Multidrug Chemotherapy Research Articles

Clinical efficacy and safety of flumatinib combined with multidrug chemotherapy in the treatment of 12 cases with Ph(+) acute lymphoblastic leukemia

Clinical efficacy and safety of flumatinib combined with multidrug chemotherapy in the treatment of 12 cases with Ph(+) acute lymphoblastic leukemia

HERPES SIMPLEX VIRUS PNEUMONIA MASQUERADING AS DRUG-INDUCED PNEUMONITIS

TOPIC: Chest Infections TYPE: Fellow Case Reports INTRODUCTION: Drug induced pneumonitis is a major cause of adverse events during cancer therapy, and has become increasingly common with the use of immune-checkpoint inhibitor (ICI) therapy. Due to its rarity, ICI pneumonitis is a diagnosis of exclusion, and infection and malignancy must be ruled out. While multiple types of infection are typically assessed for, Herpes Simplex Virus (HSV) pneumonia is often not considered. We report the case of a 75 year old man with non-small cell lung cancer (NSCLC) on pembrolizumab who died despite aggressive treatment for a presumed ICI pneumonitis, and was found on autopsy to have had HSV pneumonia. CASE PRESENTATION: A 75 year old man with NSCLC presented to hospital with two days of dyspnea. The patient was being treated with a multi-drug chemotherapy regimen, including pembrolizumab. His last cycle was five days prior to admission. On admission, he was found to be hypoxic, saturating 70% on room air, with course bilateral crackles, and extensive bilateral ground glass opacities on chest CT. He did not have leukocytosis. Multiple infectious studies, including COVID-19, CMV, respiratory viral panel, legionella, mycoplasma, beta-D glucan, and galactomannan were negative. ICI pneumonitis was highest on the differential, and the patient was therefore started on solumedrol. After two days of no improvement, the solumedrol was increased and infliximab was added. The patient's respiratory status continued to worsen, and he was ultimately intubated. The patient underwent bronchoscopy once intubated, however, he expired before the studies resulted. Autopsy revealed a severe HSV pneumonia. DISCUSSION: ICI pneumonitis occurs in approximately 5% of patients treated with PD(L)-1 inhibitors, of which approximately 25% of cases are graded as severe or life-threatening. While the vast majority of patients with non-severe disease are successfully treated by withholding the ICI alone or in conjunction with glucocorticoids, those with more severe disease may require additional immunosuppression, and a small number of these patients die despite treatment. Due to its rarity, ICI pneumonitis is a diagnosis of exclusion, and diagnoses such as infection and malignancy should always be ruled out. The fact that its radiographic presentation is so heterogenous, with patterns as variable as those seen with COP, NSIP, HP, and AIP/ARDS, makes it all the more difficult to diagnose. HSV pneumonia is known to infrequently cause pneumonia in severely immunocompromised patients. A prospective observational study conducted in 2018 on immunocompromised adults with pneumonia not responding to empiric antibiotic therapy found it to be much more common than expected, with 42% of patients testing positive for HSV-1 on BAL, and 24% meeting criteria for HSV pneumonia. CONCLUSIONS: HSV pneumonia should be more frequently considered in immunocompromised patients suspected of having an ICI pneumonitis. REFERENCE #1: Nishino M, et al. Drug-related pneumonitis in the era of precision cancer therapy. JCO Precision Oncology. 2017 May 26; 1: 1-12. REFERENCE #2: Naidoo J, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clinical Oncology. 2017 Mar; 35 (7): 709-717. REFERENCE #3: Luzzati R, et al. Herpex simplex virus (HSV) pneumonia in the non-ventilated immunocompromised host: burden and predictors. J Infect. 2019 Feb; 78 (2): 127-133. DISCLOSURES: No relevant relationships by Jeffrey Ordner, source=Web Response No relevant relationships by Ariella Pratzer, source=Web Response No relevant relationships by Mark Sloane, source=Web Response No relevant relationships by Kristen Thomas, source=Web Response No relevant relationships by Karen Yang, source=Web Response

Surgery for locally advanced pancreatic ductal adenocarcinoma-is it only about the vessels?

