Combination of T-DM1 and platinum-based chemotherapy in patient-derived xenograft models of muscle-invasive bladder cancer.

Objectives: To assess the efficacy and safety of T-DM1, as an anti-HER2 antibody-drug conjugate (ADC), alone and in combination with two platinum-based chemotherapy regimens in patient-derived xenografts (PDXs) of muscle-invasive bladder cancer (MIBC) established in immunodeficient mice. Materials and Methods: After treatment initiation, tumor size was measured twice a week. Percent of tumor growth inhibition (TGI) and tumor response rates were calculated as efficacy endpoints. To evaluate treatment toxicity, relative body weight (RBW) was calculated for each group. For comparison of TGIs between treatment groups, the Kruskal-Wallis test was used. Also, the significance of the overall response (OR) rate between placebo groups with treatment groups was analyzed using Fisher's exact test. Immunohistochemistry and fluorescence in situ hybridization techniques were used to evaluate the level of HER2 expression. Results: Our data showed that T-DM1 alone induced a moderate antitumor activity. While chemotherapy regimens induced a slight TGI when administered alone, interestingly, they showed strong antitumor activity when administered combined with T-DM1. The OR rates were higher when T-DM1 was combined with chemotherapy regimens than T-DM1 alone. When compared with the placebo group, the OR rates of combination groups were statistically significant. Our data also showed that the administered dose of each drug was well tolerated in mice. Conclusion: The combination of T-DM1 and platinum-based chemotherapy may represent a new treatment option for bladder tumors with even low HER2 expression, and could also provide substantial novel insight into tackling the challenges of MIBC management.

Oncological Outcomes of Neoadjuvant Gemcitabine plus Carboplatin versus Gemcitabine plus Cisplatin in Locally Advanced Bladder Cancer: A Retrospective Analysis.

PURPOSE: Cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care in non-metastatic muscle-invasive bladder cancer (MIBC). There are limited data regarding the alternative choices for cisplatin-ineligible patients. This study has investigated the oncological outcomes of gemcitabine plus cisplatin (Gem/Cis) and gemcitabine plus carboplatin (Gem/Carbo) in this setting. MATERIALS AND METHODS: One hundred forty consecutive patients with MIBC (cT2-T4a) receiving neoadjuvant Gem/Cis or Gem/Carbo before chemoradiation (CRT) or radical cystectomy (RC) were retrospectively evaluated between April 2009 and April 2019. Patients with ECOG performance status 2, creatinine clearance < 60 mL/min, hydronephrosis, ejection fraction < 50%, or single kidney received Gem/Carbo. The complete clinical response (cCR) and overall survival (OS) of NAC regimens were compared. Prognostic significance was assessed with Cox proportional hazards model. RESULTS: In total, 79 patients (56.4%) received Gem/Cis. The cCR was not significantly different between Gem/Cis and Gem/Carbo regimens (38.7% vs. 36.2%, P = .771). After NAC, 79 patients (56.4%) received CRT, and other cases underwent RC. After a median follow-up of 43 months, patients in the Gem/Cis group had significantly better OS than Gem/Carbo (median OS: 41.0 vs. 26.0 months, P = .008). Multivariable Cox proportional hazards models identified cT4a stage (95% confidence interval [95% CI]: 1.001-4.85, hazard ratio [HR] = 2.08, P = .03) and cCR (95% CI: 0.26-0.99, HR = 0.51, P = .04) as the only independent prognostic factors of OS, and ruled out the type of NAC regimen. CONCLUSION: The choice of NAC (between Gem/Cis and Gem/Carbo) is not the predictor of survival and both regimens had similar cCR.

Combined effect of oral famotidine and cimetidine on the survival of lethally irradiated mice: An in vivo study.

AIMS: The study aims at evaluating the effects of the combinatory famotidine/cimetidine diet on radiated mice's survival. MATERIALS AND METHODS: Two hundred and seventy male mice were categorized into 11 groups, a number of which were comprised of subgroups too. The groups under analysis were posed to varying doses of gamma-radiation, including 6, 7, 8, and 9 Gy, followed by treatments using various drug doses 2, 4, and 8 mg/kg, with survival fractions as long as a month after irradiation being measured and recorded. RESULTS: LD50/30 was calculated as 7.47 Gy for the group with radiation only. Following mouse treatment with a concentration of 4 and 20 mg/kg for famotidine and cimetidine, respectively, the survival fraction for the mice grew significantly compared to LD50/30. The combinatory famotidine/cimetidine diet had a higher dose-reduction factor (DRF) than single doses of the drug in radioprotection. The DRF for combinatory famotidine/cimetidine, famotidine, and cimetidine diets was 08.09, 1.1, and 1.01, respectively. CONCLUSIONS: Results imply that the combined regimen of famotidine + cimetidine in radioprotection had no significant higher DRF than with regimens including each of them separately. In addition, we did not find a synergic effect of combined oral famotidine and cimetidine on irradiated mice.

