Adjuvant Radiation Therapy After Radical Nephrectomy in Patients with Localized Renal Cell Carcinoma: A Systematic Review and Meta-analysis.

CONTEXT: Adjuvant radiation therapy has been recommended for patients at higher risk of relapse from renal cell carcinoma (RCC) to improve disease-free survival (DFS) and overall survival (OS) after radical nephrectomy. OBJECTIVE: To quantify the benefit of adjuvant radiation therapy. EVIDENCE ACQUISITION: A systematic review of electronic databases identified publications exploring the association between adjuvant radiation therapy and locoregional recurrence (LRR), DFS, and OS among patients after radical nephrectomy for early-stage RCC. Hazard ratios for DFS were weighted and pooled using the generic inverse variance and random effects model. Odds ratios for LRR, DFS, and OS at 5yr were weighted and pooled in a meta-analysis using Mantel-Haenszel random-effects modeling. EVIDENCE SYNTHESIS: Twelve studies comprising 1624 patients were included in the analysis. Ten studies were retrospective and two were randomized controlled trials. Adjuvant radiation therapy was delivered to 37% of patients. The median follow-up was 49mo. Adjuvant radiation therapy was not associated with better DFS or OS at 5yr, but was associated with less LRR. CONCLUSIONS: With the caveat that confounding by indication may result from pooling data from predominantly nonrandomized studies, adjuvant radiation after radical nephrectomy was not associated with improved DFS or OS but was associated with less LRR. PATIENT SUMMARY: Radiation therapy after resection of renal cell carcinoma with a high risk of relapse may reduce the risk of local recurrence but not the risk of disease recurrence or death after 5yr.

PD-L1 expression and clinical outcomes in patients with advanced urothelial carcinoma treated with checkpoint inhibitors: A meta-analysis.

CONTEXT: Five checkpoint inhibitors have been approved as 1st line (cisplatin-ineligible) or 2nd line therapies for patients with metastatic urothelial carcinoma of the bladder. As only about 30% of patients respond, the need for a biomarker for patient selection exists. OBJECTIVE: To determine if PD-L1 expression is a prognostic factor of objective response rate (ORR) and overall survival (OS) in patients with urothelial carcinoma being treated with checkpoint inhibitors. EVIDENCE ACQUISITION: A search of PubMed and major conference proceedings identified trials of PD-L1 inhibitors as first- or second-line therapies for metastatic bladder cancer. Odds ratios (OR) for ORR and OS compared PD-L1 positive and PD-L1 negative patients. Data were weighted and pooled in a meta-analysis, and subgroup analyses compared PD-L1 status cut-offs. EVIDENCE SYNTHESIS: Ten studies comprising 2755 patients were identified, of which 2030 patients (74%) received immune checkpoint inhibitors. Eight studies were eligible for ORR analysis (1530 patients) and five studies for OS (829 patients). PD-L1 patients had a significantly higher ORR than PD-L1 negative patients (1.82, 95%CI 1.18-2.77; p = 0.007). Weighted mean OS was 11.5 months (range 8.7-15.9 months). PD-L1 status was not prognostic for 12 month OS (OR = 0.81, 95%CI 0.47-1.40; p = 0.45). CONCLUSION: In patients treated with PD-L1 inhibitors for metastatic urothelial carcinoma, PD-L1 status is prognostic for ORR but not OS. Our findings warrant additional investigation. PATIENT SUMMARY: Five immunotherapy drugs are approved for bladder cancer therapy. PD-L1 expression predicts higher ORR but not OS. More data is needed to identify the patient population most benefitted by immunotherapy.

Pediatric mature B-cell NHL, early referral and supportive care problems in a developing country.

OBJECTIVE: Mature B-cell non-Hodgkin lymphoma (B-NHL) comprises more than 50% of all non-Hodgkin lymphoma (NHL) in children and adolescents. An official report published by the Mexican National Center for the Control and Prevention of Cancer in the Pediatric and Adolescent Populations, reported a lymphoma OS of 71% (including all Hodgkin and NHL). The Mexican Association of Pediatric Oncology and Hematology conducted a retrospective study to analyze the clinical characteristics and outcomes of children with diagnosis of B-NHL in Mexico, in order to perceive the main areas of improvement in the health care. METHODS: From 1 January 2000 to 31 December 2016, 166 pediatric patients were diagnosed with B-cell NHL at the participant institutions. RESULTS: According to histology the outcomes were 5-year EFS 63%, for BL/BLL, and 80% DLBCL, (P = .051), 5-year PFS 81%, for BL/BLL, and 91% for DLBCL, (P = .126), and 5-year OS 71%, for BL/BLL, and 83% for DLBCL, (P = .095). DISCUSSION: Overall, 18 patients died due to acute treatment toxicity, resulting in a cumulative incidence of toxic death of 10.84% and an early death rate of 7.23%, defined as <30 days after initial treatment. In conclusion, there is an urgent need to establish an academic collaboration to create strategies to improve pediatric cancer care according to our resources, especially in diseases with expected excellent prognosis as B-NHL. These strategies must include comprehensive supportive care, early referral, and the creation of easy communication between pediatric and adults centers as well as late-effects clinics.

