EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

ExPert ConsEnsus on the management of Advanced clear-cell RenaL celL carcinoma: INDIAn Perspective (PEARL-INDIA).

In advanced Renal Cell Carcinoma (aRCC), systemic therapy is the mainstay of treatment, with no or little role for surgery in these patients. Tyrosine kinase inhibitors (TKIs) and immune-oncological (IOs) therapies, either alone or in combination, are recommended in these patients depending on patient and tumour factors. The sequencing of therapies is critical in RCC because the choice of subsequent line therapy is heavily dependent on the response and duration of the previous treatment. There are additional barriers to RCC treatment in India. Immunotherapy is the cornerstone of treatment in ccRCC, but it is prohibitively expensive and not always reimbursed, effectively putting it out of reach for the vast majority of eligible patients in India. Furthermore, in advanced RCC (particularly the clear cell variety), Indian oncologists consider the disease burden of the patients, which is particularly dependent on the quantum of the disease load, clinical symptoms, and performance status of the patient, before deciding on treatment. There are no India-specific guidelines for clear cell RCC (ccRCC) treatment or the positioning and sequencing of molecules in the management of advanced ccRCC that take these country-specific issues into account. The current consensus article provides expert recommendations and treatment algorithms based on existing clinical evidence, which will be useful to specialists managing advanced ccRCC.

Secondary impacts of constipation in acute lymphoblastic leukemia in U.S. children's hospitals.

BACKGROUND: Childrenwith acute lymphoblastic leukemia (ALL) suffer a litany of chemotherapy-induced side effects. Constipation secondary to vinca alkaloids, psychological stressors, and opioid use are common issues for children newly diagnosed with leukemia. This study investigated the morbidity associated with constipation including infections, mucositis, and healthcare utilization in hospitalized children with ALL receiving induction chemotherapy. METHODS: We analyzed data from 48 children's hospitals in the Pediatric Health Information System, extracting patients 1-21 years of age with ALL, hospitalized for induction from October 2015 through December 2019. Data were analyzed using nonparametric statistics, and comparisons of outcomes between those with and without constipation were presented as adjusted odds ratios (aOR). RESULTS: We identified 2586 (56%) patients with constipation out of a total of 4622 unique ALL patients in induction. Compared to patients without constipation during induction, patients with constipation were significantly more likely to have mucositis (aOR = 2.30; p = 0.0010), perirectal issues (aOR = 3.21; p = 0.0092), or abdominal radiograph exposure (aOR = 2.40; p < 0.0001). The median length of induction hospitalization was significantly greater in those with constipation compared to those without constipation (10 days vs. 8 days; p < 0.0001). CONCLUSIONS: Children with ALL suffering from constipation during induction therapy have increased length of stay, mucositis, imaging, and overall healthcare utilization compared to children without constipation. Further research should explore the causative relationship between constipation and infections. Increased attention should be given to constipation management in patients with ALL at the start of induction therapy, particularly in patients with complications or prolonged hospitalizations.

Rare Hematologic Malignancies and Pre-Leukemic Entities in Children and Adolescents Young Adults.

There are a variety of rare hematologic malignancies and germline predispositions syndromes that occur in children and adolescent young adults (AYAs). These entities are important to recognize, as an accurate diagnosis is essential for risk assessment, prognostication, and treatment. This descriptive review summarizes rare hematologic malignancies, myelodysplastic neoplasms, and germline predispositions syndromes that occur in children and AYAs. We discuss the unique biology, characteristic genomic aberrations, rare presentations, diagnostic challenges, novel treatments, and outcomes associated with these rare entities.

Migrated Peripherally Inserted Central Catheter in the Right Ventricle and Bilateral Pulmonary Arteries: A Case Report.