Association of immunohistochemical markers of tumor subtype with response to neoadjuvant chemotherapy and survival in patients with muscle-invasive bladder cancer.

PURPOSE: A readily accessible biomarker to identify which patients with bladder cancer are more likely to respond to neoadjuvant chemotherapy (NAC) could help clinicians avoid unnecessary chemotherapy and prevent its subsequent complications in some patients. The primary objective of this study was to investigate the association of immunohistochemical markers of tumor subtype with response to NAC and survival of patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: MIBC patients treated with NAC were retrospectively included. The tissue microarrays were assembled from transurethral resection of bladder tumor (TURBT) specimens and immunohistochemistry (IHC) was performed. The association of independent variables, including IHC markers, and clinical covariates with clinical complete response to NAC and with overall survival was assessed by using logistic regression and Cox proportional hazard regression analysis, respectively. Kaplan-Meier curves were plotted for different IHC-based tumor subtypes. RESULTS: Data from 140 MIBC patients treated with NAC were retrospectively reviewed. A total of 63 patients with available TURBT specimens were eligible to be included in the analysis. Our results showed that the IHC signature of KRT5/6(+)/KRT20(-), as a combined marker of basal subtype, was the only covariate significantly associated with complete response to NAC (p=0.037). Moreover, we found no statistically significant differences in overall survival between different IHC-based subtypes (p=0.721). CONCLUSIONS: The IHC expression of KRT5/6 and KRT20, as a readily accessible combined marker, may help us to identify the patients most likely to benefit from chemotherapy. The clinical utility of this marker needs to be established in larger prospective studies.

Data-Driven Discovery of Molecular Targets for Antibody-Drug Conjugates in Cancer Treatment.

Antibody-drug conjugate therapy has attracted considerable attention in recent years. Since the selection of appropriate targets is a critical aspect of antibody-drug conjugate research and development, a big data research for discovery of candidate targets per tumor type is outstanding and of high interest. Thus, the purpose of this study was to identify and prioritize candidate antibody-drug conjugate targets with translational potential across common types of cancer by mining the Human Protein Atlas, as a unique big data resource. To perform a multifaceted screening process, XML and TSV files including immunohistochemistry expression data for 45 normal tissues and 20 tumor types were downloaded from the Human Protein Atlas website. For genes without high protein expression across critical normal tissues, a quasi H-score (range, 0-300) was computed per tumor type. All genes with a quasi H - score ≥ 150 were extracted. Of these, genes with cell surface localization were selected and included in a multilevel validation process. Among 19670 genes that encode proteins, 5520 membrane protein-coding genes were included in this study. During a multistep data mining procedure, 332 potential targets were identified based on the level of the protein expression across critical normal tissues and 20 tumor types. After validation, 23 cell surface proteins were identified and prioritized as candidate antibody-drug conjugate targets of which two have interestingly been approved by the FDA for use in solid tumors, one has been approved for lymphoma, and four have currently been entered in clinical trials. In conclusion, we identified and prioritized several candidate targets with translational potential, which may yield new clinically effective and safe antibody-drug conjugates. This large-scale antibody-based proteomic study allows us to go beyond the RNA-seq studies, facilitates bench-to-clinic research of targeted anticancer therapeutics, and offers valuable insights into the development of new antibody-drug conjugates.

Development and immunohistochemical characterization of patient-derived xenograft models for muscle invasive bladder cancer.

