Post-transplantation Cyclophosphamide-based Graft-versus-host-disease Prophylaxis Compared to Methotrexate-cyclosporine a in Matched-related Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND AND OBJECTIVES: Post-transplant cyclophosphamide (PTCy) has shown promising results with low rates of severe graft-versus-host-disease (GVHD), either alone or combined with conventional immunosuppression (CIS). However, studies comparing PTCy with CIS as a GVHD prophylaxis are scarce. The study aimed to determine the rates of GVHD and survival outcomes for patients undergoing peripheral blood stem cell transplant (PBSCT) from HLA-matched related donors (MRD) receiving PTCy-based GVHD prophylaxis and compare these outcomes with those of patients receiving methotrexate (MTX) and cyclosporine-A (CsA) as a GVHD prophylaxis. PATIENTS AND METHODS: Seventy-five patients with advanced hematologic malignancies who underwent MRD allogeneic hematopoietic cell transplantation (allo-HCT) were analyzed prospectively. These patients received PTCy and CSA as a GVHD prophylaxis (therapeutic group) and their outcomes were compared with those of 75 retrospectively collected patients who received methotrexate and CsA as a GVHD prophylaxis (historical group) from the same two transplant centers. RESULTS: The median recipient age was significantly lower in the MTX/CsA group at 28 years compared to 34 years in the PTCy/CSA group. Peripheral blood was the only graft source used. All patients had a complete MRD, with two patients having a one-antigen mismatched related donor within the PTCy/CsA group. The 1-year cumulative incidence (CI) of chronic GVHD was 13.4% with PTCy/CsA and 38.6% with MTX/CsA (P = .001). Acute GVHD CI across all grades did not differ between the groups, with 10.7% for PTCy/CsA and 14.7% for MTX/CsA (P = .46). At two years, the overall survival (OS) (54.4% vs 67.2%, P = 0.282), disease-free survival (DFS) (54.1% vs 66.1%, P = 0.358), relapse rates (27.4% vs 20.1%, P = 0.245), and non-relapse mortality (NRM) (29.3% vs 25%, P = 0.904) did not differ between PTCy/CsA and MTX/CsA, respectively. CONCLUSION: PTCy-based GVHD prophylaxis in MRD transplant is feasible and leads to lower chronic GVHD rates without causing a significantly different risk of relapse or survival than MTX/CsA. More extensive studies are needed to confirm our results.

Her2/EGFR-PDGFR pathway aberrations associated with tamoxifen response in metastatic breast cancer patients.

BACKGROUND: Metastatic breast cancer (MBC) is a major health problem worldwide. Some patients improve on tamoxifen and others do not respond to treatment. Therefore, the aim of the current study is to assess genetic aberrations in the Her2/EGFR-PDGFR pathway associated with tamoxifen response in MBC patients. METHODS: This is a retrospective cohort study, including 157 hormone receptors positive, locally recurrent inoperable and/or MBC patients on tamoxifen treatment. Patients were categorized into 78 (49.7%) tamoxifen responders and 79 (50.3%) tamoxifen non-responder patients. Genetic aberrations of 84 genes involved in the Her2/EGFR-PDGFR pathway were assessed in the tumor tissue samples obtained from the patients using SA-Bioscience assay. The identified panel was correlated to patients' response to treatment, to detect the differentially expressed genes in tamoxifen responders and non-responders. RESULTS: One hundred twenty-three (78.3%) patients were estrogen receptor (ER) and progesterone receptor (PR) positive, 108 (68.8%) were ER only positive, and 78 (49.7%) were PR only positive. There were 56 genes overexpressed in the refractory group compared to responders. However, only five out of these 56 genes, Janus kinase 1 (JAK1), collagen type I alpha 1 (COL1A1), GRB2-associated binding protein 1 (GAB1), fibronectin-1 (FN1), and MAP kinase-interacting serine/threonine-protein kinase (MKNK1), showed statistical significance between the two groups. Patients with bone metastasis showed a better response to treatment compared to those with metastatic deposits in other sites such as visceral metastasis (P < 0.005). CONCLUSIONS: Genetic profiling using simple quantitative real-time polymerase chain reaction (qRT-PCR) protocols could be used to assess response to tamoxifen treatment in MBC patients. According to our data, a five-gene panel in the EGFR pathway (JAK1, COL1A1, GAB1, FN1 and MKNK1) could be used to categorize MBC patients into groups according to treatment response.

