Chronic lymphocytic leukemia and the central nervous system: a clinical and pathological study.

Chronic lymphocytic leukemia is the most common human leukemia but infrequently causes neurologic symptoms. We have reviewed all previously reported cases of chronic lymphocytic leukemia in the CNS along with three new cases; one patient was diagnosed antemortem and treated with immediate improvement and 4-year survival. In addition, we reviewed all autopsy cases since 1972 and available lumbar puncture data on patients with chronic lymphocytic leukemia admitted to the Massachusetts General Hospital. Invasion of the CNS by chronic lymphocytic leukemia often leads to confusional state, meningitis with cranial nerve abnormalities, optic neuropathy, or cerebellar dysfunction. Lumbar puncture shows a lymphocytosis consisting of monoclonal B cells, but CSF cytology studies are of limited value in establishing the diagnosis. Long-term survival may be related to the stage of chronic lymphocytic leukemia at the time of CNS disease and may be associated with intrathecal chemotherapy. A mild, asymptomatic infiltration of the brain, frequently noted in late-stage chronic lymphocytic leukemia in autopsy series, may explain the CSF lymphocytosis in some patients with late-stage chronic lymphocytic leukemia

Bond formation in mass spectrometry electron impact induced migration of arylthio groups and clustering reactions in chemical ionisation reagent gases

Electron impact induced rearrangements have been observed in compounds containing either two arylthio groups or an arylthio group and an arylsulphonyl group. In addition to the loss of sulphur dioxide from the molecular ion and a sulphone-sulphinate rearrangement, 3-arylsulphonyl-2-arylthiopropenes exhibited the rearrangement a bisarylsulphide ion (analogous to that reported for the isomeric l-arylsulphonyl-2-arylthiopropenes). A series of l-arylsulphonyl-4-arylthio-2-butynes also underwent sulphone-sulphinate rearrangement and rearranged to the bisarylsulphide ions, in the absence of sulphur dioxide or sulphur extrusion. The formation of the bisarylsulphide ion from the molecular ion of these compounds is postulated to occur after an initial {1,3} arylthio shift giving an ion analogous to the molecular ion of 3-arylsulphonyl-2-arylthiopropene.A skeletal rearrangement of N-(4'-arylsulphonyl -2 '-butynyl)-N-(4"-arylthio-2"-butynyl)anilines1 2resulted in the elimination of Ar SCSAr from the molecular ion, but notions arising from a sulphone-sulphinate rearrangement or extrusion of sulphur or sulphur dioxide.The rearrangement of N,N- bis(4'-arylthio-2'-butynyl)anilines via consecutive {1,3} arylthio shifts,followed by elimination of a bisaryldisulphide moiety, was supported by the behaviour of N-(4'-arylthio-2'-butynyl)-N-(2"-arylthio-2"-propenyl)-p-toluidines and N,N-bis(2'arylthio-2'-propenyl)-p-toluidines. Theirmolecular ions are analogous to the rearranged molecular ions of the N,N-bis(4'-arylthio-2'-butynyl)anilines after one or two arylthio shifts, respectively. No extrusion of sulphur is observed, but rather the elimination of a bisaryldisulphide moiety occurs.A series of 1,8-bis(arylthiomethyl)naph-thalenes and 1,2-bis(arylthio)acenaphthenes were1 2synthesised. Electron impact showed no loss of Ar SSAr from the naphthalene derivatives, owing to the predominance of C-S bond cleavage. However, the acenaph-thene derivatives readily eliminated a bisaryldi-sulphide moiety and a qualitative substituent effect was1 2 +observed for the formation of Ar SSAr &dot; ions. In a separate investigation, the kinetics of ion-molecule clustering reactions in a number of chemical ionisation reagent gases were studied. Rate coefficients were obtained at various ion-source field strengths for the formation of proton or deuteron bound dimers at pressures of ca.0.01-0.4 Torr (450&deg;K).Changes from overall third to second order kinetics were observed with increasing pressure, in accord with an energy transfer mechanism. Using the higher values of pressure, rate coefficients were obtained and corresponded to the formation of the excited collision complexes. Rate coefficients for the association reaction of the MH (or MD ) ions in methylamine, dimethylamine, trimethyl-Simple kinetic methods for estimating the ion-source pressures of these gases are described. The disappearance rate coefficients for the major primary ions of the above gases were also determined.<p

Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy.