Delivery of Pediatric Cancer Care in Mexico: A National Survey.

Purpose Limited data describe the delivery of pediatric cancer care in Mexico. We report a nationwide survey of pediatric cancer units. Methods An electronic survey was distributed to 74 pediatric cancer units in Mexico to describe case volumes; organization of care; and availability of medical/surgical specialists, supportive care, complex therapies, and diagnostic services. Centers were classified as low (< 30 new patients/year), medium (30 to 59/year) and high (≥ 60/year). Results Sixty-two centers completed the survey (response rate, 84%). The median annual new case volume per center was 50 (interquartile range [IQR], 23 to 81). Thirty-four percent (n = 21), 26% (n = 16), and 40% (n = 25) of units were low-, medium-, and high-volume centers, respectively. Treatment units reported a median of two pediatric oncologists (IQR, 2) and one pediatric hematologist (IQR, 1 to 2). Availability of medical and surgical subspecialists varied by center size, with substantially more specialist support at higher-volume centers ( P < .01). Multidisciplinary tumor boards are available at 29% (six of 21), 56% (nine of 16), and 76% (19 of 25) of low- to high-volume centers, respectively ( P = .005). Radiation and palliative care services are available at 42% (n = 26) and 63% (n = 36) of all centers, which did not vary by center volume. Educational support for hospitalized children and school reintegration programs are available at 56% (n = 36) and 58% (n = 36) of centers, respectively. One third (38% [n = 23]) of centers reported that at least one half of patients were lost to follow-up during the transition from pediatric to adult programs. Conclusion A large variation exists in annual case volumes across Mexican pediatric cancer centers. Additional efforts to increase access to multidisciplinary, supportive, and palliative care across all pediatric cancer units in Mexico are required.

Epidermal growth factor receptor overexpression and outcomes in early breast cancer: A systematic review and a meta-analysis.

BACKGROUND: The epidermal growth factor receptor (EGFR) is a member of the ErbB family of membrane tyrosine-kinase receptors. Studies exploring the prognostic role of EGFR-overexpression in early breast cancer have shown variable results, and the true prognostic value of EGFR is unknown. METHODS: A systematic review of identified publications exploring the association between EGFR-overexpression (as defined from different techniques and cut-offs) and outcomes [disease-free (DFS) and, overall survival (OS)] in women with early breast cancer. The hazard ratios (HR) for DFS and OS were weighted and pooled in a meta-analysis using generic inverse variance and random effects modeling. RESULTS: Fifty-three studies comprising 21,418 women were included. EGFR-overexpression was found in 27% of the patients. Primary analysis included studies reporting HRs from multivariable analyses (10 studies including 4857 patients with HRs for OS and 17 studies comprising 8747 patients with HRs for DFS), EGFR-overexpression was associated with worse OS (HR 1.98, 95% CI: 1.59-2.47, p < .001) and DFS (HR 1.59, 95% CI 1.30-1.95, p < .001). The influence of EGFR overexpression on DFS was greater in women with triple negative tumors compared to women with non-triple negative tumors (HR 2.35 versus HR 1.45, respectively; p = .01). Analysis looking at odd ratios for both 5-year and 10-year for DFS and OS showed similar results. CONCLUSION: EGFR-overexpression appears to be associated with reduced OS and DFS in women with early breast cancer. Patients with triple negative and EGFR-overexpression have poorer OS and DFS than those with triple negative tumors and normal EGFR expression.

Prognostic role of Ki-67 score in localized prostate cancer: A systematic review and meta-analysis.