The Role of CYP2D6 Polymorphisms in Determining Response to Tamoxifen in Metastatic Breast Cancer Patients: Review and Egyptian Experience.

BACKGROUND: Metastatic breast cancer (MBC) represents a major health problem in Egypt and worldwide. Prognostic and predictive factors for patients with MBC are highly required for better management and improved survival. The aim of this study was to assess the prognostic and predictive value(s) of CYP2D6 polymorphisms in Tamoxifen responders and non-responders. METHODS: A cohort of 157 hormone receptor positive, locally recurrent inoperable and/or metastatic (MBC) Egyptian female patients was assessed for CYP2D6 polymorphisms. Data were correlated to relevant clinic-pathological features of the patients, response to tamoxifen, and survival rates. RESULTS: CYP2D6 polymorphisms were detected in 44/157 cases (28%), 30 of them (68.2%) were refractory and 14 (31.8%) were responders (P=0.027). The CYP2D6 *3,*4 variants were significantly prevalent in the refractory group 26/30 (86.6%), while the *10/*10 and *10/*3 variants were more common in the responders 12/14 (85.71%, P=0.027). CYP2D6 polymorphism associated significantly with Her-2 amplification (P=0.001) as well as reduced overall survival rates in both refractory and responder patients (p < 0.001). CONCLUSION: CYP2D6 polymorphisms can significantly predict response to Tamoxifen treatment, and also associates with poor overall survival rates in MBC patients.

Relation between GSTP1 polymorphism and oxidative stress in patients with hepatocellular carcinoma.

BACKGROUND: Glutathione can reduce the oxidative stress by converting the unstable to stable molecules and its status in hepatocellular carcinoma (HCC) is correlated with tumor growth and metastasis. Glutathione S-transferase Pi (GSTP1) is reported to detoxify the xenobiotic substrates by catalyzing their conjugation to reduced glutathione (GSH) and its over-expression was demonstrated in the early stages of HCC, while loss of GSTP1 has been suggested to increase the risk of deoxyribonucleic acid (DNA) damage and mutation. The aim of this study is to assess the relationship of GSTP1 polymorphism Ile105Val (rs1695 A > G) with HCC risk, and to investigate the oxidative stress status of HCC patients by measuring the antioxidant glutathione (GSH) levels. This study was conducted on 99 newly diagnosed HCC patients and 80 apparently healthy individuals as a normal control group. All participants were subjected to the measurement of plasma GSH levels according to Ellman's method, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for the detection of GSTP1 polymorphismIle105Val (rs1695 A > G). RESULTS: The occurrence of either the mutant homozygous or the mutant heterozygous genotype of GSTP1 was significantly higher in HCC patients, while the occurrence of the wild genotype was significantly higher among the normal control subjects. Mutant GSTP1 genotype, older age, male gender, and high serum alanine aminotransferase (ALT) were associated with increased risk of development of HCC. The best sensitivity, specificity, PPV (positive predictive value), NPV (negative predictive value), and overall diagnostic performance for plasma GSH at a cutoff level of 2003.5 µM/mg were 57.6%, 52.5%, 60%, and 40%. The area under the curve for GSH was 0.562. CONCLUSION: Mutant GSTP1 genotype was an independent prognostic factor for increased HCC risk which can be used in a risk assessment model for HCC. Plasma GSH presents insufficient sensitivity and specificity for HCC.