In part A of this study, patients were randomised to cohorts receiving darbepoetin alfa at doses of 0.5 to 8.0 m.c.g x kg(-1) x wk(-1) or to a control group receiving epoetin alfa at an initial dose of 150 U x kg(-1) three times weekly. In part B, the cohorts were darbepoetin alfa 3.0 to 9.0 m.c.g x kg(-1) every 2 weeks or epoetin alfa, initial dose 40 000 U x wk(-1). Safety was assessed by adverse events, changes in blood pressure, and formation of antibodies to darbepoetin alfa. Efficacy was assessed by several haematologic endpoints, including change in haemoglobin from baseline. The adverse event profile of darbepoetin alfa was similar to that of epoetin alfa. No relationship between the rapidity of haemoglobin response and any adverse event was observed. No antibodies to darbepoetin alfa were detected. Higher doses of darbepoetin alfa increased the proportion of patients with a haemoglobin response and decreased the median time to response. The overall dose of darbepoetin alfa required to produce a mean increase in haemoglobin does not increase when the dosing interval is increased from 1 to 2 weeks. Therapy with darbepoetin alfa is safe and effective in producing a dose-related increase in haemoglobin levels in patients with cancer receiving chemotherapy

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop

Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies

PURPOSE: Sotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer. METHODS: In study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of \u3e/=1 g/dL from baseline. RESULTS: Both studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of \u3e/=1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of \u3e/=1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon. CONCLUSIONS: Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA

CRNA perception of lung protective ventilation for the intubated patient

Background: Alveolar collapse [atelectasis] occurs in over 90% of intubated patients and leads to altered lung mechanics. Atelectasis can lead to postoperative pulmonary complications (PPCs), which increase morbidity and mortality. Lung Protective Ventilation has the potential to reduce PPCs intraoperatively. Purpose: This QI project seeks to evaluate the current evidence supporting LPV and to provide consensus recommendations to practicing anesthesia providers with the goal of standardizing lung-protective ventilation strategies for intubated patients receiving general anesthesia. Methods: Practicing anesthesia providers received an education in-service detailing current research in support of LPV and practice recommendations. Prior to the presentation, a pre-intervention survey was administered and approximately 8 weeks later an identical survey was administered to determine if practice changed. Results: McNemar test was used to assess binary paired data and revealed acceptance of the null hypothesis. Qualitative analysis reveals varied growth in knowledge and utilization of LPV following the educational intervention. Recommendations and Conclusion: Research studies are needed to determine patient-specific optimal PEEP levels. Facilities should prioritize continuing education and LPV protocols to encourage uniformity in practice

Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations

<p>Abstract</p> <p>Background</p> <p>A molecular linkage between the MAPK and the LKB1-AMPK energy sensor pathways suggests that combined MAPK oncogene inhibition and metabolic modulation of AMPK would be more effective than either manipulation alone in melanoma cell lines.</p> <p>Materials and methods</p> <p>The combination of the BRAF inhibitor vemurafenib (formerly PLX4032) and metformin were tested against a panel of human melanoma cell lines with defined BRAF and NRAS mutations for effects on viability, cell cycle and apoptosis. Signaling molecules in the MAPK, PI3K-AKT and LKB1-AMPK pathways were studied by Western blot.</p> <p>Results</p> <p>Single agent metformin inhibited proliferation in 12 out of 19 cell lines irrespective of the BRAF mutation status, but in one NRAS^Q61Kmutant cell line it powerfully stimulated cell growth. Synergistic anti-proliferative effects of the combination of metformin with vemurafenib were observed in 6 out of 11 BRAF^V600Emutants, including highly synergistic effects in two BRAF^V600Emutant melanoma cell lines. Antagonistic effects were noted in some cell lines, in particular in BRAF^V600Emutant cell lines resistant to single agent vemurafenib. Seven out of 8 BRAF wild type cell lines showed marginally synergistic anti-proliferative effects with the combination, and one cell line had highly antagonistic effects with the combination. The differential effects were not dependent on the sensitivity to each drug alone, effects on cell cycle or signaling pathways.</p> <p>Conclusions</p> <p>The combination of vemurafenib and metformin tended to have stronger anti-proliferative effects on BRAF^V600Emutant cell lines. However, determinants of vemurafenib and metformin synergism or antagonism need to be understood with greater detail before any potential clinical utility of this combination.</p