Pancreatic ductal adenocarcinoma (PDAC) is an oligosymptomatic disease, that is usually diagnosed in an advanced tumor stage. Traditionally, only the small subset of patients with tumors that showed no signs of vascular infiltration and distant metastases proceeded to surgery-still the only curative therapeutic modality to date. The remaining majority of patients received palliative chemotherapy or chemoradiation, usually with gemcitabine monotherapy. While gemcitabine monotherapy results in improved survival compared to best supportive care, most patients still succumb to the disease under therapy in a relatively short amount of time. Over the last years and decades, paradigms have shifted in PDAC treatment and potent multidrug chemotherapy protocols, including gemcitabine plus nab-paclitaxel and FOLFIRINOX, result in sufficient downstaging of advanced tumors in many patients. In this context, more and more patients are eligible for exploration and often resection. In this review we discuss the current state of the art in the clinical management and surgical treatment of patients with locally advanced pancreatic cancer, including classifications of locally advanced and borderline disease and surgical strategies for extended resections. An emphasis is put on arterial and venous resections and their outcome. In the end, we discuss current gaps in the literature and propose directions future research endeavors should focus on.

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with primary metastatic Ewing sarcoma.

Ewing sarcomas are solid tumours of the bone and soft tissue, that usually affect children, adolescents, and young adults. The incidence is about three cases per million a year, with a peak incidence at 12 years of age. Metastatic disease is detected in about 20 % to 30% of people, and is typically found in the lungs, bone, bone marrow, or a combination of these. Presence of metastatic disease at diagnosis (primary metastatic disease) is the most important adverse prognostic factor, and is associated with a five-year survival lower than 30%.High-dose chemotherapy (HDC) followed by autologous haematopoietic cell transplantation (AHCT)is used in various solid tumours with unfavourable prognoses in children, adolescents, and young adults. It has also been used as rescue after multifocal radiation of metastases. The hypothesis is that HDC regimens may overcome the resistance to standard multidrug chemotherapy and improve survival rates. To assess the effects of high-dose chemotherapy with autologous haematopoietic cell transplantation compared with conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with primary metastatic Ewing sarcoma, and to determine the toxicity of the treatment. We searched CENTRAL, MEDLINE, Embase, conference proceedings from major international cancer-related conferences, and ongoing trial registers until January 2020. We also searched reference lists of included articles and review articles. We included randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC and AHCT with conventional chemotherapy for children, adolescents, and young adults (younger than 30 years at the date of diagnostic biopsy) with primary metastatic Ewing sarcoma. We used standard methodological procedures expected by Cochrane. We identified one RCT, which investigated the effects of HDC with AHCT versus conventional chemotherapy with whole lung irradiation (WLI) in people with Ewing sarcoma metastasised to the lungs only at diagnosis. Only a selection of the participants were eligible for our review (N = 267: HDC with AHCT group N = 134; control group N = 133). There may be no difference in event-free survival between the two treatment groups (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.59 to 1.17; low-certainty evidence). We downgraded one level each because of study limitations and imprecision. Overall survival and toxicity were not reported separately for the participants eligible for this review, while quality-adjusted survival and progression-free survival were not reported at all. We did not identify any studies that addressed children, adolescents, and young adults with Ewing sarcoma with metastases to other locations. In people with Ewing sarcoma with primary metastases to locations other than the lungs, there is currently no evidence from RCTs or CCTs to determine the efficacy of HDC with AHCT compared to conventional chemotherapy. Based on low-certainty evidence from one study (267 participants), there may be no difference in event-free survival between children, adolescents, and young adults with primary pulmonary metastatic Ewing sarcoma who receive HDC with AHCT and those who receive conventional chemotherapy with WLI. Further high-quality research is needed. Results are anticipated for the EuroEwing 2008R3 study, in which the effects of HDC with treosulfan and melphalan followed by AHCT on survival, in people with Ewing sarcoma with metastatic disease to bone, other sites, or both were explored. Achieving high-quality studies in a selection of people with rare sarcoma requires long-term, multi-centre, international participant inclusion.