Access to oral rehydration solution and zinc supplementation for treatment of childhood diarrhoeal diseases in Sudan.

OBJECTIVES: The decline in diarrhoeal disease-related mortality globally has been attributed to the use of oral rehydration solution (ORS) and zinc supplementation. However, data on ORS and zinc supplementation in Sudan are scarce. We aimed to investigate the access to ORS and zinc treatments and the associated factors, through the analysis of the latest available data from Sudan-Multiple Indicator Cluster Survey (MICS)-2014 obtained from the United Nations Children's Fund (UNICEF). RESULTS: A total of 14,081 children were included in this analysis. During the 2 weeks preceding the survey, 29.3% of these children had a diarrhoeal disease. Only 18.9% and 14.8% of these children had received ORS and zinc supplements, respectively. Whereas children from the higher wealth index groups were more likely to receive ORS treatment (fourth group: AOR = 1.301; 95% CI 1.006-1.682), children from rural areas were less likely to receive ORS treatment (AOR = 0.666; 95% CI 0.552-0.803) and zinc supplements (AOR = 0.603; 95% CI 0.500-0.728). The results indicate the existence of unequal access to treatment of childhood diarrhoeal diseases among children under 5 years in Sudan.

Targeted next generation sequencing identifies somatic mutations in a cohort of Egyptian breast cancer patients.

Breast cancer (BC) incidence is progressively increasing in Egypt. However, there is insufficient knowledge of the acquired somatic mutations in Egyptian BC patients which limit our understanding of its progression. To the best of our knowledge, this is the first Egyptian cohort to sequence a multiple-gene panel of cancer related genes on BC patients. Four hundred and nine cancer related genes were sequenced in 46 fresh breast tumors of Egyptian BC patients to identify somatic mutations and their frequencies. TP53 and PIK3CA were the most top two frequently mutated genes. We detected 15 different somatic mutations in TP53 and 8 different ones in PIK3CA, each in 27 samples (58.7%). According to Clinvar database; we found 19 pathogenic somatic mutations: 7 in Tp53, 5 in PIK3CA, and single variants of VHL, STK11, AKT1, KRAS, IDH2, PTEN and ERBB2. We also identified 5 variants with uncertain significance (4 in TP53 and 1 in CEBPA) and 4 variants with conflicting interpretations of pathogenicity (2 in TP53 and 1 in each of APC and JAK3). Moreover, one drug response variant (p.P72R) in TP53 was detected in 8 samples. Furthermore, four novel variants were identified in JAK2, MTOR, KIT and EPHB. Further analysis, by Ingenuity Variant Analysis software (IVA), showed that PI3K/AKT signaling is altered in greater than 50% of Egyptian BC patients which implicates PI3K/AKT signaling as a therapeutic target. In this cohort, we shed the light on the most frequently detected somatic mutations and the most altered pathway in Egyptian BC patients.

Hyperthermic Intraperitoneal Chemotherapy as a Treatment for Epithelial Ovarian Cancer.

Treatment by cytoreductive surgery (CRS) and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) has been an option for selected patients with peritoneal carcinomatosis. This study aims to evaluate the impact of HIPEC in epithelial ovarian cancer (EOC). A retrospective observational cohort study including 48 EOC patients treated and followed up between 2012 and 2016. Thirty-seven cases were treated by CRS only, while 11 cases were treated by CRS and HIPEC. The study was performed at National Cancer Institute (NCI)-Cairo University. There was no statistically significant difference regarding overall survival or disease-free survival between the group of EOC patients treated by CRS only and the one treated by CRS and HIPEC. Presence of ascites and histological types (serous/non-serous) were the significant independent variables related to overall survival. Presence of ascites was the only independent variable associated with a significant relation to disease-free survival. No statistically significant impact of HIPEC in treatment of EOC was found in this study.

