Gastrointestinal toxicity of high-dose melphalan in autologous hematopoietic stem cell transplantation: identification of risk factors and a benchmark for experimental therapies.

Gastrointestinal side effects are the dose-limiting toxicity of high-dose melphalan (HDM) in autologous hematopoietic stem-cell transplantation, but there are limited contemporary data on the incidence and severity of gastrointestinal toxicity associated with this regimen. We retrospectively studied 100 consecutive patients who received HDM alone or in combination with other conditioning agents. Patients had a median age of 56 (range 20-73); underlying diseases were myeloma (42%), lymphoma (42%), or amyloidosis (16%) and melphalan dosages were 200 (40%), 140 (59%), or 100 mg/m2 (1%). Ninety-seven percent of patients experienced diarrhea with a range of 1-18 bowel movements per day, 88% developed nausea, and 60% experienced vomiting. Abdominal CT scans rarely altered patient management, but stool studies were useful in identifying a treatable infectious source. Grade ≥ 2 diarrhea was associated with longer duration of diarrhea, longer length of stay, worse hypoalbuminemia, higher use of antibiotics, abdominal imaging, electrolyte repletions, and anti-diarrheal agents. Risk factors for severe diarrhea were female sex, melphalan dose, age > 50, creatinine clearance < 60 ml/min, and having a plasma cell neoplasm as opposed to lymphoma. Female sex was also associated with more severe nausea and vomiting. In summary, diarrhea remains an important toxicity of HDM and novel therapies for chemotherapy-induced diarrhea for patients undergoing stem-cell transplantation are needed. Grade 2 or higher diarrhea is associated with significant clinical consequences and should be used as the primary endpoint in prospective clinical trials.

Cost of care for the initial management of cervical cancer in women with commercial insurance.

BACKGROUND: Women with newly diagnosed cervical cancer are often treated with extensive, multimodal therapies that may include a combination of surgery, radiation, and chemotherapy. Little is known about the cost of treatment or how these costs are passed on to the patients. OBJECTIVE: The objectives of this study were to examine the cost of care during the first year after a diagnosis of cervical cancer, to estimate the sources of the costs, and to explore the out-of-pocket costs. STUDY DESIGN: We performed a study of women with commercial insurance who received a new diagnosis of cervical cancer, and whose cases were recorded in the MarketScan database from 2008 to 2016. Patients were categorized based on the primary treatment received being either surgery (hysterectomy with or without adjuvant radiation or chemotherapy) or radiation. The inflation-adjusted medical expenditures for a 12-month period beginning on the date of the first treatment were estimated. The payments were divided into the expenditures of inpatient care, outpatient care (including chemotherapy), and outpatient pharmacy costs. The out-of-pocket costs incurred by the patients in the form of copayments, coinsurance, and deductibles were estimated. RESULTS: A total of 4495 patients, including 3014 (67%) who underwent surgery and 1481 (33%) who primarily underwent radiotherapy, were identified. The median total expenditure per patient during the first year after the diagnosis was $56,250 (interquartile range, $25,767-$107,532). The median total expenditure for patients with surgery as the primary treatment was $37,222 (interquartile range, $20,957-$75,555). The median total expenditure for patients treated primarily with radiotherapy was $101,266 (interquartile range, $63,155-$160,760). For patients treated primarily with surgery, inpatient services accounted for $15,145 (interquartile range, $0-$26,898), outpatient services accounted for $18,430 (interquartile range, $5354-$48,047), and outpatient pharmacy costs accounted for $628 (interquartile range, $141-$1847). The median cost for those women who did not require adjuvant therapy was $26,164 compared with $89,760 for women treated with adjuvant radiation. The median out-of-pocket costs for the cohort was $2253 (interquartile range, $1137-$3990) or 3.9% of the total costs. CONCLUSION: The cost of care for women with newly diagnosed cervical cancer is substantial. Overall, patients are responsible for approximately 3.9% of the costs in the form of out-of-pocket expenditures.

Corrigendum: HIV-1 Env associates with HLA-C free-chains at the cell membrane modulating viral infectivity.

This corrects the article DOI: 10.1038/srep40037.

HIV-1 Env associates with HLA-C free-chains at the cell membrane modulating viral infectivity.

HLA-C has been demonstrated to associate with HIV-1 envelope glycoprotein (Env). Virions lacking HLA-C have reduced infectivity and increased susceptibility to neutralizing antibodies. Like all others MHC-I molecules, HLA-C requires ß2-microglobulin (ß2m) for appropriate folding and expression on the cell membrane but this association is weaker, thus generating HLA-C free-chains on the cell surface. In this study, we deepen the understanding of HLA-C and Env association by showing that HIV-1 specifically increases the amount of HLA-C free chains, not bound to ß2m, on the membrane of infected cells. The association between Env and HLA-C takes place at the cell membrane requiring ß2m to occur. We report that the enhanced infectivity conferred to HIV-1 by HLA-C specifically involves HLA-C free chain molecules that have been correctly assembled with ß2m. HIV-1 Env-pseudotyped viruses produced in the absence of ß2m are less infectious than those produced in the presence of ß2m. We hypothesize that the conformation and surface expression of HLA-C molecules could be a discriminant for the association with Env. Binding stability to ß2m may confer to HLA-C the ability to preferentially act either as a conventional immune-competent molecule or as an accessory molecule involved in HIV-1 infectivity.