Objectives: Patient-derived xenograft (PDX) models have become a valuable tool to evaluate chemotherapeutics and investigate personalized cancer treatment options. The role of PDXs in the study of bladder cancer, especially for improvement of novel targeted therapies, continues to expand. In this study, we aimed to establish autochthonous PDX models of muscle-invasive bladder cancer (MIBC) to provide a useful tool to conduct research on personalized therapy. Materials and Methods: Tumors from MIBC patients undergoing radical cystectomy were subcutaneously transplanted into immunodeficient mice. The tumor size was measured by a caliper twice a week for up to five months. After the first growth in mice, they were serially passaged. Hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) of 11 markers (Ki67, P63, GATA3, KRT5/6, KRT20, E-cadherin, 34ßE12, PD-L1, EGFR, Nectin4, and HER2) were used to evaluate phenotype maintenance of original tumors. Results: From 10 MIBC patients, two PDX models (P8X20 and P8X26) were successfully established (20% success rate). These models mostly retained primary tumor characteristics including histology, morphology, and molecular nature of the original cancer tissues. IHC analysis showed that the expression level of 7 markers for the model P8X20, and 8 markers for the model P8X26 was exactly similar between the patient tumor and the next generations. Conclusion: We developed the first autochthonous PDX models of MIBC in Iran. Our data suggested that the established MIBC PDX models reserved mostly histopathological characteristics of primary cancer and could provide a new tool to evaluate novel biomarkers, therapeutic targets, and drug combinations.

Randomized, Double-blind Pilot Study of Nanocurcumin in Bladder Cancer Patients Receiving Induction Chemotherapy.

PURPOSE: To evaluate the feasibility and potential efficacy of nanocurcumin supplementation in patients with localized muscle-invasive bladder cancer (MIBC) undergoing induction chemotherapy. MATERIALS AND METHODS: In this double-blind, placebo-controlled trial, 26 MIBC patients were randomized to receive either nanocurcumin (180 mg/day) or placebo during the course of chemotherapy. All patients were followed up to four weeks after the end of treatment to assess the complete clinical response to the chemotherapy as primary endpoint. Secondary endpoints were the comparisons of chemotherapy-induced nephrotoxicity, hematologic nadirs, and toxicities between the two groups. Hematologic nadirs and toxicities were assessed during the treatment. RESULTS: Nanocurcumin was well tolerated. The complete clinical response rates were 30.8 and 50% in the placebo and nanocurcumin groups, respectively. Although nanocurcumin was shown to be superior to placebo with respect to complete clinical response rates as the primary endpoint, there was no significant difference between the groups (p = 0.417). No significant difference was also found between the two groups with regard to grade 3/4 renal and hematologic toxicities as well as hematologic nadirs. CONCLUSION: These preliminary data indicate the feasibility of nanocurcumin supplementation as a complementary therapy in MIBC patients and support further larger studies. Moreover, a substantial translational insight to fill the gap between the experiment and clinical practice in the field is provided.

Terazosin or baclofen in young men with chronic orchialgia: A cohort study of 499 patients.

PURPOSE: We aimed to investigate the comparative efficacy of terazosin and baclofen in young men with chronic orchialgia using National Institutes of Health Chronic Prostatitis Symptom Index measurement. PATIENTS AND METHODS: Of 499 young men with chronic orchialgia, 255 received a daily 2 mg terazosin at bedtime and 244 received 10 mg baclofen during a period of 3 months. A daily 10-min hot-tub hip-bath rest was administered for all patients. Moreover, all patients with grade 3 and 18 patients with grade 2 varicocele underwent varicocelectomy. The National Institutes of Health Chronic Prostatitis Symptom Index score was assessed at baseline and 3 months later. RESULTS: Both terazosin and baclofen groups experienced a significant reduction in mean National Institutes of Health Chronic Prostatitis Symptom Index score (24.78 and 24.81 at baseline to 19.68 and 19.60 after the treatment for terazosin and baclofen groups, respectively). However, there was no significant difference between the groups with regard to post-treatment National Institutes of Health Chronic Prostatitis Symptom Index score after adjustment for the pre-treatment score (p = 0.987). A total of 85 patients (33.4%) in terazosin group and 74 patients (30.3%) in baclofen group underwent varicocelectomy. Addition of the varicocelectomy to the treatment as a multimodal approach had no further improvement in the National Institutes of Health Chronic Prostatitis Symptom Index score. CONCLUSION: Although a significant reduction was observed in mean National Institutes of Health Chronic Prostatitis Symptom Index score for both terazosin and baclofen groups, there was no significant difference between the treatments. Moreover, addition of varicocelectomy to terazosin or baclofen could not significantly decrease National Institutes of Health Chronic Prostatitis Symptom Index score; thus, varicocelectomy may not be appropriate for men who have some success with medical management. Further randomized studies are warranted.