Hyperthermic Intraperitoneal Chemotherapy Versus Systemic Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer NCI Case Control Study

Objectives: To assess the efficacy of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent platinum-sensitive ovarian cancer patients in comparison with standard intravenous chemotherapy in terms of progression free survival and overall survival. Methods: Retrospective case control study matching 15 cases with 20 controls with at least 24 months of follow up. Results: The two groups were comparable and well matched in all aspects. Median follow up was 36 months in cases and 38 months in controls. The PFS2 revealed a median of 6 months (range 2-14) in cases and 5 months (range 2-18) in controls. The median OS was 36 and 38 months in cases and controls respectively. No statistically significant difference between the cases and controls were observed in progression free survival (PFS2) and overall survival OS (P-value, 0.350 and 0.711 respectively). However, the PFS2 was in favor of cases and OS was in favor of controls without reaching significance. The percentage of patients who survived 5 years or more was 20% in cases and 35% in controls. The only issue in favor of HIPEC is the significant reduction in chemotherapeutic toxicity when given by the intraperitoneal way (P- value 0.003). Conclusion: According to our study, CRS and HIPEC do not seem to have impact on OS and PFS in the setting of recurrent platinum sensitive ovarian cancer. However, we recommend on going researches with much more refined selection criteria and with larger sample size.

Combined cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as a treatment for recurrent epithelial ovarian cancer-National Cancer Institute experience.

BACKGROUND: Complete cytoreduction has been associated with survival benefit in the treatment of recurrent epithelial ovarian cancer (EOC). In this study, the aim is to investigate the role of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of recurrent EOC. PATIENTS AND METHODS: This is a descriptive (case series) study including 9 patients with recurrent EOC treated by CRS and HIPEC. They were treated and followed up between December 2011 and December 2017. The study was performed at The National Cancer Institute (NCI) - Cairo University (CU). RESULTS: Postoperative death occurred in 2 cases, while recurrence occurred in one case. Six cases had smooth postoperative course and free follow-up. Median follow-up period was 39 months, ranging from 29 to 47 months. Median overall survival was 42 months while median disease-free survival was not reached. CONCLUSIONS: Treatment of recurrent EOC by CRS and HIPEC appears to be promising. However, this line of treatment requires further evaluations and larger studies for better assessment of the potential survival benefits and possible complications.

Pelvic exenteration and composite sacral resection in the surgical treatment of locally recurrent rectal cancer.

BACKGROUND: The incidence of rectal cancer recurrence after surgery is 5-45%. Extended pelvic resection which entails En-bloc resection of the tumor and adjacent involved organs provides the only true possible curative option for patients with locally recurrent rectal cancer. AIM: To evaluate the surgical and oncological outcome of such treatment. PATIENTS AND METHODS: Between 2006 and 2012 a consecutive series of 40 patients with locally recurrent rectal cancer underwent abdominosacral resection (ASR) in 18 patients, total pelvic exenteration with sacral resection in 10 patients and extended pelvic exenteration in 12 patients. Patients with sacral resection were 28, with the level of sacral division at S2-3 interface in 10 patients, at S3-4 in 15 patients and S4-5 in 3 patients. RESULTS: Forty patients, male to female ratio 1.7:1, median age 45 years (range 25-65 years) underwent extended pelvic resection in the form of pelvic exenteration and abdominosacral resection. Morbidity, re-admission and mortality rates were 55%, 37.5%, and 5%, respectively. Mortality occurred in 2 patients due to perineal flap sepsis and massive myocardial infarction. A R0 and R1 sacral resection were achieved in 62.5% and 37.5%, respectively. The 5-year overall survival rate was 22.6% and the 4-year recurrence free survival was 31.8%. CONCLUSION: Extended pelvic resection as pelvic exenteration and sacral resection for locally recurrent rectal cancer are effective procedures with tolerable mortality rate and acceptable outcome. The associated morbidity remains high and deserves vigilant follow up.

Primary chemotherapy with low-dose prolonged infusion gemcitabine and cisplatin in patients with bladder cancer: a Phase II trial.