BACKGROUND: Ki-67 for quantifying tumor proliferation is widely used. In localized prostate cancer (PCa), despite a suggested predictive role of Ki-67 for outcomes after therapies, it has not been incorporated into clinical practice. Herein, we conduct a systematic review and meta-analysis of the literature reporting the association of Ki-67 and disease outcomes in PCa treated radically. METHODS: Medline and EMBASE databases were searched without date or language restrictions, using "KI67" and "prostate cancer" MeSH terms. Studies reporting Ki-67 association with clinical outcomes (disease-free survival [DFS], biochemical failure-free survival, rate of distant metastases [DM], disease-specific survival [DSS], or overall survival [OS], or all of these) in patients with PCa managed actively were included, and relevant data extracted by 2 independent reviewers. Odds ratios (OR) were weighted and pooled in a meta-analysis using Mantel-Haenszel random-effect modeling. RESULTS: Twenty-one studies comprising 5,419 patients met eligibility for analysis, and 67.6% of patients had low Ki-67. Mean Ki-67 was 6.14%. High Ki-67 was strongly associated with worse clinical outcomes. DFS was better in those patients with low Ki-67 at 5 and 10 years (OR = 0.32, 95% CI: 0.23-0.44, P<0.00001; OR = 0.31, 95% CI: 0.20-0.48, P<0.00001). Similarly, low Ki-67 was related to improved DSS at 5 and 10 years (OR = 0.15, 95% CI: 0.10-0.21, P<0.00001; OR = 0.16, 95% CI: 0.06-0.40, P<0.00001). Association between low Ki-67 scores with improved OS (OR = 0.47; 95% CI: 0.37-0.61; P<0.00001) and high Ki-67 scores with DM at 5 years (OR = 4.07; 95% CI: 2.52-6.58; P<0.00001) was consistently observed. CONCLUSIONS: High Ki-67 expression in localized PCa is a factor of poor prognosis for DSS, biochemical failure-free survival, DFS, DM, and OS after curative-intent treatments. Incorporation into clinical routine of this widely available and standardized biomarker should be strongly considered.

Safety and tolerability of intrathecal delivery of autologous bone marrow nucleated cells in children with cerebral palsy: an open-label phase I trial.

BACKGROUND AIMS: Cerebral palsy (CP) is related to severe perinatal hypoxia with permanent brain damage in nearly 50% of surviving preterm infants. Cell therapy is a potential therapeutic option for CP by several mechanisms, including immunomodulation through cytokine and growth factor secretion. METHODS: In this phase I open-label clinical trial, 18 pediatric patients with CP were included to assess the safety of autologous bone marrow-derived total nucleated cell (TNC) intrathecal and intravenous injection after stimulation with granulocyte colony-stimulating factor. Motor, cognitive, communication, personal-social and adaptive areas were evaluated at baseline and 1 and 6 months after the procedure through the use of the Battelle Developmental Inventory. Magnetic resonance imaging was performed at baseline and 6 months after therapy. This study was registered in ClinicaTrials.gov (NCT01019733). RESULTS: A median of 13.12 × 10(8) TNCs (range, 4.83-53.87) including 10.02 × 10(6) CD34+ cells (range, 1.02-29.9) in a volume of 7 mL (range, 4-10.5) was infused intrathecally. The remaining cells from the bone marrow aspirate were administered intravenously; 6.01 × 10(8) TNCs (range, 1.36-17.85), with 3.39 × 10(6) cells being CD34+. Early adverse effects included headache, vomiting, fever and stiff neck occurred in three patients. No serious complications were documented. An overall 4.7-month increase in developmental age according to the Battelle Developmental Inventory, including all areas of evaluation, was observed (±SD 2.63). No MRI changes at 6 months of follow-up were found. CONCLUSIONS: Subarachnoid placement of autologous bone marrow-derived TNC in children with CP is a safe procedure. The results suggest a possible increase in neurological function.

Feasibility of an outpatient HLA haploidentical stem cell transplantation program in children using a reduced-intensity conditioning regimen and CD3-CD19 depletion.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been developed as an alternative transplant strategy for children with hematological disorders who do not have an HLA-matched donor. We report the analysis of the outcome for 18 consecutive pediatric patients with various hematological diseases, who underwent haplo-HSCT using a reduced-intensity conditioning regimen and CD3/CD19 depletion in an outpatient setting. Twelve of the 18 patients (66.6%) engrafted either transiently or definitively (9 patients engrafted with full donor chimerism and 3 with mixed chimerism). Six patients with acute lymphoblastic leukemia were disease-free between 2 and 35 months (median 25 months) post-HSCT. The overall survival was 33.3% with a median of 25 months (range 2-35). Our results suggest that haplo-HSCT can be a feasible therapeutic alternative for children who do not have a suitable family donor or available cord blood units. These results also demonstrate that it is possible to perform this regimen on an outpatient basis.

CD20 expression in B-cell precursor acute lymphoblastic leukemia is common in Mexican patients and lacks a prognostic value.

