Mechanistic insights into the pathogenesis of microtubule-targeting agent-induced peripheral neuropathy from pharmacogenetic and functional studies.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity that affects 30%-40% of patients undergoing cancer treatment. Although multiple mechanisms of chemotherapy-induced neurotoxicity have been described in preclinical models, these have not been translated into widely effective strategies for the prevention or treatment of CIPN. Predictive biomarkers to inform therapeutic approaches are also lacking. Recent studies have examined genetic risk factors associated with CIPN susceptibility. This review provides an overview of the clinical and pathologic features of CIPN and summarizes efforts to identify target pathways through genetic and functional studies. Structurally and mechanistically diverse chemotherapeutics are associated with CIPN; however, the current review is focused on microtubule-targeting agents since these are the focus of most pharmacogenetic association and functional studies of CIPN. Genome-wide pharmacogenetic association studies are useful tools to identify not only causative genes and genetic variants but also genetic networks implicated in drug response or toxicity and have been increasingly applied to investigations of CIPN. Induced pluripotent stem cell-derived models of human sensory neurons are especially useful to understand the mechanistic significance of genomic findings. Combined genetic and functional genomic efforts to understand CIPN hold great promise for developing therapeutic approaches for its prevention and treatment.

From Microcytosis to Macrodiagnosis.

A 12-year-old Hispanic girl presented with fatigue, lightheadedness, and intermittent headaches. She was depressed and appeared pale to her mother. Her examination was unremarkable except for palpebral conjunctival pallor and was otherwise noncontributory. She had a profound hypoproliferative microcytic anemia with low iron level, low transferrin saturation, and a normal ferritin level. The patient experienced improvement in clinical symptoms following transfusion of packed red blood cells and oral iron therapy. At follow-up 2 months later, she presented with similar symptoms and persistent microcytic anemia with low iron levels. Her ferritin level was increased along with markedly elevated C-reactive protein and erythrocyte sedimentation rate. An oral iron challenge demonstrated lack of absorption, and hepcidin level was also significantly elevated. Thorough gastrointestinal and rheumatologic evaluations were performed to search for a source of inflammation. Key components of the patient's social history supplemented by serology, radiographic, and pathologic findings ultimately cinched an unexpected diagnosis.

Concordance of Identified Cases of Pediatric HA-VTE with American College of Physicians and Cincinnati Children's Hospital HA-VTE Prophylaxis Guidelines Over a 10-Year Period.

Objective: Our aim is to (1) ascertain the proportion of pediatric patients at a tertiary hospital in Western Massachusetts over a 10-year period with hospital-acquired venous thromboembolism (VTE) of particular characteristics and (2) determine whether ACCP or Cincinnati Children's guidelines would have recommended VTE prophylaxis in these patients. Setting: Urban teaching hospital in the United States. Participants: Data from 98 477 pediatric hospital admissions (roughly 10 000 admission per year) from 2008 to 2017 were reviewed. There were a total of 177 VTE cases identified. Outcome measures: Hospital-acquired venous thromboembolism (including deep venous thrombosis and pulmonary embolism). Result: 177 charts were extracted that carried the diagnosis of VTE based on ICD-9 and ICD-10 codes over a 10-year-period. Among these patients, 34 (19%) met the inclusion criteria for HA-VTE; 5 (16%) would qualify for prophylaxis according to ACCP and 7 (21%) according to Cincinnati Children's guideline. The most common age group to have a VTE was infants under 1 year of age (41%), and the most common characteristic was the presence of a central line (82%). Age outside of the recommended range was the sole reason that excluded patients from prophylaxis qualification per Cincinnati Children's. Conclusion: HA-VTE carries increased morbidity and mortality. Although recognition and prevention of HA-VTE in adult populations are routine, prophylaxis for pediatric HA-VTE is not commonly practiced. This may be due to paucity of strong evidence supporting prophylaxis and the challenge of identifying risk factors for HA-VTE. Our results suggest that published guidelines recommend prophylaxis in only a minority of pediatric patients who would have subsequently developed HA-VTE. Further modification and validation of current guidelines are needed to effectively prevent pediatric HA-VTE.

Risk Factors for Transplant-Associated Thrombotic Microangiopathy after Autologous Hematopoietic Cell Transplant in High-Risk Neuroblastoma.