Introduction Central venous catheterization is a common tool widely used in medical treatment for long-term intravenous administration of medication (e.g. chemotherapy or antibiotics) or parenteral nutrition. Here, we present a case of a missing peripherally inserted central catheter (PICC) which was detected on computed tomography (CT) scan thorax. Case Report A 50-year-old female admitted for follow-up for adenocarcinoma rectum was found to have a missing PICC line and advised CT thorax for evaluation. The imaging findings revealed coiled PICC line in the right atrium extending to inferior vena cava and into right ventricle and further extending and coiled PICC is seen in the main, right, and left pulmonary arteries. Through emergency interventional procedure, the PICC line was successfully retrieved percutaneously via the right femoral vein. Conclusion PICC fracture is less common and always seen without significant discomfort if not found timely, and it may lead to serious complications, such as pulmonary embolism, and even death. Early detection and removal may help to prevent significant mortality.

Early Discharge of Adolescent and Young Adult Patients During Induction Chemotherapy for Newly Diagnosed Acute Lymphoblastic Leukemia: Is It Safe?

There is a lack of consensus for safely discharging adolescent and young adults (AYA) with newly diagnosed acute lymphoblastic leukemia. From 2017 to 2019 we evaluated predefined early discharge criteria for 41 AYA patients during induction chemotherapy. Only 17% (7/41) of patients met criteria for early discharge. Two (29%) patients who were discharged early were readmitted, but not to the pediatric intensive care unit (PICU). This outcome was compared to a historic cohort at our institution of 73 patients who were discharged without predefined discharge criteria. Twenty-seven (37%, p = 0.7) patients were readmitted, but 13 (48%) were readmitted to the PICU (p = 0.004).

Venous Thromboembolic Events in Adolescent and Young Adult Patients with Acute Lymphoblastic Leukemia.

Acute venous thromboembolisms (VTEs) are serious complications that occur during acute lymphoblastic leukemia (ALL) chemotherapy. The data elucidating risk factors for developing VTEs are limited in adolescent and young adult patients being treated per pediatric ALL protocols. In a cohort of 66 patients, 14 (21%) experienced VTEs. The majority of VTEs occurred during induction chemotherapy after the first dose of asparaginase, and in the upper extremities. Five-year relapse-free and overall survival were not impacted by VTEs. Contrary to VTEs in adults, hypoalbuminemia and increased body mass index were not associated with an elevated risk of VTE.

Sequencing of Systemic Therapies in the Management of Advanced Prostate Cancer in India: a Delphi-Based Consensus.

INTRODUCTION: With the availability of an increasing number of therapeutic options for advanced prostate cancer (APC), optimal sequencing and combination of therapies have emerged to be the areas of challenges. In the Indian context, there is a dearth of consensus recommendations to guide clinicians regarding optimal sequencing of therapy in APC management. A Delphi-based consensus regarding optimal therapy sequencing in APC management was developed by an expert panel of medical oncologists from across India. METHODS: An expert scientific committee of 11 medical oncologists and an expert panel of 53 medical oncologists from India constituted the panel for the Delphi consensus. In the first phase, a questionnaire with 41 clinical statements was developed in several critical controversial areas in APC treatment. In the second phase, 29 clinical statements were reworked and sent to eight experts to obtain their opinions on best practices. The consensus ratings were based on a 9-point Likert scale. Based on the overall response, statements with a mean score of ≥ 7 with 1 outlier were considered as "consensus." RESULTS: Degarelix was the preferred androgen deprivation therapy (ADT). While ADT plus docetaxel was the preferred option for metastatic castrate-sensitive/naïve prostate cancer patients with high-volume disease, ADT with abiraterone was the preferred choice for low-volume disease. Docetaxel was the preferred first-line treatment option in men who received ADT alone in the castrate-sensitive/naïve setting. For patients progressing on or after docetaxel for metastatic castrate-resistant prostate cancer (without prior abiraterone or enzalutamide), the experts reached a consensus on the use of enzalutamide as the preferred second-line treatment option. No consensus was reached for the third-line treatment options. CONCLUSION: This article is intended to serve as a guide to help clinicians discuss with their patients as part of the shared and multidisciplinary decision-making for improved APC management in India.

Asparagine bioavailability regulates the translation of MYC oncogene.

