No abstract

Studies were conducted on serum removed from 15 patients before, during, and after, clozapine-induced agranulocytosis. Cytotoxic studies were compared with samples taken from patients during treatment with clozapine who did not develop agranulocytosis or treatment controls (TC); additional controls consisted of allogeneic (NC) and autogeneic serum from apparently normal people. The effect of serum on measurable functions of polymorphonuclear neutrophils (PMNs) taken from normal people was tested. Procedures under study included suppression of postphagocytosis-induced 14C02-indicated respiratory burst, as well as ejection of try pan blue by test PMNs. PMNs exposed to active agranulocytosis serum plus complement displayed diminished 14C02 emission during phagocytosis or failed to eject trypan blue. PMNs exposed to serum of TC and NC continued to function normally as regards 14C02 emission and trypan blue ejection. Five patients studied before the development of agranulocytosis showed suppressed PMN function, which increased to peak value during agranulocytosis and then disappeared within 40 days of recovery. Similar suppression of colony forming units of granulocytes and macrophages (CFU-GM) was found whenever agranulocytosis serum was included in the marrow culture. The cytotoxic material required complement for its full expression, was not dialysable, was neutralised by anti-IgM serum, and was absorbed by test PMNs. Furthermore, solutions of clozapine or 5 of its metabolites offered no similar suppression of PMN function in vitro after incubation in an aqueous medium or with normal serum. These observations favour development of an immunogenic clone in sensitive people during active treatment with clozapine, which eventually leads to precipitous depletion of PMNs and their precursors. The early appearance of this suppressive substance may offer an early warning for development of agranulocytosis.

T cell-replete post-transplant cyclophosphamide (PTCy)-based protocols have led to increasing use of haploidentical allogeneic hematopoietic cell transplantation (haploHCT). With this approach, bidirectional alloreactivity causing nonengraftment or severe graft-versus-host disease (GVHD) is no a longer major barrier to haploHCT. PTCy eliminates alloreactive lymphocytes but spares CD34 stem cells and regulatory T lymphocytes, resulting in reliable hematopoietic recovery with relatively low incidence of GVHD. The immediate post-haploHCT course, usually before PTCy administration, is often complicated by cytokine release syndrome (CRS). The predictors of CRS and its effect on outcomes post-transplant have not been fully ascertained. We analyzed the outcomes of 66 patients who received haploHCT at our institution. Using published CRS criteria we identified 48 patients who developed CRS. In multivariate analysis peripheral blood grafts were significantly associated with grade ≥ 2 CRS, compared with bone marrow. Grade ≥ 2 CRS (compared with grade < 2) was not associated with differences in overall survival or nonrelapse mortality. Severe CRS was associated with a statistically nonsignificant trend toward higher incidences of grades III to IV acute GVHD, especially in the context of peripheral blood grafts. CRS is a common complication after T cell-replete peripheral blood haploHCT, but post-transplant survival outcomes may not be affected in those with severe CRS.

We aimed to determine the role of HPV in the pathogenesis and outcome of oropharyngeal squamous cell carcinoma (OSCC) in lifelong nonsmoking and nondrinking patients. A case-case analysis was performed to compare the presence of HPV-DNA in tumor cells of 16 nonsmoking and nondrinking with 16 matched smoking and drinking patients (matching criteria: age at incidence, gender, tumor sublocation, tumor stage). HPV was detected using 2 PCR tests, FISH analysis, and p16INK4A immunostaining. Nonsmoking and nondrinking patients had more HPV-positive tumors than smoking and drinking patients (n = 12; 75% versus n = 2; 13%; P < 0.001). All HPV-positive tumors showed p16INK4A overexpression, and 1 HPV-negative tumor had p16INK4A overexpression, (P < 0.001). Overall survival and disease-specific survival were higher for HPV-positive compared to HPV-negative cases (P = 0.027, P = 0.039, resp.). In conclusion, HPV is strongly associated with OSCC of nonsmoking and nondrinking patients. Specific diagnostic and therapeutic actions should be considered for these patients to achieve a better prognosis.