High-risk neuroblastoma has a poor prognosis, and research studies have shown that increasing the intensity of therapy improves outcomes. Autologous hematopoietic cell transplant (aHCT) as consolidation therapy confers a significant survival advantage but is accompanied by significant morbidity. Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication caused by endothelial injury that often leads to hemolytic anemia, microthrombotic platelet consumption, and renal injury. Here we investigated the incidence, potential risk factors, and sequelae of TA-TMA in patients with high-risk neuroblastoma. We conducted a retrospective chart review of all patients (n = 141) with neuroblastoma in our institutions who underwent aHCT from 2000 to 2017. Ten patients (7%) developed TA-TMA. The patients in the TA-TMA group were similar to the rest of the subjects in demographics, disease burden, prior therapies, renal function, and timing of transplant. The type of conditioning regimen was the only statistically significant pretransplant variable (P < .001). Six of 15 patients (40%) intended to receive tandem transplants (cyclophosphamide/thiotepa and then carboplatin/etoposide/melphalan (CEM)), 4 of 68 patients (6%) who received conditioning with single CEM, and none of the 56 patients who received busulfan/melphalan were diagnosed with TA-TMA. Patients with TA-TMA were more likely to require intensive care unit transfer, have a longer length of stay in the hospital, and experience a delay or change in their subsequent therapy. In our cohort overall, patients with a delay in therapy after transplant appeared to have a worse overall survival, although the difference was not statistically significant. Because of this high incidence and significant morbidity, we have implemented standardized screening for TA-TMA during and after transplant. We anticipate that screening will lead to earlier intervention and decreased severity of disease.

Newborn Screening for SCD in the USA and Canada.

Sickle cell disease (SCD) encompasses a group of inherited red cell disorders characterized by an abnormal hemoglobin, Hb S. The most common forms of SCD in the United States and Canada are identified through universal newborn screening (NBS) programs. Now carried out in all fifty U.S. states and 8 Canadian provinces, NBS for SCD represents one of the major public health advances in North America. The current status of NBS programs for hemoglobinopathies and the screening techniques employed in many regions worldwide reflect in large part the U.S. and Canadian experiences. Although the structure, screening algorithms and laboratory procedures, as well as reporting and follow up, vary between NBS programs, the overall workflow is similar. The current review summarized the historical background, current approaches, and methods used to screen newborns for SCD in the United States and Canada.

Use of the blood substitute HBOC-201 in critically ill patients during sickle crisis: a three-case series.

BACKGROUND: Red blood cell (RBC) transfusion is an important treatment modality during severe sickle cell crisis (SCC). SCC patients who refuse, or cannot accept, RBCs present a unique challenge. Acellular hemoglobin (Hb)-based oxygen carriers (HBOCs) might be an alternative for critically ill patients in SCC with multiorgan failure due to life-threatening anemia. HBOC-201 (HbO2 Therapeutics) has been administered to more than 800 anemic patients in 22 clinical trials, but use of any HBOCs in critically ill sickle cell patients with organ failure is exceedingly rare. In the United States, HBOC-201 is currently only available for expanded access. CASE REPORT: We report three cases of HBOC-201 administered to critically ill sickle cell disease patients in SCC with multiorgan failure, either who refused RBCs (Jehovah's Witnesses) or for whom compatible RBCs were not available. RESULTS: Two patients received more than 20 units of HBOC-201, while the other received 6. The 27 units used in the third case equals the largest volume a patient has successfully received to date. All three patients survived to hospital discharge. CONCLUSION: These reports suggest that blood substitutes such as HBOC-201 can provide an oxygen bridge in SCC with multiorgan failure, until corpuscular Hb levels recover to meet metabolic demand, and highlight the compelling biochemical properties that warrant further investigation.

Sun protection in a pill: the photoprotective properties of Polypodium leucotomos extract.

BACKGROUND: Physical blocks (i.e. wearing appropriate clothing), exposure avoidance, and the use of sunscreens are the main methods of photoprotection currently used. However, phytochemical and natural botanical extracts such as polypodium leucotomos, a tropical fern found in Central and South America, demonstrate a strong potential as adjuncts to sunscreen protection. METHOD: A review of the literature was performed focusing on the photoprotective properties of PL extracts, including antioxidant, immunoregulatory, anti-inflammatory and antitumorigenic effects in the context of sunburn, photodermatoses, chronic skin damage, photoaging, and skin cancer. RESULTS: PL supplementation acts at a molecular and cellular level to enhance endogenous antioxidant systems and inhibit generation of reactive oxygen species, thus decreasing UV-mediated oxidative DNA mutations. PL has also been shown to accelerate removal of UV-induced photoproducts, highlighting its anti-carcinogenic role. By reducing UV-induced inflammatory responses and inhibiting extracellular matrix remodeling, PL demonstrates some protective effects against photoaging and PUVA induced phototoxicity. CONCLUSION: The use of a systemic protective agent would provide significant advantages such as a more uniform coverage over the total body surface area, regardless of individual factors such as potency of the creams, amount applied, sweating, or bathing. Oral administration of PL extracts and its favorable safety profile could have significant implications in the prevention of skin cancer.

Secondary Hemophagocytic Syndrome Associated with Richter's Transformation in Chronic Lymphocytic Leukemia.

Hemophagocytic syndrome (HPS) is an extremely rare condition arising from the overactivation of one's own immune system. It results in excessive inflammation and tissue destruction. Prompt initiation of treatment is warranted in either scenario in order to decrease mortality. Most cases are triggered by infectious agents, malignancy, or drugs. We describe the first case of a CLL patient presenting with HPS due to acquisition of EBV-related large cell lymphoma in the setting of profound immunodeficiency.