Phase I and pharmacokinetic study of tiazofurin (TCAR,NSC 286193) administered by continuous infusion

Summary Tiazofurin (2--D-ribofuranosylthiazole-4-carboxamide, TCAR) is a synthetic C-nucleoside that demonstrated significant in vivo activity against a variety of animal tumors as well as in vitro activity against human tumor-derived cell lines. Thirteen patients were treated with TCAR administered as a 5-day continuous infusion in this Phase I trial. Seventeen complete cycles were administered in three dose levels ranging from 550 to 1450 mg/M². Dose-limiting toxicities were myelosuppression and neurotoxicity including severe lethargy. Other toxicities including superficial skin peeling, myalgias, and tearing were seen at all doses. One patient had chest pain on day 4 resulting in stopping the drug, however, there was no evidence of cardiac or pericardial disease. Uric acid levels rose within one day in the absence of allopurinol treatment. There were no treatment related deaths. HPLC measurement of drug levels demonstrated steady-state plasma levels during the infusion, and a half-life following the infusion of 7.7 ± 0.6 hours. Minor abnormalities in renal function were associated with dramatic changes in pharmacokinetics and toxicity. No clinical responses were observed in this trial.Abbreviations TCAR Tiazofurin - HPLC High performance liquid chromatography - IMPD Inosine monophosphate dehydrogenase - WBC white blood cell - CPK creatine phosphokinase - C_ss steady-state concentration     

Determination of left ventricular mass in dogs with rapid-acquisition cardiac computed tomographic scanning

The development of left ventricular hypertrophy in patients with heart disease often has far-reaching clinical implications with respect to overall morbidity and mortality. Approaches used to assess left ventricular mass include electrocardiography, echocardiography, contrast ventriculography, single photon-emission tomography, and conventional computed tomography. However, all of these modalities suffer from some major draw back that precludes widespread application to all patients. In this study we assessed the accuracy of determinations of left ventricular mass in 22 dogs by rapid-acquisition (50 msec) computed axial tomography (RACAT), an ultrafast computed tomographic (CT) instrument. Electrocardiographically triggered, end-diastolic, short-axis cardiac scans were obtained from apex to base during administration of intravenous iodinated contrast. Myocardial edges were determined for each tomographic scan by two methods: the regional half-contour method (the CT density half way between that of the left ventricular myocardium and adjacent ventricular cavities or lung) and "interactive plateau thresholding" of the cardiac borders. Left ventricular mass by RACAT was calculated as the sum of the mass of each individual scan from apex to base (modified Simpson's rule). Postmortem left ventricular mass ranged from 58 to 160 g. The correlation between true left ventricular mass and tomographically determined mass was excellent (r = .99), with the slope and y intercept not statistically different from 1 and 0, respectively. The standard error of the estimate was 4.1 g. Interobserver and intraobserver variability for determining left ventricular mass demonstrated excellent agreement (r = .99 and r = .99, respectively). We conclude that quantitative assessment of left ventricular mass can be accurately and reproducibly performed in dogs by rapid acquisition CT scanning. It is likely that this technique will be readily transferable to the clinical settings and prove to be an important method for quantifying left ventricular mass in patients.     

Effects of ketamine on low intensity tactile sensory input are not dependent upon a spinal site of action

The development of a technique for studying spinal dorsal horn electrophysiology in intact, awake, drug-free cats enables the study of spinal sites and mechanisms of action of anesthetic and analgesic agents in a system that more closely reflects normal physiology. Using this technique, we reevaluated the effect of ketamine on spinal dorsal horn sensory transmission. The results of our study confirm previous work done in acute preparations. Ketamine (maximum dose 20 mg/kg) did not significantly reduce the response of low threshold (n = 11) dorsal horn neurons to low intensity sensory stimulation. However, that same dose of ketamine did suppress noxiously evoked activity of the two wide dynamic range neurons encountered in the study, while having a varied effect on neurons responsive to proprioceptive input (n = 7). These findings confirm that, in the intact animal with all modulatory systems intact, ketamine "dissociation" of low intensity tactile stimuli does not appear to involve a spinal mechanism of action. The results also support the importance of spinal sites of action for the analgesia produced by ketamine, as well as the importance of distinguishing between the anesthetic and analgesic effects of that drug.     

The Excess Preterm Birth Rate Among US-Born (Compared to Foreign-Born) Black Women: The Role of Father’s Education

Maternal and Child Health Journal - To ascertain the component of the excess preterm birth (<?37 weeks, PTB) rate among US-born (compared to foreign-born) Black women...     

Is Preoperative Staphylococcus aureus Screening and Decolonization Effective at Reducing Surgical Site Infection in Patients Undergoing Orthopedic Surgery? A Systematic Review and Meta-Analysis With a Special Focus on Elective Total Joint Arthroplasty

BackgroundStaphylococcus aureus is a major pathogen implicated in orthopedic infections worldwide. Preoperative decolonization has been promoted but different strategies present mixed results. Thus, the goals of this study are to determine (1) whether S aureus screening and/or decolonization is effective at reducing surgical site infection in orthopedic surgery, (2) with a special focus on elective total joint arthroplasty (TJA), and (3) which preoperative S aureus screening/treatment strategy is most cost-effective for TJA.MethodsPubMed, Ovid MEDLINE, and Cochrane databases were searched on January 1, 2020, using a systematic strategy. We included papers with data comparing surgical site infection and periprosthetic joint infection rate in orthopedic surgery and/or elective total hip and knee arthroplasty patients before/after S aureus screening and/or decolonization protocol and papers evaluating the cost-effectiveness of different S aureus screening/treatment strategies.ResultsA total of 1260 papers were screened, and 32 papers were ultimately included. Results showed an increased risk of developing any infection (relative risk [RR] = 1.71 ± 0.16) and S aureus infection (RR = 2.79 ± 0.45) after orthopedic surgery without previous nares and whole-body decolonization. Focusing exclusively on elective TJA, there was an increased risk of developing any infection (RR = 1.70 ± 0.17) and S aureus infection (RR = 2.18 ± 0.41) if no decolonization is performed. All strategies appeared to be cost-effective, although universal decolonization without screening seemed to be the most advantageous.ConclusionPreoperative S aureus screening/decolonization protocol lowered the risk of infection after elective orthopedic and TJA surgeries. However, further studies are needed to determine optimal clinical and cost-effective methodologies.     