Predictors of chemotherapy-induced severe anemia in cancer patients receiving chemotherapy.

PURPOSE: Chemotherapy-induced anemia is a frequent complication of systemic chemotherapy and is associated with decreased functional capacity and quality of life. The objective of this study was to identify the candidate variables most likely to be associated with chemotherapy-induced severe anemia (hemoglobin < 8 g/dL) in patients treated with cytotoxic chemotherapy. METHODS: A total of 14 clinical and laboratory covariates were prospectively evaluated at baseline in a cohort of consecutive cancer patients receiving cytotoxic chemotherapy. The anemia risk category for each chemotherapy regimen used was determined based on pivotal trials published in the literature. All regimens were classified to three categories (high risk, intermediate risk, and low risk). Logistic regression analysis adjusted for the regimen risk was used to determine the candidate risk factors associated with chemotherapy-induced anemia. RESULTS: A total of 305 patients were included in the study. Administration of high-risk regimens (i.e., regimens with ≥ 20% risk of anemia in a pivotal trial) was demonstrated to be a novel independent predictive factor for severe anemia (odds ratio 3.33, p = 0.005). Considering regimen risk as an adjustment factor, 5 readily available predictors including low hemoglobin, body mass index (BMI) less than 23 kg/m2, low hematocrit, high haptoglobin, and high ferritin were associated with the outcome. CONCLUSIONS: The application of these candidate predictors would be helpful in classifying patients at risk for severe anemia, who might be appropriate candidates for prophylactic erythropoietin. Multivariable models including such promising candidate predictors need to be developed.

Predicting chemotherapy-induced thrombocytopenia in cancer patients with solid tumors or lymphoma.

PURPOSE: Chemotherapy-induced thrombocytopenia is a serious complication in chemotherapy-treated patients. Identification of patients at risk for chemotherapy-induced thrombocytopenia could have clinical value in personalized management of patients and optimized administration of prophylactic thrombopoietic agents. The aim of this study was to develop a predictive model for chemotherapy-induced thrombocytopenia (platelet count < 100,000/µl) in cancer patients undergoing chemotherapy. METHODS: A total of 14 covariates were prospectively assessed as explanatory variables in a cohort of consecutive patients with solid tumors or lymphoma. A multivariable logistic regression model was developed after univariable analysis. A bootstrapping technique was applied for internal validation. RESULTS: Data from 305 patients during 1732 chemotherapy cycles were considered for analysis. Forty-eight patients (15.73%) developed chemotherapy-induced thrombocytopenia during their treatment course. The multivariable model exhibited three final predictors for chemotherapy-induced thrombocytopenia, including high ferritin (odds ratio, 4.41; bootstrap P = 0.001), estimated glomerular filtration rate <60 ml/min/1.73 m2 (odds ratio, 3.08; bootstrap P = 0.005), and body mass index <23 kg/m2 (odds ratio, 2.23; bootstrap P = 0.044). The main characteristics of the model include sensitivity 75%, specificity 65.4%, positive likelihood ratio 2.16, and negative likelihood ratio 0.382. Moreover, the model was well calibrated (Hosmer-Lemeshow P = 0.713) and the area under the receiver operating characteristic curve was 0.735 (95% confidence interval, 0.654-0.816; P < 0.001). CONCLUSIONS: We developed a predictive model for chemotherapy-induced thrombocytopenia based on readily available and easily assessable clinical and laboratory factors. This study may provide a valuable insight to guide optimized treatment of cancer patients. Further studies with larger sample size are warranted.

CT imaging markers to improve radiation toxicity prediction in prostate cancer radiotherapy by stacking regression algorithm.

