherapy. METHODS: This is a secondary analysis of the outcomes of patients in the comparator arm of the BCIRG005 study who received adjuvant adriamycin/cyclophosphamide (AC)-docetaxel regimen. Overall survival was assessed according to RDI through Kaplan-Meier analysis. Univariate and multivariate analyses of parameters affecting overall survival were then conducted through Cox regression analysis. RESULTS: Kaplan-Meier analysis of overall survival according to RDI for the AC-docetaxel regimen (< 90 vs. ≥ 90%) was conducted and it showed that RDI < 90% is associated with worse overall survival (P = 0.006). In univariate Cox regression analysis, the following parameters significantly affected overall survival (P < 0.05): age, T stage, lymph node ratio, hormone receptor status, and grade of the disease and RDI for AC-docetaxel regimen. When these factors were included in multivariate analysis, the following factors were associated with worse overall survival: age less than 40 years (P < 0.0001), greater T stage (P < 0.0001), greater lymph node ratio (P < 0.0001), negative hormone receptor status (P = 0.001), high grade (P < 0.0001) and RDI ≤ 90% (P = 0.015). Formal interaction testing between RDI and hormone receptor status has a non-significant P value (P = 0.794). CONCLUSION: Lower RDI for the whole anthracycline-taxane protocol is associated with worse patient survival. Every effort should be exercised to avoid unnecessary dose reductions and/or interruptions among early breast cancer patients receiving adjuvant anthracycline-taxane chemotherapy.

Impact of diabetes comorbidity on the efficacy and safety of FOLFOX first-line chemotherapy among patients with metastatic colorectal cancer: a pooled analysis of two phase-III studies.

BACKGROUND: The current analysis aims to provide an evaluation of the impact of diabetes mellitus (DM) on the efficacy and safety of first-line FOLFOX chemotherapy for patients with metastatic colorectal cancer (mCRC). METHODS: This is a pooled analysis of the comparator arms of two clinical trials (NCT00272051; NCT00305188) which evaluated first-line FOLFOX chemotherapy for patients with mCRC. The overall survival and progression-free survival according to patient subsets (non-diabetic and diabetic patients) were assessed through Kaplan-Meier analysis and log-rank testing. Propensity score matching was additionally conducted to account for heterogeneity in baseline characteristics of different subsets of patients. RESULTS: A total of 756 patients were enrolled in the current analysis; of which 64 patients have pre-existing DM while 692 patients were non-diabetic. Through Kaplan-Meier analysis, no evidence for overall or progression-free survival difference was found among the two patient subsets (P = 0.501; P = 0.960, respectively). Moreover, metformin treatment does not affect overall or progression-free survival among diabetic patients (P = 0.598; P = 0.748, respectively). Repetition of overall and progression-free survival assessment following propensity score matching does not reveal any differences. Comparing diabetic to non-diabetic patients, there were no differences between the two groups in terms of acute oxaliplatin-induced neurological symptoms including cold-induced dysthesia (P = 0.600), laryngeal dysthesia (P = 0.707), jaw pain (P = 0.743) or muscle pain (P = 0.506). Moreover, no difference was seen between the two groups in terms of the incidence of long-term oxaliplatin-induced paresthesia (P = 0.107), highest grade of paresthesia (P = 0.498) or rates of recovery from paresthesia (P = 0.268). Diabetic patients have, however, a shorter time to develop oxaliplatin-induced paresthesia (P = 0.024). CONCLUSION: DM does not seem to affect overall or progression-free survival of mCRC patients treated with first-line FOLFOX chemotherapy. Moreover, DM does not influence the incidence or severity of oxaliplatin-induced paresthesia in those patients while it might lead to a shorter time to develop oxaliplatin-induced paresthesia compared to non-diabetic patients.

Statin treatment and outcomes of metastatic pancreatic cancer: a pooled analysis of two phase III studies.