Reduced Intensity Conditioning for Allogeneic Transplantation: Modified Fludarabine Dose Plus Cyclophosphamide/Total Body Irradiation Yields Promising Outcomes

Reduced intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unsuitable for myeloablative conditioning. We prospectively studied a RIC HCT approach for patients with hematologic malignancies and sibling or unrelated donors (URD) from 2001-2016. Patients received cyclophosphamide (Cy) 50mg/kg/day IV day -6, fludarabine (Flu) 40mg/m2/d IV days -6 to -2 and TBI 200cGy on day -1 +/- anti-thymocyte globulin (ATG) on days -6 to -4 for those without prior autografting or recent multidrug chemotherapy. After identifying potential increased non-relapse mortality from excess fludarabine metabolite (F-ara-A) exposure we reduced the fludarabine dosing to 30 mg/m2/d IV days -6 to -2 in late 2009.The 292 patients (median age 58: range 19-75); median follow-up 8 years (IQR range 4-12) included 127 with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), 40 aggressive non-Hodgkin lymphoma (NHL), 11 indolent NHL, 21 Hodgkin Lymphoma (HL), 26 multiple myeloma, 14 chronic myeloid leukemia (CML), 23 chronic lymphocytic leukemia (CLL), 17 acute lymphocytic leukemia (ALL), 13 myeloproliferative neoplasms (MPN). Five year overall survival (OS) was 73% (95% CL, 37-90%) for patients with indolent NHL, 53% (95% CL, 36-67%) for aggressive NHL, 55% (95% CL, 31-74%) for HL, 39% (95% CL, 30-48%) for AML/MDS, 32% (95% CL, 15-50%) for myeloma, 50% (95% CL, 23-72%) for CML, 45% (95% CL, 24-46%) for CLL, 15% (95% CL, 2-39%) for MPN and 34% (95% CL, 12-59%) for those with ALL. By donor source, 5 year OS was 46% (95% CL, 40-53%), 25% (95% CL, 6-50%), 38% (95% CL, 22-54%), and 11% (95% CL, 1-35%) using matched sibling donors (n=225), mismatched (MM) sibling PBSC (n=12), matched marrow unrelated donor (URD) (n=37), and matched peripheral blood URD (n=18) (p<0.01) (Figure 1). Fludarabine dosing (30 vs. 40 mg/m2/day x 5) had no significant influence on OS (45 vs. 40%, p=0.42) or 2 year NRM (25% vs. 26%, p=0.86). NRM (overall 26%; 95% CI 21-31%) was significantly worse with MM sibling or URD (either BM or PBSC) compared to matched sibling BM/PBSC. Relapse at 5 years was significantly worse in patients with myeloma (76%) and Hodgkins (53%), intermediate in AML/MDS (37%), but lowest in aggressive (25%) and particularly indolent NHL (0%).These results suggest that: 1) this Cy/Flu/TBI RIC conditioning was well tolerated by an older population; 2) indolent and aggressive NHLs responded best to RIC conditioning highlighting the importance of the graft versus lymphoma (GVL) effect; and 3) reduction in fludarabine dosing did not compromise disease control or survival but did not appear to diminish NRM. Diagnosis, donor source, and HCT-CI remain the dominant factors influencing outcomes. Targeted disease treatments or maintenance therapy to limit relapse might be the best approach to improve overall survival. [Display omitted] DisclosuresBrunstein:Novartis: Research Funding; Magenta Therapeutics: Research Funding. MacMillan:Magenta Therapeutics: Research Funding.