PURPOSE: Radiomic features, clinical and dosimetric factors have the potential to predict radiation-induced toxicity. The aim of this study was to develop prediction models of radiotherapy-induced toxicities in prostate cancer patients based on computed tomography (CT) radiomics, clinical and dosimetric parameters. METHODS: In this prospective study, prostate cancer patients were included, and radiotherapy-induced urinary and gastrointestinal (GI) toxicities were assessed by Common Terminology Criteria for adverse events. For each patient, clinical and dose volume parameters were obtained. Imaging features were extracted from pre-treatment rectal and bladder wall CT scan of patients. Stacking algorithm and elastic net penalized logistic regression were used in order to feature selection and prediction, simultaneously. The models were fitted by imaging (radiomics model) and clinical/dosimetric (clinical model) features alone and in combinations (clinical-radiomics model). Goodness of fit of the models and performance of classifications were assessed using Hosmer and Lemeshow test, - 2log (likelihood) and area under curve (AUC) of the receiver operator characteristic. RESULTS: Sixty-four prostate cancer patients were studied, and 33 and 52 patients developed ≥ grade 1 GI and urinary toxicities, respectively. In GI modeling, the AUC for clinical, radiomics and clinical-radiomics models was 0.66, 0.71 and 0.65, respectively. To predict urinary toxicity, the AUC for radiomics, clinical and clinical-radiomics models was 0.71, 0.67 and 0.77, respectively. CONCLUSIONS: We have shown that CT imaging features could predict radiation toxicities and combination of imaging and clinical/dosimetric features may enhance the predictive performance of radiotoxicity modeling.

MRI Radiomic Analysis of IMRT-Induced Bladder Wall Changes in Prostate Cancer Patients: A Relationship with Radiation Dose and Toxicity.

BACKGROUND: The main purpose of this study was to assess the structural changes in the bladder wall of prostate cancer patients treated with intensity-modulated radiation therapy using magnetic resonance imaging texture features analysis and to correlate image texture changes with radiation dose and urinary toxicity. METHODS: Ethical clearance was granted to enroll 33 patients into this study who were treated with intensity-modulated radiation therapy for prostate cancer. All patients underwent two magnetic resonance imagings before and after radiation therapy (RT). A total of 274 radiomic features were extracted from MR-T2W-weighted images. Wilcoxon singed rank-test was performed to assess significance of the change in mean radiomic features post-RT relative to pre-RT values. The relationship between radiation dose and feature changes was assessed and depicted. Cystitis was recorded as urinary toxicity. Area under receiver operating characteristic curve of a logistic regression-based classifier was used to find correlation between radiomic features with significant changes and radiation toxicity. RESULTS: Thirty-three bladder walls were analyzed, with 11 patients developing grade ≥2 urinary toxicity. We showed that radiomic features may predict radiation toxicity and features including S5.0SumVarnc, S2.2SumVarnc, S1.0AngScMom, S0.4SumAverg, and S5. _5InvDfMom with area under receiver operating characteristic curve 0.75, 0.69, 0.65, 0.63, and 0.62 had highest correlation with toxicity, respectively. The results showed that most of the radiomic features were changed with radiation dose. CONCLUSION: Feature changes have a good correlation with radiation dose and radiation-induced urinary toxicity. These radiomic features can be identified as being potentially important imaging biomarkers and also assessing mechanisms of radiation-induced bladder injuries.

Machine learning-based radiomic models to predict intensity-modulated radiation therapy response, Gleason score and stage in prostate cancer.

OBJECTIVE: To develop different radiomic models based on the magnetic resonance imaging (MRI) radiomic features and machine learning methods to predict early intensity-modulated radiation therapy (IMRT) response, Gleason scores (GS) and prostate cancer (Pca) stages. METHODS: Thirty-three Pca patients were included. All patients underwent pre- and post-IMRT T2-weighted (T2 W) and apparent diffusing coefficient (ADC) MRI. IMRT response was calculated in terms of changes in the ADC value, and patients were divided as responders and non-responders. A wide range of radiomic features from different feature sets were extracted from all T2 W and ADC images. Univariate radiomic analysis was performed to find highly correlated radiomic features with IMRT response, and a paired t test was used to find significant features between responders and non-responders. To find high predictive radiomic models, tenfold cross-validation as the criterion for feature selection and classification was applied on the pre-, post- and delta IMRT radiomic features, and area under the curve (AUC) of receiver operating characteristics was calculated as model performance value. RESULTS: Of 33 patients, 15 patients (45%) were found as responders. Univariate analysis showed 20 highly correlated radiomic features with IMRT response (20 ADC and 20 T2). Two and fifteen T2 and ADC radiomic features were found as significant (P-value ≤ 0.05) features between responders and non-responders, respectively. Several cross-combined predictive radiomic models were obtained, and post-T2 radiomic models were found as high predictive models (AUC 0.632) followed by pre-ADC (AUC 0.626) and pre-T2 (AUC 0.61). For GS prediction, T2 W radiomic models were found as more predictive (mean AUC 0.739) rather than ADC models (mean AUC 0.70), while for stage prediction, ADC models had higher prediction performance (mean AUC 0.675). CONCLUSIONS: Radiomic models developed by MR image features and machine learning approaches are noninvasive and easy methods for personalized prostate cancer diagnosis and therapy.