BACKGROUND: The current analysis aims to evaluate the impact of statin co-treatment on the survival of patients with metastatic pancreatic cancer. METHODS: This is a pooled analysis of de-identified patient data from two clinical trials (NCT01124786; NCT00844649). Overall and progression-free survival according to patient subsets (patients who received or who did not receive statins) were assessed through Kaplan-Meier analysis and log-rank test. Univariate and multivariate Cox regression analysis was performed to evaluate different factors potentially affecting overall and progression-free survival. Propensity score matching was performed to address heterogeneity in baseline characteristics of different subgroups of patients. RESULTS: A total of 797 patients were assessed in the current study; of which 156 patients received statins and 641 did not receive statins. Using Kaplan-Meier survival estimates, patients who received statins seem to have better overall and progression-free survival compared to patients who did not (P = 0.008; P < 0.001, respectively). In multivariate analysis for factors affecting overall survival, the following factors were associated with worse overall survival: worse performance status (P < 0.001), no statin use (P = 0.044) and multiple sites of metastatic disease (P = 0.023); likewise in multivariate analysis for factors affecting progression-free survival, the following factors were associated with worse progression-free survival: worse performance status (P < 0.001), gemcitabine elaidate chemotherapy (P = 0.015) and no statin use (P = 0.048). Following propensity score matching and using Kaplan-Meier estimates, statin use was also associated with better overall and progression-free survival (P = 0.005; P = 0.040, respectively). CONCLUSION: Statin use seems to be associated with better overall survival among patients with metastatic pancreatic cancer treated with first-line chemotherapy. Prospective studies designed specifically to assess this potential effect of statins are needed.

Revisiting Dukes' paradigm; some node positive colon cancer patients have better prognosis than some node negative patients.

BACKGROUND: The current study tried to evaluate the prognostic value of a modified staging system compared to the American Joint Committee on Cancer (AJCC) staging system for patients with colon cancer. PATIENTS AND METHODS: Surveillance, epidemiology and end results (SEER) database (2004-2014) was queried through SEER*Stat program and AJCC 7th stages were constructed. Through recursive partitioning analysis and subsequent decision tree formation, suggested new stages were formulated based on T and N descriptors. Overall survival analyses were performed through Kaplan-Meier analysis. The cancer-specific Cox regression hazard (adjusted for age, gender, sub-site, grade, race and surgery) was calculated and pair wise comparisons of hazard ratios were conducted. RESULTS: A total of 159,683 non-metastatic patients with colon cancer were recruited in the analysis. Pair wise hazard ratio comparisons among different AJCC 7th stages were conducted and all comparisons were significant (P < 0.0001). However, it should be noted that the adjusted risk of death among stage IIC patients was higher than stage IIIA and IIIB. Pair wise hazard ratio comparisons among different modified system stages were also conducted and all comparisons were significant (P < 0.0001). The outcomes of survival analysis were the same regardless of the number of examined lymph nodes (< 12 vs. ≥ 12). Concordance index (using death from colon cancer as the dependent variable) for AJCC 6th staging system was 0.704 (SE 0.002; 95% CI 0.701-0.708); for AJCC 7th staging system was 0.708 (SE 0.002; 95% CI 0.704-0.711); for Dukes staging system was 0.670 (SE 0.002; 95% CI 0.666-0.674); and for modified staging system was 0.712 (SE 0.002; 95% CI 0.709-0.716). CONCLUSION: The proposed modified staging system provided an improved prognostication for colon cancer patients (particularly for stage II/III disease) compared to AJCC staging system. Further external validation of the proposed staging system is needed before adoption into routine practice.

Validation of the AJCC 8th lung cancer staging system among patients with small cell lung cancer.