Acromioclavicular joint tuberculosis: A report of two cases

Acromioclavicular joint tuberculosis is an extremely rare presentation with only 16 cases reported so far and has a relatively high propensity to be misdiagnosed. India being a tuberculosis endemic region accounts for almost 27% of cases worldwide (global index of 2018 was 10 million). With a higher index of suspicion an earlier diagnosis can be made. We report two patients of AC joint tuberculosis, treated with multidrug chemotherapy resulting in a good functional outcome.

PCN85 Real-World Treatment Patterns and Healthcare Costs Among Patients With Muscle-Invasive Urothelial Carcinoma Undergoing Radical Surgery in MarketScan Databases

Evidence demonstrating clinical benefits of adjuvant chemotherapy following radical surgery for muscle-invasive urothelial carcinoma (MIUC) is limited. This study describes real-world treatment patterns and quantifies the economic burden of patients with MIUC undergoing radical surgery in the United States. Adults with MIUC undergoing radical surgery (index date) between July 1, 2011, and June 30, 2019, were selected from the IBM MarketScan Commercial and Medicare Supplemental Plan databases using administrative and surgical procedure claims. Eligible patients had ≥6 months of continuous enrollment before and after index, no diagnoses of metastases before index, and no other primary cancers. Results were analyzed descriptively, and costs were adjusted to 2019 USD per patient per month. Among 855 patients included, mean age was 65.1 years, most were male (n=580, 67.8%), and had disease originating in bladder (n=825, 96.5%). Median follow-up from index was 16.5 months. Platinum-based multidrug chemotherapy use was limited—193 (22.6%) patients received neoadjuvant, and 26 (3.0%) received adjuvant; the most common regimen was gemcitabine plus cisplatin. Almost all patients (n=813, 95.1%) experienced ≥1 hospitalization during follow-up, with length of stay averaging 8 days. Mean medical and drug costs after surgery were $15,637, with costs slightly higher among patients without reported neoadjuvant or adjuvant chemotherapy ($16,009). Among 155 (18.1%) patients who developed metastatic disease, the mean time from index to metastatic systemic therapy was 5.4 months. These patients incurred an average of $50,161 in medical and drug costs and an increase of $331 out-of-pocket costs per month versus all patients. Real-world use of neoadjuvant and adjuvant chemotherapy was limited among patients with MIUC undergoing radical surgery. Metastatic disease was associated with increased resource burden. Our results signify a need for more efficacious adjuvant therapies to reduce disease recurrence and progression, and minimize healthcare resource utilization in these patients.

Expression of DEP Domain-Containing 1B in Canine Lymphoma and Other Types of Canine Tumours

Canine lymphoma is the most common haematological malignancy in dogs and is typically treated with multidrug chemotherapy. Most cases are at risk of relapse after several courses of chemotherapy and the oncogenic mechanism remains unknown. This study was aimed at identifying genes expressed in canine lymphoma by cDNA microarray. We found elevated expression of Dishevelled, EGL-10 and pleckstrin (DEP) domain-containing 1B (DEPDC1B) in canine lymphoma cells compared with cells and tissues from healthy dogs. Canine DEPDC1B protein was detected in 13 of 41 lymphoma specimens by immunohistochemistry, but was not detected in lymph nodes from normal dogs. Immunoreactive DEPDC1B protein was also detected in several other types of canine tumour. This is the first report documenting the association of DEPDC1B with canine cancer and the results suggest that DEPDC1B might serve as a potential marker or therapeutic target for canine malignancies.

Outcomes of Surgical Treatment for Mycobacterium abscessus Complex Pulmonary Disease

