Clinical implications of gastrointestinal symptoms in systemic amyloidosis.

BACKGROUND: Gastrointestinal (GI) symptoms in systemic amyloidosis patients are poorly characterized. This purpose of this study is to define the epidemiology and clinical implications of such symptoms. METHODS: This was a retrospective cohort study of 583 amyloid patients seen at a tertiary referral center. Of 96 symptomatic patients, 82 received endoscopic biopsies, subsequently grouped into those with histologic evidence of GI amyloid (biopsy proven) vs without (biopsy absent). KEY RESULTS: 16.8% of patients had GI symptoms, and had more abnormal NT-proBNP, cardiac ejection fraction, serum albumin, and alkaline phosphatase (P < .01). Of those who received endoscopy, the sites of highest diagnostic yield were stomach, duodenum and colon. The most common symptom was abdominal pain, nausea, or vomiting (50.0%). Of the symptomatic patients, only 37 (45%) had biopsy proven GI amyloid. Biopsy proven patients more often had cardiac involvement (P < .005), and more often received hematologic therapy or transplant (P = .01). Biopsy absent patients had more frequent neurologic involvement (P = .17). Biopsy status had no significant correlation with other indicators of amyloid burden, GI symptoms or management. CONCLUSIONS & INFERENCES: Nearly one in six amyloid patients have GI symptoms, and half do not have GI amyloid. The type of symptom does not predict endoscopic findings. Most biopsy absent patients are not managed as a functional disorder despite no alternative etiology. Gastroenterologists may have an increased role to play in the care of systemic amyloidosis beyond performing endoscopies, such as evaluating cardiac amyloid patients for concurrent GI amyloid.

Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial.

Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

HIV Pharmacist's Impact on Inpatient Antiretroviral Errors.

OBJECTIVES: Transitions in care between out-patient and in-patient settings provide ample opportunity for medication errors to occur in HIV-infected patients. The purpose of this study was to examine the effectiveness of an HIV pharmacist monitoring service in decreasing antiretroviral medication errors in a large south central teaching hospital in the USA. METHODS: A retrospective, observational study was conducted to examine the frequency of antiretroviral medication errors in HIV-seropositive patients with hospital admissions between 1 September 2011 and 30 September 2013 at a single tertiary care centre in Oklahoma. Patient assignment to the 12-month pre-intervention and intervention study periods was determined by admission date. Demographic, laboratory, and in-patient medication data were collected. Bivariate analyses were conducted using χ2 analysis with the Yates correction factor for continuity to examine frequencies in specific antiretroviral classes and error categories. A multivariable Poisson regression was employed to examine the frequency of medication errors before and after initiation of the pharmacist service. RESULTS: Medication errors were examined in a total of 330 patient admissions during the 2-year study period. A multivariable-adjusted decrease of 73.9% in the number of errors was observed between the pre-intervention and intervention periods (P < 0.001). Patients on protease inhibitor regimens or with impaired renal function had 2.6-fold and 2.8-fold higher numbers of errors, respectively (P < 0.001). CONCLUSIONS: HIV pharmacist monitoring can decrease medication errors in HIV-infected patients as they transition between out-patient and in-patient care. Patients receiving protease inhibitor-based therapy or with renal insufficiency are at higher risk for medication errors upon admission.

Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era.

We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population.

BACKGROUND: Approximately one-third of the patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) are cured by second-line chemotherapy followed by high-dose consolidation. The age-adjusted international prognostic index determined at the time of relapse (sAAIPI) predicts outcome in relapsed diffuse large B-cell lymphoma, suggesting that the success of salvage therapy could be enhanced by early relapse detection. This study evaluated the role of surveillance imaging in detection of relapsed disease and its impact on outcome of salvage treatment. PATIENTS AND METHODS: One hundred and eight patients with relapsed aggressive NHL were treated with ICE-based second-line chemotherapy. Relapses were categorized as detected by imaging, examination, or patient-reported symptoms. RESULTS: Twenty per cent of relapses were detected by routine imaging while 80% were identified by reported symptoms or abnormalities on exam. Patients were 4.1 times (95% CI: 1.7-10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those diagnosed by reported symptoms or physical findings (group 2). Median overall 5-year survival for group 1 versus group 2 was 54% and 43% respectively (P = 0.13). CONCLUSION: These results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.

Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase.

The oncogenic Bcr-Abl variant of the c-Abl tyrosine kinase transforms cells by a mechanism dependent on activation of the stress-activated protein kinase (SAPK). Other work has shown that c-Abl interacts with the SHPTP1 protein tyrosine phosphatase in induction of SAPK activity by genotoxic stress. The present studies demonstrate that Bcr-Abl binds constitutively to SHPTP1. We show that Bcr-Abl phosphorylates SHPTP1 on C-terminal Y536 and Y564 sites. The functional significance of the Bcr-Abl/SHPTP1 interaction is supported by the finding that SHPTP1 regulates Bcr-Abl-induced SAPK activity. Importantly, SHPTP1 also decreases Bcr-Abl-dependent transformation of fibroblasts. These findings indicate that SHPTP1 functions as a tumor suppressor in cells transformed by Bcr-Abl.

T3 hyperthyroidism and thyroid cancer.