BACKGROUND: The current study tried to validate the prognostic significance of the 8th American Joint Committee on Cancer (AJCC) staging system among small cell lung cancer (SCLC) patients recorded within the surveillance, epidemiology, and end results (SEER) database. PATIENTS AND METHODS: SEER database (2004-2014) has been queried through SEER*Stat program, and both AJCC 7th and 8th edition stages were constructed. Cancer-specific and overall survival analyses according to both editions were performed through Kaplan-Meier analysis. The cause-specific Cox regression hazard for both AJCC editions (adjusted for age, gender, race, and surgery) was calculated and pair-wise comparisons of hazard ratios were conducted. RESULTS: A total of 39,286 patients with SCLC were recruited in the period from 2004 to 2014. For overall and cancer-specific survival assessment, according to the AJCC 7th edition, P values for all pair-wise comparisons among different stages were significant (<0.0001) except for the comparisons between stage IB vs. stage IIA, and stage IIB vs. stage IIIA. For overall survival assessment, according to AJCC 8th, P values for all pair-wise comparisons were significant (<0.05) except for IA2 vs. IA3, IA3 vs. IB, IB vs. IIA, IIA vs. IIB, and IIIB vs. IIIC. For cancer-specific survival, according to AJCC 8th, P values for all pair-wise comparisons among different stages were significant (<0.05) except IA1 vs. IA2, IA2 vs. IA3, and IIA vs. IIB. When conducting pair-wise hazard ratio comparisons among different AJCC stages (for both editions), similar findings to the Kaplan-Meier analyses were reported. CONCLUSION: While there is a clear improvement for both the AJCC 7th and 8th systems compared to the old veterans' administration system, there is a modest improvement for the 8th compared to the 7th system among patients with SCLC.

Modified staging system for pulmonary carcinoids on the basis of lung cancer TNM system.

BACKGROUND: Pulmonary carcinoids are being staged along the lines of lung cancer American Joint Committee on Cancer (AJCC) staging system. The current study evaluated the prognostic value of a modified staging system for patients with pulmonary carcinoid. PATIENTS AND METHODS: Surveillance, Epidemiology and End Results (SEER) database (2004-2014) was searched through SEER*Stat program. Through recursive partitioning analysis and subsequent decision tree formation, suggested stages were constructed. Overall survival analyses were performed through Kaplan-Meier analysis. The cancer-specific Cox regression hazard (adjusted for age, gender, race, sub-site and surgery) was calculated and pairwise comparisons of hazard ratios were conducted. RESULTS: A total of 6395 pulmonary carcinoid patients were recruited in the period from 2004-2014. Pairwise hazard ratio comparisons among different AJCC 8th stages were conducted and all comparisons were non-significant except for stage IIB vs. stage IIIA and stage IIIA vs. stage IIIB. Pairwise hazard ratio comparisons among different modified staging system stages were conducted and all comparisons were significant except for stage III vs. stage IV. C-statistic (using death from pulmonary carcinoid as the dependent variable) for AJCC 8th staging system was: 0.794 (SE 0.013; 95% CI 0.769-0.818); for AJCC 7th staging system was: 0.789 (SE 0.013; 95% CI 0.764-0.815), while c-statistic for the modified staging system was: 0.802 (SE 0.012; 95% CI 0.778-0.827). CONCLUSION: The proposed modified staging system provided a simpler yet prognostically more relevant classification of pulmonary carcinoids compared to AJCC staging systems (both 7th and 8th editions).

Prostascore: A Simplified Tool for Predicting Outcomes among Patients with Treatment-naive Advanced Prostate Cancer.

AIMS: To develop and internally validate a new simplified model 'prostascore' to help predict the outcomes of treatment-naive patients with advanced prostate cancer. PATIENTS AND METHODS: Through the SEER*Stat program, the Surveillance, Epidemiology and End Results (SEER) database was queried for eligible records spanning the period from 2010 to 2013. The resulting group of patients was equally divided into two sets: training group (to guide model development) and validation group (to validate the model prediction). Multivariate analysis for the candidate prognostic factors (extent of extra-prostatic disease, prostate-specific antigen [PSA] level and grade) was conducted through a Cox proportional model. Prostascore was then calculated for each patient. Cancer-specific and overall survival analyses according to prostascore were conducted through Kaplan-Meier analysis/Log-rank testing. RESULTS: In total, 8727 patients with treatment-naive advanced prostate cancer and complete baseline data were identified in the period from 2010 to 2013. The following factors were associated with better cancer-specific survival in the training set (isolated regional nodal disease, lower PSA level and lower grade group; P < 0.0001). After assignment of a prostascore for each patient, cancer-specific survival was compared according to the score. Pairwise comparisons between all different scores were conducted. For cancer-specific survival evaluation according to the prostascore model, P values for pairwise comparisons among different score points were significant (P < 0.05) in the validation set. CONCLUSION: Prostascore is an easy and reliable tool for predicting the outcomes of patients with treatment-naive advanced prostate cancer. Further validation within the context of other treatment settings and population-based cohorts is recommended.