Randomized, double-blind, placebo-controlled phase II trial of nanocurcumin in prostate cancer patients undergoing radiotherapy.

Clinical potential of curcumin in radiotherapy (RT) setting is outstanding and of high interest. The main purpose of this randomized controlled trial (RCT) was to assess the beneficial role of nanocurcumin to prevent and/or mitigate radiation-induced proctitis in prostate cancer patients undergoing RT. In this parallel-group study, 64 eligible patients with prostate cancer were randomized to receive either oral nanocurcumin (120 mg/day) or placebo 3 days before and during the RT course. Acute toxicities including proctitis and cystitis were assessed weekly during the treatment and once thereafter using CTCAE v.4.03 grading criteria. Baseline-adjusted hematologic nadirs were also analyzed and compared between the two groups. The patients undergoing definitive RT were followed to evaluate the tumor response. Nanocurcumin was well tolerated. Radiation-induced proctitis was noted in 18/31 (58.1%) of the placebo-treated patients versus 15/33 (45.5%) of nanocurcumin-treated patients (p = 0.313). No significant difference was also found between the two groups with regard to radiation-induced cystitis, duration of radiation toxicities, hematologic nadirs, and tumor response. In conclusion, this RCT was underpowered to indicate the efficacy of nanocurcumin in this clinical setting but could provide a considerable new translational insight to bridge the gap between the laboratory and clinical practice.

Rectal wall MRI radiomics in prostate cancer patients: prediction of and correlation with early rectal toxicity.

PURPOSE: To investigate MRI radiomic analysis to assess IMRT associated rectal wall changes and also for predicting radiotherapy induced rectal toxicity. MATERIAL AND METHODS: At first, a machine learning radiomic analysis was applied on T2-weighted (T2W) and apparent diffusion coefficient (ADC) rectal wall MR images of prostate cancer patients' pre- and post-IMRT to predict rectal toxicity. Next, Wilcoxon singed ranked test was performed to find radiomic features with significant changes pre- and post-IMRT. A logistic regression classifier was used to find correlation between features with significant changes and radiation toxicity. Area under the curve (AUC) of receiver operating characteristic (ROC) curve was used in two levels of study for finding performances. RESULTS: AUCmean, 0.68 ± 0.086 and 0.61 ± 0.065 were obtained for pre- and post-IMRT T2 radiomic models, respectively. For ADC radiomic models, AUCmean was 0.58 ± 0.034 for pre-IMRT and was 0.56 ± 0.038 for post-IMRT. Wilcoxon-signed rank test revealed that 9 T2 radiomic features vary significantly post-IMRT. The AUC of logistic-regression was in the range of 0.46-0.58 for single significant features and was 0.81 when all significant features were combined. CONCLUSIONS: Pre-IMRT MR image radiomic features could predict rectal toxicity in prostate cancer patients. Radiotherapy associated complications may be assessed by studying the changes in the MR radiomic features.

Development of a simplified multivariable model to predict neutropenic complications in cancer patients undergoing chemotherapy.

PURPOSE: Neutropenic complications remain the major dose-limiting toxicities of cancer chemotherapy. The aim of this study was to develop and internally validate a comprehensive and easily measurable scoring system for prediction of severe or febrile neutropenia in the first chemotherapy cycle of patients with solid tumors or lymphoma. METHODS: This prospective cohort study included consecutive patients at a tertiary referral hospital. Many clinical and laboratory-independent variables were measured at baseline. A multivariable logistic regression analysis was applied after unadjusted analysis, and the multivariable model was transformed into a simplified risk score based on 6 bootstrapped regression coefficients. The simplified scoring system was internally validated using cross-validation. All statistical tests were two-sided. RESULTS: A total of 305 patients were enrolled and followed during 1732 chemotherapy cycles. Of these, 259 were eligible for analysis. The multivariable model revealed 6 predictive factors for severe or febrile neutropenia (scores in parentheses): high-risk regimen without colony-stimulating factor (4 points), intermediate-risk regimen without colony-stimulating factor (3 points), age > 65 years and elevated ferritin (3 points), body mass index < 23 kg/m2 and body surface area < 2 m2 (2 points), estimated glomerular filtration rate < 60 mL/min/1.73m2 (2 points), and elevated C-reactive protein (1 point). The receiver operating characteristic curve was 0.832 (95% confidence interval [Cl], 0.767-0.897) for the simplified model and 0.816 (95% Cl, 0.771-0.860) for the cross-validation. CONCLUSIONS: We developed and internally validated a user-friendly prediction model to guide personalized decision-making using available clinical data and few cost-effective laboratory tests. External validation in other centers with different patients is required.