BackgroundMycobacterium abscessus complex pulmonary disease is notoriously difficult to treat by medication alone. We report our experience with resectional surgery combined with preoperative and postoperative multidrug chemotherapy for the treatment of patients with M. abscessus complex pulmonary disease. MethodsThis is a retrospective review of 33 patients undergoing lung resection for M. abscessus complex pulmonary disease at a single center in Japan between January 2008 and December 2019. ResultsThe median age of patients was 54.0 (interquartile range [IQR], 49.0-66.0) years; 27 (81.8%) were female. Nodular-bronchiectatic was the most common disease type (n = 24, 72.7%). Disease was limited in 18 (54.5%) patients and extensive in 15 (45.5%). The median duration of preoperative multidrug chemotherapy employing oral and parenteral antibiotics was 10.0 (IQR, 3.0-18.0) months. A total of 34 anatomical lung resections were performed as follows: 22 lobectomies, 5 segmentectomies, 4 combined resections, 2 bilobectomies, and 1 pneumonectomy. No operative mortalities and 4 (13.3%) morbidities occurred. The median duration of multidrug chemotherapy after the surgery was 18.0 (IQR, 12.0-31.0) months. Postoperative sputum-negative status was achieved in 31 (93.9%) patients; all 23 patients obtaining preoperative negative conversion remained negative, and 8 (80.0%) of 10 patients with preoperative positive sputum became negative postoperatively. Recurrence was observed in 2 (6.5%) patients. The recurrence-free probabilities were 96.3%, 96.3%, and 80.2% at 1 year, 3 years, and 5 years, respectively. ConclusionsCombined with preoperative and postoperative multidrug chemotherapy, resectional surgery can be performed safely and achieve favorable outcomes for patients with M. abscessus complex pulmonary disease.

Thiotepa-melphalan myeloablative therapy for high-risk neuroblastoma.

Appropriate high-dose chemotherapy (HDC) for high-risk neuroblastoma has not yet been established. In Japan, a unique HDC regimen that comprises two cycles of a total of 800mg/m2 of thiotepa and a total of 280mg/m2 of melphalan is widely utilized. To evaluate the safety and efficacy of this thiotepa-melphalan high-dose therapy for high-risk neuroblastoma, we reviewed the medical records of 41 patients with high-risk neuroblastoma who underwent this regimen followed by autologous peripheral blood stem cell rescue between 2002 and 2012. MYCN-amplified high-risk neuroblastomas were observed in 23 patients. All patients underwent intensive multidrug induction chemotherapy, but none underwent anti-GD2 antibody immunotherapy. The primary tumor was resected at the adequate time point. The median follow-up duration for living patients was 9.2years (range 5.5-14.0years). The 5-year event-free survival (EFS) and overall survival from treatment initiation were 41.5±7.7% and 56.1±7.8%, respectively. The 5-year EFS of MYCN-amplified high-risk neuroblastoma patients was 60.9±10.2%, which was significantly superior compared with those with MYCN-nonamplified high-risk neuroblastoma (16.7±8.8%; p<.001). MYCN amplification was the most favorable prognostic factor for EFS (hazard ratio=0.29; 95% confidence interval=0.12-0.66). Of the 41 patients, three died because of regimen-related toxicity (infection, n=2; microangiopathy, n=1). The thiotepa-melphalan high-dose therapy with thiotepa and melphalan may be effective for high-risk neuroblastoma. However, this regimen is toxic and warrants special attention in clinical practice.

Role of synergy and antagonism in designing multidrug adaptive chemotherapy schedules.

Chemotherapeutic resistance via the mechanism of competitive release of resistant tumor cell subpopulations is a major problem associated with cancer treatments and one of the main causes of tumor recurrence. Often, chemoresistance is mitigated by using multidrug schedules (two or more combination therapies) that can act synergistically, additively, or antagonistically on the heterogeneous population of cells as they evolve. In this paper, we develop a three-component evolutionary game theory model to design two-drug adaptive schedules that mitigate chemoresistance and delay tumor recurrence in an evolving collection of tumor cells with two resistant subpopulations and one chemosensitive population that has a higher baseline fitness but is not resistant to either drug. Using the nonlinear replicator dynamical system with a payoff matrix of Prisoner's Dilemma (PD) type (enforcing a cost to resistance), we investigate the nonlinear dynamics of this three-component system along with an additional tumor growth model whose growth rate is a function of the fitness landscape of the tumor cell populations. A key parameter determines whether the two drugs interact synergistically, additively, or antagonistically. We show that antagonistic drug interactions generally result in slower rates of adaptation of the resistant cells than synergistic ones, making them more effective in combating the evolution of resistance. We then design evolutionary cycles (closed loops) in the three-component phase space by shaping the fitness landscape of the cell populations (i.e., altering the evolutionary stable states of the game) using appropriately designed time-dependent schedules (adaptive therapy), altering the dosages and timing of the two drugs. We describe two key bifurcations associated with our drug interaction parameter which help explain why antagonistic interactions are more effective at controlling competitive release of the resistant population than synergistic interactions in the context of an evolving tumor.