BACKGROUND: Gemcitabine is an active agent in the treatment of bladder cancer. The enzyme deoxycytidine kinase catalyzes the phosphorylation of gemcitabine into the active gemcitabine triphosphate. After an infusion during 30 minutes, this enzyme will be saturated, therefore, accumulation of higher intracellular concentrations of the active gemcitabine triphosphate could be achieved by prolonging the infusion time of gemcitabine. PATIENTS AND METHODS: Based on previously published Phase I trials, the efficacy and safety of a combination of cisplatin and gemcitabine given as prolonged infusion were tried in a Phase II study of 57 untreated patients with stage III/IV bladder cancer, which is the most common malignant tumor among Egyptian males. Patients received gemcitabine (250 mg/m(2) during 6-hour infusion) on days 1 and 8, and cisplatin (70 mg/m(2)) on day 2 every 21-day cycle. RESULTS: The 41 males and 16 females had a median age of 55 years (range 37-77). A total of 37 patients had transitional cell, 15 had squamous cell, 2 had adenocarcinoma, and 3 had undifferentiated cell carcinoma. The median number of cycles given to these 57 patients was 4 (range 1-6). Of 54 evaluable patients, 5 (9.4%) had complete remission, and 27 (50%) partial remission, for an overall response rate of 59.4%. These results are comparable to those of a previous Phase II study of the same combination but with gemcitabine given in the standard dose and schedule. Responses were observed at all disease sites. Both hematologic and nonhematologic toxicity were treatable and not severe. CONCLUSIONS: Prolonged infusion of gemcitabine and cisplatin is an effective treatment for advanced bilharzial-related bladder cancer. Toxicity, especially myelosuppression, is surprisingly mild. This combination deserves to be tried in other different disease categories.

Gemcitabine plus doxorubicin as first-line treatment in advanced or metastatic breast cancer (MBC), a phase II study.

INTRODUCTION: Doxorubicin and Gemcitabine have promising antineoplastic activity and manageable toxicity as a single agent in the treatment of patients (pts) with advanced breast cancer. AIM OF THE STUDY: This study evaluated the efficacy and toxicity of the combination of gemcitabine plus doxorubicin as first-line treatment of advanced or MBC patients. PATIENTS AND METHODS: Patients with advanced or MBC received gemcitabine 1250mg/m2 IV on days 1 and 8 plus doxorubicin 60mg/m2 IV on day 1 every 21 days for a maximum of 6 cycles. RESULTS: Thirty-five patients were included, and all are evaluable for safety and efficacy. Median age was 47 years (range, 33 to 60 years). Fourteen patients (40%) were post-and 21 (60%) were premenopausal. Prior treatment included mastectomy (23pts); adjuvant nonanthracycline containing combination chemotherapy (18pts); adjuvant hormonal therapy (3pts) and 2 pts did not receive any adjuvant therapy. Twelve patients had metastatic disease at presentation. Seventeen pts were chemonaive. Hormonal receptors were positive in 6, negative in 21, and unknown in 8 pts. Site of metastasis included one site in 15 pts, two sites in 14, and three sites in 6 pts. Complete remission was observed in 6/35 (17.1%) and partial remission in 14/35 (40%) pts, for an overall response rate of 57.1%. Stable disease was observed in 8 (22.9%) and progressive disease in 7 (20%) pts. The median time to tumor progression was 7 months (range, 5-23 months; 95% CI, 6-8 months) and the median survival time was 16 months (range, 6-43 months; 95% CI, 13-19 months). The overall survival at 1 and 2 years was 74.2% and 34.2%; respectively; with 4/35 (11.4%) patients alive at 40 months. A total of 186 cycles of treatment were administered (range2-6 cycles, median 6 cycles). The doses of both doxorubicin and gemcitabine were modified after interim analysis of toxicity following the first 22 cycles administered to the first 10 patients [Mucositis grade 3-4 occurred in 6/10 (60%), grade 3-4 neutropenia in 3/10 (30%), and febrile neutropenia grade 3 in 2/10 (20%) patients] to doxorubicin 50mg/m2 on day 1 and gemcitabine to 1000 mg/m2 on days 1 and 8 in the remaining cycles. After doses reduction, the toxicity was generally tolerable. CONCLUSION: The combination of gemcitabine plus doxorubicin after doses modification can be safely administered every 21 days with promising response as first-line therapy for MBC. The response rate, time to disease progression and overall survival rates of this regimen are comparable to other standard therapies for MBC, as well as other gemcitabine combinations.