Amino acid restriction has recently emerged as a compelling strategy to inhibit tumor growth. Recent work suggests that amino acids can regulate cellular signaling in addition to their role as biosynthetic substrates. Using lymphoid cancer cells as a model, we found that asparagine depletion acutely reduces the expression of c-MYC protein without changing its mRNA expression. Furthermore, asparagine depletion inhibits the translation of MYC mRNA without altering the rate of MYC protein degradation. Of interest, the inhibitory effect on MYC mRNA translation during asparagine depletion is not due to the activation of the general controlled nonderepressible 2 (GCN2) pathway and is not a consequence of the inhibition of global protein synthesis. In addition, both the 5' and 3' untranslated regions (UTRs) of MYC mRNA are not required for this inhibitory effect. Finally, using a MYC-driven mouse B cell lymphoma model, we found that shRNA inhibition of asparagine synthetase (ASNS) or pharmacological inhibition of asparagine production can significantly reduce the MYC protein expression and tumor growth when environmental asparagine becomes limiting. Since MYC is a critical oncogene, our results uncover a molecular connection between MYC mRNA translation and asparagine bioavailability and shed light on a potential to target MYC oncogene post-transcriptionally through asparagine restriction.

Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

Pediatric Mixed-Phenotype Acute Leukemia: What's New?

Mixed-phenotype acute leukemias (MPAL) are rare in children and often lack consensus on optimal management. This review examines the current controversies and emerging paradigms in the management of pediatric MPAL. We examine risk stratification, outcomes of recent retrospective and prospective collaborative trials, and the role of transplantation and precision genomics, and outline emerging targets and concepts in this rare entity.

Asparagine: A Metabolite to Be Targeted in Cancers.

Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a nonessential amino acid, by L-asparaginase has been used in treating pediatric acute lymphoblastic leukemia (ALL) for decades. Of interest, unlike most solid tumor cells, ALL cells lack the ability to synthesize their own asparagine de novo effectively. However, only until recently, growing evidence suggests that solid tumor cells strive to acquire adequate amounts of asparagine to support tumor progression. This process is subjected to the regulation at various levels, including oncogenic signal, tumor-niche interaction, intratumor heterogeneity and dietary accessibility. We will review the literature on L-asparaginase-based therapy as well as recent understanding of asparagine metabolism in solid tumor progression, with the hope of shedding light into a broader cancer therapeutic strategy by perturbing its acquisition and utilization.

Estimating the Risk of Chemotherapy Toxicity in Indian Geriatric Patient Population and Utility of Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) Score.

Background Aging is a heterogeneous process, and elderly population is diverse in health status and functional reserve. The present study was undertaken to predict severe chemotherapy toxicity using the Chemotherapy Risk Assessment Scale for High-Age Patients' (CRASH) score. Materials and Methods Elderly patients (age ≥65 years) with malignancy, who were planned to be treated with a new course of cytotoxic chemotherapy, were enrolled. The CRASH score was calculated, and patients were stratified into four categories, that is, low (0-3), intermediate (Int)-low (4-6), Int-high (7-9), and high (<9). Patients developing grade 3/4/5 nonhematologic (NH) or grade 4/5 hematologic (H) toxicity were taken as the development of severe toxicity. Results Of 100 enrolled patients, 64 (64%) were able to complete their prescribed treatment. Forty-four percent of patients (44 patients) of our study cohort experienced grade-4 H or grade 3/4 NH toxicity. The highest score in each category (heme/nonheme/CRASH) predicts nearly 100% toxicity risk. At a critical value of CRASH ≥ 6.5, the sensitivity is calculated as 100%, while specificity is 89.09%. The accuracy of prediction is 93.88%. The median time taken to develop toxicity was 39.5 days. Conclusion CRASH score utilizes clinical assessment and basic laboratory values. Yet, it accurately predicts severe chemotherapy toxicity above a critical value of 6.5. Based on the above study, the first 30 days are crucial as 45% of patients experienced toxicity in this time frame. With the help of these clinical predictive markers, the care of elderly will be optimized.

Gallbladder cancer with tumor thrombus in the superior vena cava.