A comparative study of cisplatin-based definitive chemo-radiation in non-metastatic squamous cell carcinoma of the esophagus.

INTRODUCTION: Esophageal cancer is the seventh most frequent malignancy in Iranian men and the fourth most common cancer in Iranian women. It is also among the 10 most frequent cancers in the world. Definitive chemo-radiation using cisplatin with 5-fluorouracil (5-FU) is known as the standard of care among various chemotherapy regimens used with esophageal cancer patients who are not eligible for surgery. Cisplatin with paclitaxel and cisplatin with irinotecan also have been used often during the past five years. The aim of this research was to compare overall survival (OS) and hematological toxicity rates between these regimens. METHODS: This single-institutional study included 55 patients who were treated with definitive chemo-radiation in the radiation-oncology ward at Shohada-e-Tajrish Hospital in Tehran, Iran, between 2006 and 2013. They received one of four regimens, i.e., cisplatin, cisplatin with 5-FU (old chemotherapy regimens), cisplatin with paclitaxel, or cisplatin with irinotecan (new chemotherapy regimens) as part of their definitive chemo-radiation with curative intent. The Kaplan-Meier estimator was used to estimate the overall survival times, which were compared by using the Breslow test. RESULTS: The follow-up period was between 26-109 months, with a median of 72 months. OS was not different between the old and new chemotherapy regimen groups (p = 0.18). Hematological toxicity (leucopenia) in the old chemotherapy regimen groups (10%) was significantly lower than in the new chemotherapy regimen groups (43%, p = 0.012). But OS in cisplatin or cisplatin with 5-FU scheme was statistically better than with the cisplatin with paclitaxel scheme (p = 0.026, p = 0.028, respectively). CONCLUSION: This study showed that OS are similar in both the old and new chemotherapy treatment regimens in esophageal cancer patients who were treated with definitive chemo-radiation. The new chemotherapy treatment regimens should be used with caution as an alternative treatment of cisplatin with 5-FU for further evaluation.

Reduction in radiation-induced lymphocytopenia by famotidine in patients undergoing radiotherapy for prostate cancer.

BACKGROUND: Ionizing radiation causes a series of hematological alterations especially profound lymphocytopenia during and after the radiotherapy course. To investigate whether famotidine can reduce hematologic toxicity in patients treated with radiotherapy for prostate cancer. METHODS: A total of 36 patients undergoing radiotherapy for prostate cancer were randomized to receive either placebo or famotidine tablets. Participants were pretreated with 40 mg of oral famotidine or placebo tablets twice daily, 4 and 3 hr before each radiotherapy fraction. The patients received external-beam radiotherapy up to 70 Gy. Complete blood counts with differential, platelet counts, and hemoglobin levels were obtained at baseline, biweekly during the treatment and once 4 weeks after the end of radiotherapy course. Magnitude of changes from baseline in the hematological parameters was determined and compared using Repeated Measures ANOVA. RESULTS: Famotidine was well tolerated. A total of 112 blood samples were evaluated. A significant reduction in radiation-induced lymphocytopenia was noted in patients receiving famotidine than in patients receiving placebo (P = 0.006). No significant difference was observed between two groups for the decline in platelets, erythrocytes and leucocytes. For both groups, neutrophil, monocyte, eosinophil, and hemoglobin levels did not change significantly during the treatment. CONCLUSIONS: Our results indicate that famotidine could result in a significant reduction in radiation-induced lymphocytopenia and may consequently increase radiotherapy efficacy as well as survival times. This radioprotective effect may be chiefly associated with its antioxidant and radical scavenging properties. Further studies are required to confirm these encouraging results.