The authors present an unusual case of T3 hyperthyroidism caused by a well-differentiated thyroid follicular carcinoma and its large skull metastasis. They suggest iodine deficiency as being the single major factor in the aetiology of both disorders.

[Determination of primary prostaglandin (Pgs) and main metabolite of PgF2 alpha in blood plasma for diagnosis of primary dysmenorrhoea]. / Zur Diagnostik der primären Dysmenorrhoe durch Bestimmung primärer Prostaglandine (PG's) und des PGF2 alpha-Hauptmetaboliten im Blutplasma.

PGE2, PGF2 alpha, and 13,14-dihydro-15-keto-PGF2 alpha were determined in two-day intervals by means of radio-immuno-assay from plasma of the arm veins of eight women with primary dysmenorrhoea. No evidence could be produced to any rise in plasma concentration of primary prostaglandins and of the main metabolite of PGF2 alpha in the course of one full menstrual cycle. These findings are likely to show that in cases of dysmenorrhoea determination of prostaglandins in peripheral venous blood is unsuitable for verification of high endogenous formation from the endometrium.

Investigations of hormones during early abortion induced by prostaglandin F2alpha and 15(S)-methyl-PGF2alpha.

In early pregnancy up the 7th week of pregnancy PGF2alpha was infused and 15(S)-methyl-PGF2alpha was applied i. m. to induce menstruation in 20 or 19 cases, respectively. In the tested form of application 15(S)-methyl-PGF2alpha is effective in 89 per cent of the cases and in 74 per cent complete abortion was achieved. PGF2alpha produced bleeding in 80 per cent only and complete abortion in 55 per cent. The differences in these two groups were not statistically significant. The steroid hormones estradiol and progesterone decrease in a successful application of PGs for induction of abortion and reach a value of 75 per cent at the onset of bleeding. The LH concentration in plasma becomes smaller too. In some cases there is a temporary increase in hormones shortly after starting treatment. The results could indicate that the considerable decrease in hormones before the onset of bleeding might be caused by an alteration of the corpus luteum, which is effective during early pregnancy.

PIP: Investigations of hormones during early abortion induced by prostaglandin F2 alpha (PGF2a) and 15(s)-methyl-PGF2a are reported. Up to the 7th week of pregnancy PGF2a was infused (total of 50 mg) and 15(S)-methyl-PGF2a was applied im (3-4 injections of 250 mcg each) to induce menstruation in 20, and 19 cases, respectively. 15(S)-methyl-PGF2a was effective in 89% of the cases and in 74% complete abortion was achieved. Blood levels of estradiol and progesterone decreased in successful applications of PGs for introduction of abortion and reached a value of 75% at the onset of bleeding. Plasma luteinizing hormone decreased also. In some cases there was a termporary increase in hormones shortly after starting treatment. These results suggest that the considerable decrease in hormones before the onset of bleeding might be caused by an alteration of the corpus luteum, which is effective during early pregnancy.

[Endocrine aspects of ovarian concer. II. Biochemical and histochemical examinations]. / Endokrine Aspekte des Ovarialkarzinoms II. Biochemische und histochemische Untersuchungen.

In the values of estradiol estimated radioimmunologically in the serum in a group of 12 patients with carcinoma of the ovary there were no significant differences to a control group. The histochemical reaction for the visualiztion of steroid-3beta-ol-dehydrogenase was in 3 of 10 cases only slightly positive.

[Corpus luteum function in the middle luteal phase following treatment with prostaglandins]. / Untersuchungen zur Funktion des Corpus luteum in der mittleren Lutealphase nach Behandlung mit Prostaglandinen.

The corpus luteum of the mid-luteal phase was examined concerning of the signs of functional and morphological regression after treatment with Prostin F2alpha and 15(S)-15-methyl-PGF2alpha. By 8 patients who were operated upon out of various uterine indications steroid hormone levels were determined during the treatment with prostaglandins and corpus luteum was judged by electron-microscopy. Morphological changes in the temporary decrease of the progesteron concentration could be found.

[Effect of diuresis on the results of quantitative estrogen- and HCG determinations]. / Einflub des Diureseeffektes auf das Ergebnis quantitativer Ostrogen- und HCG-Bestimmungen

Investigations on the influence of the diuresis effect upon the results of quantitative oestrogen and HCG determinations revealed that the oestrogen values increase with the 24-hour amount of urine. Oliguria and polyuria affect oestrogen excretion to a considerable extent; they have to be taken into account in prenatal diagnosis of pregnancy. Comparative HCG checks show that HCG concentration also varies considerable depending on fluid excretion. Diagnostic errors can be diminished or avoided when the quantitative HCG assessment is made on the 24-hour urine and then referred to the whole amount of urine.

PIP: Investigations on the influence of the diuresis effect on the results of quantitative estrogen and human chorionic gonadotropin (HCG) determination revealed that the estrogen values increase with the 24-hour amount of urine. Oliguria and polyuria affect estrogen excretion to a considerable extent; they have to be taken into account in prenatal diagnosis of pregnancy. Comparative HCG checks show that HCG concentration also varies considerably depending on fluid excretion. Diagnostic errors can be diminished or avoided when the quantitative HCG assessment is made on the 24-hour urine and then referred to the whole amount of urine.