BACKGROUND: Gastrointestinal cancers, especially pancreatobiliary cancers, are frequently associated with or are complicated by thromboembolic phenomena due to hypercoagulability and/or altered venous drainage, especially of the abdomen and lower limbs. This report describes an unusual and interesting case of gallbladder carcinoma developing a viable tumor thrombus in the superior vena cava (SVC) with resultant SVC obstruction, while on gefitinib-based anti-epidermal growth factor receptor (EGFR) therapy. METHODS: A 60-year-old woman was incidentally diagnosed to have gallbladder cancer on cholecystectomy. She had disease recurrence and received systemic chemotherapy followed by gefitinib-based anti-EGFR therapy. Subsequently, while on gefitinib-based therapy, she presented with clinical signs and symptoms suggestive of SVC thrombosis. RESULTS: A whole body PET scan revealed a metabolically active tumor thrombus in the SVC, besides other sites of metabolically active disease inclusive of the lung parenchyma, lymph nodes and abdomen. She was treated with anti-thrombotics and external beam radiotherapy directed to the SVC thrombus leading to symptomatic relief. She continues to survive on the day of writing this report. CONCLUSIONS: This rare complication, though theoretically possible, is unreported because of the short overall survival of advanced gallbladder cancer patients. This highlights that with the availability of better chemotherapeutic/biotherapeutic agents for increasing in the lifespan of cancer patients, we may come across such cases more frequently in the future.

Hypogammaglobulinemia in Adolescents and Young Adults with Acute Lymphoblastic Leukemia.

Hypogammaglobulinemia is a poorly described complication of chemotherapy in adolescents and young adults (AYAs, 15-39 years) with acute lymphoblastic leukemia (ALL). The majority of AYAs treated on a Berlin-Frankfurt-Munster-based ALL regimen experienced hypogammaglobulinemia (65.0% [13/20]). Febrile neutropenia episodes (throughout the treatment course) and infectious events during maintenance occurred more frequently in hypogammaglobulinemic patients compared with patients with normal immunoglobulin G levels (n = 7) (median 1.0 vs. 0.0, p = 0.02; 7.0 vs. 3.0, p = 0.02, respectively). Hypogammaglobulinemia did not impact overall or event-free survival. Further studies are needed to elucidate the etiology of hypogammaglobulinemia and to establish criteria for immunoglobulin replacement in these patients.

Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma.

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.

Factors associated with a prolonged hospital stay during induction chemotherapy in newly diagnosed high risk pediatric acute lymphoblastic leukemia.

BACKGROUND: High Risk (HR) or Very High Risk (VHR) acute lymphoblastic leukemia (ALL) treated with 4 drug induction chemotherapy is often associated with adverse events. The aim of this study was to identify risk factors associated with a prolonged inpatient length of stay LOS during induction chemotherapy. PROCEDURE: Data from patients (N = 73) (age<21 years) was collected through a retrospective chart review. Univariable and multivariable logistic regression was used to test for statistical significance. The overall survival and disease (leukemia)-free survival were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Of the 73 patients, 42 (57%) patients were discharged on day 4 of induction (short LOS, group A), while 31 (43%) patients (group B) experienced a prolonged LOS or an ICU stay (16 ±â€¯27.7 days, median hospital stay = 8 days vs 4 days (group A), p = 0.02) due to organ dysfunction, infectious or metabolic complications. Group B patients were more likely to have a lower platelet count, serum bicarbonate, and a higher blood urea nitrogen (BUN) on day 4 of treatment (OR = 4.52, 8.21, and 3.02, respectively, p < 0.05). Multivariable analysis identified low serum bicarbonate (p = 0.002) and a platelet count<20,000/µL (p = 0.02) on day 4 of induction to be predictive of a prolonged LOS. Twenty six (group A (n = 16, 36%) and B (n = 11, 35%), p = 0.8) patients experienced unplanned admissions, within 30 days of discharge. CONCLUSIONS: A significant proportion of newly diagnosed HR or VHR pediatric ALL patients experience a prolonged LOS and unplanned re-admissions. Aggressive discharge planning and close follow up is indicated in this cohort of patients.