Validation of the prognostic value of new sub-stages within the AJCC 8th edition of non-small cell lung cancer.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for non-small cell lung cancer (NSCLC) has been released. The current study tried to validate the prognostic significance of the new system among patients registered within the surveillance, epidemiology and end results (SEER) database. METHODS: SEER database (2010-2013) has been accessed through SEER*Stat program and AJCC 8th edition stages were reconstructed utilizing the collaborative stage descriptions. Overall and lung cancer-specific survival analyses according to both 7th and 8th editions were conducted through Kaplan-Meier analysis and multivariate analysis was conducted through a Cox proportional hazard model. RESULTS: A total of 127,096 patients with NSCLC were identified in the period from 2010 to 2013. For overall survival assessment according to the 8th edition, P values for all pair-wise comparisons among different stages were significant (<0.0001) except for the comparisons between stage IB and IIA (P = 0.146); stage IIA and IIB (P = 0.165). For lung cancer-specific survival according to the 8th edition, P values for all pair-wise comparisons among different stages were significant (<0.001). Among patients with stage I disease, multivariate analysis for factors affecting overall and lung cancer-specific survival among patients with stage I disease was conducted. The following factors were associated with worse overall and lung cancer-specific survival: age ≥70 years, more advanced stage, male gender, squamous histology, no surgery and no radiotherapy (P < 0.0001 for all factors). CONCLUSION: This SEER analysis supports the prognostic significance of the added sub-stages described within AJCC 8th edition stages I and III. Further work is needed to incorporate molecular markers and personalize the future editions of the AJCC staging system.

Treatment-related Death in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.

AIMS: We carried out a meta-analysis to determine the risk of treatment-related death associated with immune checkpoint inhibitor use in cancer patients. MATERIALS AND METHODS: We examined data from the Medline and Google Scholar databases. We also examined original studies and review articles for cross-references. Eligible studies included randomised phase II and phase III trials of patients with cancer treated with ipilimumab, pembrolizumab; nivolumab; tremelimumab and atezolizumab. The authors extracted relevant information on participants, characteristics, treatment-related death and information on the methodology of the studies. RESULTS: After exclusion of ineligible records, 18 clinical trials were included in the analysis. The odds ratio for treatment-related death for CTLA-4 inhibitors (ipilimumab and tremelimumab) was 1.80 (95% confidence interval 1.25, 2.59; P=0.002) and for PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab and atezolizumab) was 0.63 (95% confidence interval 0.31, 1.30; P=0.22). Treated cancer seems to have no effect on the risk of treatment-related death. CONCLUSIONS: Analysis of our data showed that CTLA-4 inhibitors (ipilimumab and tremelimumab) in a higher dose (10 mg/kg) seem to be associated with a higher risk of treatment-related death compared with control regimens, whereas PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab and atezolizumab) do not cause the same risk. Clinicians have to be fully aware of these differential risks and council their patients appropriately.

Identification of clinical biomarkers for patients with advanced hepatocellular carcinoma receiving sorafenib.