Classification of acute lymphoblastic leukemia (ALL) by flow cytometric immunophenotyping characterizes the disease and delineates potential therapeutic intervention. We retrospectively analyzed CD20 expression in 143 patients with newly diagnosed precursor B-cell ALL. CD20 was observed in 61% of patients at diagnosis. There was no correlation between CD20 expression and age, white blood cell count, or cytogenetic abnormalities. Despite the fact that CD20-positive ALL patients had a tendency toward a worse outcome, there was no significant difference between patients with and without CD20 expression in 3-year overall survival 65 vs. 82% (P = 0.14), and cumulative incidence of relapse 36 vs. 18% (P = 0.3) in pediatric patients and 51 vs. 53% (P = 0.31) and 35 vs. 38% (P = 0.6) in adults, respectively. In conclusion, CD20 expression appears to be more common in Mexican patients with newly diagnosed precursor B-cell ALL higher than in Caucasian populations and lacks prognostic value.

Cord blood banking activities at a university hospital in northeast Mexico: an 8-year experience.

BACKGROUND: Umbilical cord blood (UCB) represents an alternative source of stem cells for transplantation for the treatment of hematologic malignancies and genetic disorders. There is scarce information detailing cord blood bank (CBB) collection and transplantation activities from developing countries. We documented our experience at a public university hospital in northeast Mexico. STUDY DESIGN AND METHODS: We carried out a retrospective and descriptive analysis of our CBB activity during an 8-year period from May 2002 to September 2010. Collection, processing, and cryopreservation of CB were carried out following standard operating procedures. The minimum volume and total nucleated cell (TNC) content for cryopreservation were 80 mL and 8.0 × 10(8) , respectively. RESULTS: A total of 1256 UCB units were collected; 428 (34%) were banked and 828 (66%) were discarded. The main reason for exclusion was biologic: low volume and/or low number of TNC accounted for 84% of the total discarded units. Cryopreserved cord blood units (CBUs) had a median volume of 113.8 mL (range, 80-213.2 mL) and 13.0 × 10(8) (range, 8 × 10(8) -36.6 × 10(8) ) TNCs. Cell viability was 99.3% (88-100%). The median CD34+ cell content was 4.0 × 10(6) (0.46 × 10(6) -19.38 × 10(6) ). Sixteen units have been released for transplantation, leading to a utilization rate of 3.7%. CONCLUSION: CBB demands considerable human and financial resources; it is then essential for centers at developing countries to share their experience, results, and databases to increase the probability of finding matching units for their patients. Efforts to create and maintain CBBs allow to offer this therapeutic option at an affordable cost.

Evaluation of volume and total nucleated cell count as cord blood selection parameters: a receiver operating characteristic curve modeling approach.

The objective of the study was to evaluate the current standard practice of using volume and total nucleated cell (TNC) count for the selection of cord blood (CB) units for cryopreservation and further transplantation. Data on 794 CB units whose CD34+ cell content was determined by flow cytometry were analyzed by using a receiver operating characteristic (ROC) curve model to validate the performance of volume and TNC count for the selection of CB units with grafting purposes. The TNC count was the best parameter to identify CB units having 2 × 10(6) or more CD34+ cells, with an area under the ROC curve of 0.828 (95% confidence interval, 0.800-0.856; P < .01) and an efficiency of 75.4%. Combination of parameters (TNC/mononuclear cells [MNCs], efficiency 74.7%; TNC/volume, efficiency 68.9%; and volume/MNCs, efficiency 68.3%) did not lead to improvement in CB selection. All CB units having a TNC count of 8 × 10(8) or more had the required CD34+ cell dose for patients weighing 10 kg or less.

Low incidence and severity of graft-versus-host disease after outpatient allogeneic peripheral blood stem cell transplantation employing a reduced-intensity conditioning.

BACKGROUND: The prevalence and features of graft-versus-host disease (GVHD) in patients receiving allografts using peripheral blood stem cells (PBSCs) after a reduced-intensity conditioning (RIC) regimen are not well known. Several features of GVHD in patients at two institutions using RIC were assessed. METHODS: We analysed the overall survival (OS) and prevalence of GVHD in patients who underwent outpatient allogeneic PBSC transplantation after RIC between October 1998 and July 2008. RESULTS: We included 301 patients with a median age of 30 yrs (range, 1-71 yrs). In 37 cases, allogeneic peripheral blood stem cell transplantation was indicated for non-malignant disease, and in 264 for malignant disease. The median OS was 35 months. The estimated 3-yr OS was 48%. A total of 154 patients developed GVHD: there were 64 acute, 50 chronic and 40 cases that progressed from acute to chronic. Of the 104 patients with acute GVHD (aGVHD), 40% had grade I and 60% had grades II-IV. Of the 90 patients with chronic GVHD (cGVHD), 67% had limited and 33% had extensive forms. A total of 160 patients died, 40 as a result of GVHD (24 from aGVHD and 16 from cGVHD), 50 as a result of progressive disease and 70 from diverse causes. CONCLUSIONS: The incidence of GVHD was lower than in other series using conventional myeloablative preparative regimens. Most importantly, the severity of GVHD did not significantly affect the long-term survival.