Optimum multi-drug regime for compartment model of tumour: cell-cycle-specific dynamics in the presence of resistance.

This work is focused on multi-objective optimisation of a multi-drug chemotherapy schedule for cell-cycle-specific cancer treatment under the influence of drug resistance. The acquired drug resistance to chemotherapeutic agents is incorporated into the existing compartmental model of breast cancer. Furthermore, the toxic effect of drugs on healthy cells and overall drug concentration in the patient body are also constrained in the proposed model. The objective is to determine the optimal drug schedule according to the patient's physiological condition so that the tumour burden is minimised. A multi-objective optimisation algorithm, non-dominated sorting genetic algorithm-II (NSGA-II) is utilised to solve the problem. The obtained results are thoroughly analysed to illustrate the impact of drug resistance on the treatment. The capability of optimised schedules to deal with parametric uncertainty is also analysed. The drug schedules obtained in this work align well with the clinical standards. It is also revealed that the NSGA-II optimised drug schedule with proper rest period between successive dosages yields the minimum cancer load at the end of the treatment.

Long Non-coding RNAs in Cisplatin Resistance in Osteosarcoma.

Osteosarcoma (OS), the most common primary malignant bone tumor, is a vastly aggressive disease in children and adolescents. Although dramatic progress in therapeutic strategies have achieved over the past several decades, the outcome remains poor for most patients with metastatic or recurrent OS. Nowadays, conventional treatment for OS patients is surgery combined with multidrug chemotherapy including doxorubicin, methotrexate, and cisplatin (CDDP). In this sense, cisplatin (CDDP) is one of the most drugs used in the treatment of OS but drug resistance to CDDP appears as a serious problem in the use of this drug in the treatment of OS. Thus, we consider that the understanding the molecular mechanisms and the genes involved that lead to CDDP resistance is essential to developing more effective treatments against OS. In this review, we present an outline of the key role of the long non-coding RNAs (lncRNAs) in CDDP resistance in OS. This overview is expected to contribute to understand the mechanisms of CDDP resistance in OS and the relationship of the expression regulation of several lncRNAs.

Prognostic Relevance of Expression of EMP1, CASP1, and NLRP3 Genes in Pediatric B-Lineage Acute Lymphoblastic Leukemia.

Glucocorticoid (GC), such as prednisolone, is an essential component of multidrug chemotherapy regimen for pediatric acute lymphoblastic leukemia (ALL). Resistance to GC in leukemia cells is associated with disease progression and poor prognosis. Despite the extensive use of GC for many years, molecular mechanisms underlying its resistance in ALL have not been fully uncovered. Recent studies have shown a potential role of EMP1, CASP1, and NLRP3 genes in prednisolone response. In this study on 148 pediatric B-ALL patients, we studied these three genes to assess their association with prednisolone response measured by day 8 blast count after 7 days of induction therapy with prednisolone. Intriguingly, ALL samples exhibited higher expression of EMP1 along with a low expression of CASP1 and NLRP3 compared to disease free normal bone marrow collected from patients with solid tumors. Among the three analyzed genes, only EMP1 was found to be overexpressed in prednisolone poor responders (p=0.015). Further, a comparison of gene expression between cytogenetic subtypes revealed higher expression of EMP1 in BCR-ABL subtype. Expression of EMP1 in multiple gene expression datasets was used for gene set enrichment analysis, which revealed TNF-α, IL-2-STAT5 signaling, inflammatory responses and hypoxia as the major positively associated pathways and E2F targets as negatively associated pathways. Interestingly, the clinical remission rate was higher in CASP1 high patients (p=0.048). In univariate survival analysis, higher EMP1 expression was associated with poor prognostic measures while higher expression of NLRP3 and CASP1 was associated with better prognostic measures in our data. Further, multivariate analysis revealed an independent association of high CASP1 and NLRP3 with a better prognosis. This study strengthens the available evidence that mRNA expression of EMP1, CASP1, and NLRP3 may serve as potential biomarkers for risk stratification of pediatric B-ALL patients.

Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia

Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization. Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m2/d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation. The primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events. A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group. Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up. ClinicalTrials.gov Identifier: NCT02393859.

Neoadjuvant Chemotherapy and Concomitant Boost Radiotherapy in the Treatment of Locally Advanced Rectal Cancer

Aims: This study aimed to examine the efficacy and toxicities of concomitant boost three-dimensional conformal radiotherapy along with multidrug chemotherapy (capecitabine and oxaliplatin) in neoadjuvant course for locally advanced rectal cancer (LARC).&#x0D; Study Design: A phase II interventional nonrandomized study.&#x0D; Place and Duration of Study: This Study was conducted at Clinical Oncology and nuclear medicine department of Mansoura University Hospitals (Egypt) between November 2016 and October 2019.&#x0D; Methodology: Thirty patients (18 women, 12 men; age range 18-75 years) with (cT3-T4 and/or cN+) histologically confirmed rectal adenocarcinoma located within 12 cm of the anal verge were included in this study. Patients received three-dimensional conformal radiotherapy (3DCRT) to the pelvis of 45 Gy and a concomitant boost of 10 Gy to the primary tumor in 25 fractions, and concurrent with oxaliplatin (50 mg/m2 d1 weekly) and capecitabine (625 mg/m2 bid d1–5 weekly). Radical surgery was scheduled six to eight weeks after chemoradiation. Acute toxicities were recorded according to Common Terminology Criteria for Adverse Event (CTCAE) v5.0. Potential prognostic factors were evaluated using a binomial logistic regression. Survival curves were estimated using the Kaplan-Meier method and compared with Log-rank test.&#x0D; Results: All patients received chemoradiation. Twenty-seven patients underwent surgical resection. Twenty-five patients underwent sphincter-sparing surgery (92.6%) and nine patients (33.3%) achieved pathological complete response (pCR). The incidences of grade III neutropenia, diarrhea, and radiation dermatitis were 6.7%, 6.7%, 3.3% respectively. The three-year local recurrence (LR), disease-free survival (DFS) and overall survival (OS) rates were 7.4%, 63% and 74.1%, respectively. We found pre-surgical negative nodal status to be significantly associated with pCR (p=0.009). The pathological nodal stage was an independent prognostic factor to DFS.&#x0D; Conclusion: The combination of oxaliplatin, capecitabine, and dose escalation using concomitant boost 3DCRT is safely administrated in patients with locally advanced rectal adenocarcinoma and it offers high pCR and sphincter preservation rate.

Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells

Wnt5a is a ligand of the non-canonical Wnt signaling pathway involved in cell differentiation, motility, and inflammatory response. Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive T-cell malignancies caused by infection of human T-cell leukemia virus type1 (HTLV-1). Among subtypes of ATL, acute-type ATL cells are particularly resistant to current multidrug chemotherapies and show remarkably high cell-proliferative and invasive phenotypes. Here we show a dramatic increase of WNT5A gene expression in acute-type ATL cells compared with those of indolent-type ATL cells. Treatment with IWP-2 or Wnt5a-specific knockdown significantly suppressed cell growth of ATL-derived T-cell lines. We demonstrated that the overexpression of c-Myb and FoxM1 was responsible for the synergistic activation of the WNT5A promoter. Also, a WNT5A transcript variant without the exon4 (the ΔE4-WNT5A mRNA), encoding ΔC-Wnt5 (1-136aa of 380aa), is overexpressed in acute-type ATL cells. The ΔC-Wnt5a is secreted extracellularly and enhances cellular migration/invasion to a greater extent compared with wildtype (WT)-Wnt5a. Moreover, the ΔC-Wnt5a secretion was not suppressed by IWP-2, indicating that this mutant Wnt5a is secreted via a different pathway from the WT-Wnt5a. Taken together, synergistic overexpression of the ΔC-Wnt5a by c-Myb and FoxM1 may be responsible for the malignant phenotype of acute-type ATL cells.