BACKGROUND: Identification of patients with advanced HCC-deriving preferential benefit from sorafenib is desirable, and treatment-related adverse events are potential clinical biomarkers. METHODS: Survival and toxicity data for patients with HCC treated with sorafenib at the Christie NHS Foundation Trust from 11/09 to 02/15 were collected retrospectively. RESULTS: Eighty-five eligible patients were identified. The most common grade 3 or 4 treatment-related toxicities were hypertension (HTN, 45 %), fatigue (8 %), and hand-foot syndrome (HFS, 8 %). Any-grade HFS and/or worsening HTN (HFS/HTN) were experienced by 58 % of patients. Estimated median progression-free and overall survival (OS) were 4.6 (95 % CI 2.8-5.2) and 6.5 (95 % CI 4.9-8.01) months, respectively. Child-Pugh score (p value <0.001) and the development of HFS/HTN were independent prognostic factors impacting on OS on multivariable analysis. Patients who developed HFS/HTN had median OS of 8.2 months (95 % CI 6.5-12.4) compared with 4.1 (95 % CI 2.7-5.4) for those without this toxicity (Hazard Ratio (HR) 0.4, 95 % CI 0.2-0.7, p value 0.003). The prognostic impact of HFS/HTN was confirmed by landmark analyses limited to patients who lived a minimum of 2 months (p value 0.019) or who developed HFS/HTN in the first 3 months of treatment (p value 0.006). CONCLUSION(S): The development of toxicities specific to sorafenib is associated with prolonged survival in a UK-based HCC patient series; prospective assessment of their significance is required.

Treatment-associated Fatigue in Cancer Patients Treated with Immune Checkpoint Inhibitors; a Systematic Review and Meta-analysis.

AIMS: Fatigue is one of the most prominent side-effects of immune checkpoint inhibition. Therefore, we assessed the risk of fatigue associated with inhibitors of the immune checkpoints. MATERIALS AND METHODS: We examined data from the Medline and Google Scholar databases. We also examined original studies and review articles for cross-references. Eligible studies included randomised phase II and phase III trials of patients with cancer treated with ipilimumab, nivolumab, pembrolizumab and tremelimumab. The authors extracted relevant information on participants(') characteristics, all-grade and high-grade fatigue and information on the methodology of the studies. RESULTS: In total, 17 trials were considered eligible for the meta-analysis. The odds ratio for all-grade fatigue for CTLA-4 inhibitors was 1.23 (95% confidence interval 1.07, 1.41; P = 0.003) and for high-grade fatigue was 1.72 (95% confidence interval 1.26, 2.33; P = 0.0005). Moreover, the odds ratio for all-grade fatigue for PD-1 inhibitors was 0.72 (95% confidence interval 0.62, 0.84; P < 0.0001) and for high-grade fatigue was 0.36 (95% confidence interval 0.23, 0.56; P < 0.00001). CONCLUSIONS: The analysis of data showed that CTLA-4 inhibitors seem to be associated with a higher risk of all- and high-grade fatigue compared with control regimens, whereas PD-1 inhibitors seem to be associated with a lower risk of all- and high-grade fatigue compared with control regimens.

Doublet BRAF/MEK inhibition versus single-agent BRAF inhibition in the management of BRAF-mutant advanced melanoma, biological rationale and meta-analysis of published data.

BACK GROUND: We executed a comparative systematic review and meta-analysis of the efficacy and toxicity of doublet BRAF/MEK inhibition versus single-agent BRAF inhibitor in the management of BRAF-mutant advanced melanoma. METHODS: Eligible studies included prospective studies evaluating doublet regimens versus BRAF-inhibitor monotherapy for the management of BRAF-mutant advanced melanoma. RESULTS: Our search strategy yielded 200 potentially relevant citations from searched databases. After preclusion of ineligible studies, four studies were included in the final analysis. Efficacy analyses demonstrate that BRAF/MEK inhibition strategy is associated with a significant improvement in ORR [OR 1.35; 95 % CI (1.16, 1.58); P = 0.0002], PFS [HR 0.56; 95 % CI (0.49, 0.64); P < 0.00001] and OS [HR 0.70; 95 % CI (0.58, 0.84); P = 0.0001]. Moreover, this combination is associated with a higher RR for diarrhea [1.30; 95 % CI (1.30, 1.49); P = 0.0002], decreased ejection fraction [4.63; 95 % CI (2.56, 8.37); P = <0.00001], acneiform dermatitis [1.61; 95 % CI (1.03, 2.53); P = 0.04] and pyrexia [1.98; 95 % CI (1.72, 2.27); P < 0.00001]. CONCLUSIONS: Our meta-analysis has demonstrated that combination of MEK/BRAF inhibitors is associated with higher ORR, PFS and OS. However, this comes at the expense of a higher risk of selected toxicities.