Long-term results of placental blood allografting using reduced-intensity conditioning: multicenter experience in a developing country.

BACKGROUND: Placental blood (PLB) hematopoietic stem cell transplantation has recently been explored in an increasing number of patients; the best conditioning regimen has not been established. MATERIAL AND METHODS: In an eight-year period, 66 consecutive patients, both children and adults (40 males and 26 females), were grafted with allogeneic placental blood cells using a reduced-intensity conditioning regimen: 23 patients were grafted because of a non-malignant condition and 43 patients for a malignant disease. The median age was 7 years (range 5 months to 72 years). RESULTS: Median time to recover >0.5×10(9)/l granulocytes was 19 days, whereas median time to recover >20×10(9)/l platelets was 23 days. Thirty-eight individuals failed to engraft and they either recovered endogenous hematopoiesis or died. Patients have been followed for periods ranging from 0.5 to 66 months, median 9 months. The median overall post-transplant survival (OS) was 22 months and the 36-month OS was 32%; it was significantly better for individuals grafted with 6/6 matched cords (45%). The cumulative incidences of grade II-IV acute graft-versus-host disease (GVHD) and grade III-IV acute GVHD for the patients who engrafted were 33 and 10%, respectively. DISCUSSION: The low engraftment rate should be improved by selecting better cord blood units; additional studies are needed to define if non-myeloablative conditioning is preferable over conventional conditioning.

Subcutaneous alemtuzumab plus cyclosporine for the treatment of aplastic anemia.

Aplastic anemia (AA) is most frequently due to autoimmune attack on its own stem cells. Alemtuzumab is a monoclonal antibody which recognizes the CD52 antigen on the surface of T and B cells. It has proved useful in autoimmune diseases, lymphoproliferative conditions, and graft versus host disease. Based on its immunosuppressive properties, we treated 14 AA patients with alemtuzumab. Median age was 23 years. Ten milligrams of alemtuzumab were injected subcutaneously each day for five consecutive days. Cyclosporine A was also administered orally at a dose of 2 mg/kg every 12 h for 3 months, and then gradually tapered. Response to alemtuzumab was followed for a median of 20 months. There were eight responses (57.1%), two complete and six partial. Whereas six (42.8%) patients were non-responders. Median complete blood count values on alemtuzumab responders were Hb 13.1 mg/dL, absolute neutrophil count 2.4 x 10(9)/L, and platelets 97.5 x 10(9)/L. A good response was produced in 57% of AA patients with the administration of alemtuzumab, who lacked a stem cell donor.

Dimethyl sulfoxide-induced toxicity in cord blood stem cell transplantation: report of three cases and review of the literature.

Umbilical cord blood transplantation using nonmyeloablative conditioning is currently considered by many as a valid potential alternative for any patient who requires an unrelated donor allograft and who is without a suitably matched and readily available volunteer. Dimethyl sulfoxide (DMSO) has been used for years as a cryoprotectant agent; it acts by penetrating the cell and binding water molecules and it has been described as harmless for the individual who receives it in limited amounts. In this paper, we describe 3 cases of DMSO-induced toxicities and briefly review the most common adverse reactions of the DMSO when used as a cryopreservation agent for the long-term storage of cord blood cells. Two of the 3 cases had a dismal prognosis. A brief review of the literature is presented.

Allogeneic hematopoietic stem cell transplantation using a reduced-intensity conditioning regimen in infants: experience at a single institution in Mexico.

The authors report their experience with allogeneic hematopoietic stem cell transplantation in infants at a university hospital in México. Five infants had one of each of the following diagnoses: acute lymphoblastic leukemia, osteopetrosis for which the patient underwent 2 procedures, acute disseminated multiorgan Langerhans cell histiocytosis, and two cases of hemophagocytic lymphohistiocytosis. The source of stem cells for grafting in 2 children was peripheral blood, and in 3 children was unrelated cord blood. A reduced-intensity conditioning regimen including fludarabine, cyclophosphamide, and melphalan was administrated. Three patients are disease-free transplant survivors without graft-versus-host disease after 46, 34, and 16 months.