The association of Hospital Medicare beneficiary payer-mix,national quality rankings and outcomes following hepatopancreatic surgery

IntroductionWe sought to determine the impact of payer-mix on post-operative outcomes among Medicare beneficiaries following hepatopancreatic surgery.MethodsMedicare beneficiaries who underwent hepatopancreatic surgery were identified. Hospital quality markers were obtained from the Hospital General Information dataset. Hospitals were dichotomized (low/average vs. high) based on Medicare patient days versus all patient days irrespective of payer type.ResultsHigh Medicare patient-mix hospitals were more likely to be ranked higher than the national average relative to safety of care (29.4% vs. 38.1%) and timeliness of care (15.4% vs. 26.3%) versus low burden Medicare hospitals (both p < 0.001). However, Medicare beneficiaries who had hepatopancreatic surgery at a high Medicare patient-mix hospital were at higher risk of a complication (OR = 1.13, 95%CI 1.04–1.22), and death within 30-days (OR = 1.37, 95%CI 1.23–1.53) following surgery.ConclusionWhile hospitals caring for higher numbers of Medicare beneficiaries generally performed better on CMS quality indicators, these rankings did not equate to improved post-operative outcomes.     

Transcriptomic and Immunophenotypic Characterization of Tumor Immune Microenvironment in Squamous Cell Carcinoma of the Oral Tongue

The tumor immune microenvironment of oral tongue squamous cell carcinoma may be accountable for differences in clinical behavior, particularly between different age groups. We performed RNA expression profiling and evaluated tumor infiltrating lymphocytes (TILs) and their T-cell subsets in order to assess the functional status of oral tongue squamous cell carcinoma tumor microenvironment and detect potentially clinically useful associations. Archival surgical pathology material from sixteen oral tongue squamous cell carcinoma patients was microscopically evaluated for TIL densities. RNA was extracted from macrodissected whole tumor sections and normal controls and RNA expression profiling was performed by the NanoString PanCancer IO 360 Gene Expression Panel. Immunostains for CD4, CD8 and FOXP3 were evaluated manually and by digital image analysis. Oral tongue squamous cell carcinomas had increased TIL densities, numerically dominated by CD4 + T cells, followed by CD8 + and FOXP3 + T cells. RNA expression profiling of tumors versus normal controls showed tumor signature upregulation in inhibitory immune signaling (CTLA4, TIGIT and PD-L2), followed by inhibitory tumor mechanisms (IDO1, TGF-β, B7-H3 and PD-L1). Patients older than 44 years showed a tumor microenvironment with increased Tregs and CTLA4 expression. Immunohistochemically assessed CD8% correlated well with molecular signatures related to CD8 + cytotoxic T-cell functions. FOXP3% correlated significantly with CTLA4 upregulation. CTLA4 molecular signature could be predicted by FOXP3% assessed by immunohistochemistry (R² = 0.619, p = 0.026). Oral tongue squamous cell carcinoma hosts a complex inhibitory immune microenvironment, partially reflected in immunohistochemically quantified CD8 + and FOXP3 + T-cell subsets. Immunohistochemistry can be a useful screening tool for detecting tumors with upregulated expression of the targetable molecule CTLA4.Electronic supplementary materialThe online version of this article (10.1007/s12105-020-01229-w) contains supplementary material, which is available to authorized users.     

Large-cell lymphomas: clinical and prognostic features

We reviewed the clinical and pathologic features in 186 patients with large-cell lymphomas seen at Vanderbilt University Hospital between 1970 and 1986. Ninety-two cases (49%) were large noncleaved-cell lymphoma (LNCCL), 61 cases (33%) were large-cleaved-cell lymphoma (LCCL), 17 cases (9%) were peripheral T-cell lymphoma (PTCL), and 16 cases (9%) were immunoblastic sarcoma of B cells (IBS-B). These subsets of large-cell lymphoma did not differ with respect to median age, distribution by stage, or incidence of bone marrow involvement. Significant differences between groups were noted with regard to male:female ratio, incidence of symptoms, incidence of extranodal disease, and pattern of adenopathy. However, when LCCL was excluded from the analysis, none of these differences were significant. By univariate analysis, age, stage, marrow involvement, extranodal disease, B symptoms, elevated serum lactic dehydrogenase (LDH), and diffuse pattern were unfavorable prognostic features in large-cell lymphoma. However, when cases were stratified by cell of origin, nodular versus diffuse pattern was of no prognostic significance. Nodularity was favorable only because 71% of nodular and nodular-diffuse cases were LCCL, while the majority of diffuse cases were LNCCL. Although IBS-B is considered a "high-grade" lymphoma, we found no evidence for inferior survival in these patients compared with LNCCL or LCCL. In fact, survival was better in IBS-B than in LNCCL or LCCL, although this difference was not significant. However, survival was significantly inferior in PTCL (median, 11 months) compared with the other subsets of large-cell lymphoma (median, 46 months; P = .038, log-rank test). Since the association of PTCL and an inferior survival has most often been noted in the context of "second-generation" chemotherapy, we believe that this association may be therapy-dependent and may be minimized by the use of more aggressive chemotherapy regimens.