Gemcitabine and cisplatin in the treatment of advanced non-small cell lung cancer: National Cancer Institute Cairo experience.

AIM OF THE WORK: The aim of the present study is to document the antitumor activity of the combination of gemcitabine and cisplatin for the treatment of advanced NSCLC, asses the nature and severity of the side effects and elicit the impact of the combination chemotherapy on progression free survival and overall survival. PATIENTS AND METHODS: From August 1997 to August 2001, we conducted a phase II study of gemcitabine and cisplatin in 60 chemonaive patients (21 stage IIIB and 39 stage IV). For the first 34 cases, gemcitabine was given at a dose of 1,000 mg/m2 IV on days 1, 8 and 15 with cisplatin 100 mg/m2 on day 15, every 28 days. In the following 26 patients, the regimen was modified to gemcitabine 1,250 mg/m2 days 1 and 8 and cisplatin 80 mg/m2 day 1, every 21 days. RESULTS: Patients included 53 males and 7 females [median age, 52 years (range, 28-69)]. Twenty-nine had adenocarcinoma, 18 large-cell carcinoma and 13 squamous-cell carcinoma. Thirty-one patients had a performance status (PS) of 2 and 22 presented with weight loss. All patients were evaluable for response. Three patients achieved a complete response (CR) and 22 had partial response (PR), giving an overall response of 41.7%, with a median duration of 10 months (range, 4-46 months). The time to progression (TTP) was 8 months (range, 2-46 months), with a median overall survival of 9 months (range, 2-46 months). The one-year survival rate was 30.3% for the entire study population, 44% for responders, and statistically improved in patients with a PS of I and those with no weight loss. A total of 255 cycles were administered (median, four cycles/patient). Myelosuppression was significant (but manageable) with grade 3/4 neutropenia in 32.6% of cases, anemia in 18.6% and thrombocytopenia in 20.4%. Nonhematologic toxicity was limited to grade 3/4 nausea and vomiting in 28.8% of cases and impaired liver enzymes in 13.6%. CONCLUSION: Inspite of the relatively poor prognostic characteristics in the study population, gemcitabine and cisplatin, was an effective combination with tolerable, manageable toxicity in advanced NSCLC.

The potential palliative role and possible immune modulatory effects of low-dose total body irradiation in relapsed or chemo-resistant non-Hodgkin's lymphoma.

In a group of 35 patients with relapsed and/or chemo-resistant non-Hodgkin's lymphoma (NHL), low-dose total body irradiation (LTBI) (+involved-field radiotherapy to bulky sites) achieved a complete remission rate of 29%, 2-years progression-free survival of 32% and a median progression-free survival of 12 months. The 2-year survival was 42% and the median survival was 17 months. Immuno-staining and flow cytometry of peripheral blood in 14 patients showed that LTBI leads to a significant increase in the percentage of CD4+ cells with a consequent significant increase in the CD4+/CD8+ ratio. High lymphocytic percent and a high percentage of CD4+ cells before LTBI were significantly correlated with longer response duration and overall survival. These data may suggest that the palliative potential of LTBI should be investigated as an alternative to chemotherapy in NHL patients. The pre-treatment percentage of lymphocytes and CD4+ cells may be used as predictors for response to LTBI.