Mechanisms of Resistance to Conventional Therapies for Osteosarcoma.

Simple SummaryOsteosarcoma (OS), the most common primary bone tumor, mainly affects children and adolescents. Unfortunately, in some cases, the absence of response to chemotherapy agents is observed, leading to metastases development and death of the patient. Resistance is one of the biological processes at the origin of therapeutic failure. In order to improve the therapeutic management of patients, it is necessary to identify and better understand the mechanisms underlying resistance. Here, we summarize molecular mechanisms of OS resistance to conventional chemotherapy and list some strategies that overcome resistance.Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is around 75% for patients with localized OS but dramatically drops to 20% for bad responders to chemotherapy or patients with metastases. Resistance is one of the biological processes at the origin of therapeutic failure. Therefore, it is necessary to better understand and decipher molecular mechanisms of resistance to conventional chemotherapy in order to develop new strategies and to adapt treatments for patients, thus improving the survival rate. This review will describe most of the molecular mechanisms involved in OS chemoresistance, such as a decrease in intracellular accumulation of drugs, inactivation of drugs, improved DNA repair, modulations of signaling pathways, resistance linked to autophagy, disruption in genes expression linked to the cell cycle, or even implication of the micro-environment. We will also give an overview of potential therapeutic strategies to circumvent resistance development.

Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.

PurposeThe critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.Patients and MethodsWe combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.ResultsThe mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.ConclusionOur study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.

Neutropenia in dogs receiving vincristine for treatment of presumptive immune-mediated thrombocytopenia.

BackgroundNeutropenia is an adverse effect of vincristine when used in multidrug chemotherapy protocols.ObjectiveTo determine the incidence of neutropenia, identify potential risk factors for neutropenia, and determine the effect of neutropenia on outcome, in dogs receiving vincristine for treatment of immune‐mediated thrombocytopenia (ITP).AnimalsOne hundred twenty‐seven client‐owned dogs presumptively diagnosed with ITP.MethodsIn this retrospective cohort study, medical records were reviewed to identify dogs presumptively diagnosed with ITP, and treated with vincristine, over a 15‐year period. Logistic regression was used to identify risk factors for the development of neutropenia in dogs receiving vincristine. Time to platelet count ≥40 000 platelets/μL, survival, and duration of hospitalization were compared between neutropenic and non‐neutropenic dogs.ResultsVincristine was administered to 127 dogs with presumptive ITP; 19 became neutropenic. Administration of cyclosporine was significantly (P < .001) associated with the development of neutropenia (odds ratio: 12.97, 95% confidence interval: 4.17, 40.35). There was no difference in median time to ≥40 000 platelets/μL between neutropenic dogs (4 days; range, 1‐14 days) and non‐neutropenic dogs (3 days; range, 0‐48 days). Percentage survival to discharge was 95% in both groups, but median duration of hospitalization was significantly longer in neutropenic dogs (6 days; range, 3‐22 days) compared to non‐neutropenic dogs (4 days; range, 2‐15 days).Conclusions and Clinical ImportanceCyclosporine administration was associated with the development of neutropenia in dogs receiving vincristine, which might be related to effects on metabolism of vincristine. Neutrophil counts should be monitored in dogs receiving vincristine treatment for ITP, particularly if administered in conjunction with cyclosporine.