Study protocol P-MAPS: microbiome as predictor of severity in acute pancreatitis-a prospective multicentre translational study.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disorder that causes a considerable economic health burden. While the overall mortality is low, around 20% of patients have a complicated course of disease resulting in increased morbidity and mortality. There is an emerging body of evidence that the microbiome exerts a crucial impact on the pathophysiology and course of AP. For several decades multiple clinical and laboratory parameters have been evaluated, and complex scoring systems were developed to predict the clinical course of AP upon admission. However, the majority of scoring systems are determined after several days and achieve a sensitivity around 70% for early prediction of severe AP. Thus, continued efforts are required to investigate reliable biomarkers for the early prediction of severity in order to guide early clinical management of AP patients. METHODS: We designed a multi-center, prospective clinical-translational study to test whether the orointestinal microbiome may serve as novel early predictor of the course, severity and outcome of patients with AP. We will recruit 400 AP patients and obtain buccal and rectal swabs within 72 h of admission to the hospital. Following DNA extraction, microbiome analysis will be performed using 3rd generation sequencing Oxford Nanopore Technologies (ONT) for 16S rRNA and metagenomic sequencing. Alpha- and beta-diversity will be determined and correlated to the revised Atlanta classification and additional clinical outcome parameters such as the length of hospital stay, number and type of complications, number of interventions and 30-day mortality. DISCUSSION: If AP patients show a distinct orointestinal microbiome dependent on the severity and course of the disease, microbiome sequencing could rapidly be implemented in the early clinical management of AP patients in the future. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04777812.

Predicting responsiveness to fampridine in gait-impaired patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Fampridine leads to significant improvements in walking in many people with multiple sclerosis (PwMS). However, a relevant proportion of PwMS does not respond to fampridine and predictors of initial drug responsiveness are unknown. METHODS: Drug response to prolonged-release (PR)-fampridine was assessed in 55 PwMS using the timed 25-foot walk (T25FW), 6-min walk test (6MWT) and 12-item multiple sclerosis walking scale as outcome parameters. Patients were treated with PR-fampridine and placebo for 6 weeks each in a randomized, double-blind, placebo-controlled trial with crossover design (NCT01576354). Possible predictors of drug responsiveness were investigated by multiple correlation analysis and binary logistic regression models. An additional longitudinal analysis followed the drug responses of 32 patients treated with PR-fampridine over 3 years to identify potential predictors of long-term drug responsiveness. RESULTS: Severity of walking disability was positively correlated with enhanced responses to PR-fampridine. The strongest single predictor of drug responsiveness was poor 6MWT performance at baseline, which was positively correlated with enhanced drug response in the 6MWT (R = -0.541; P < 0.001). A multivariable logistic regression model including 6MWT and T25FW baseline performances predicted PR-fampridine responder status with an accuracy of 85.5% (specificity, 90.0%; sensitivity, 73.3%), with a threshold of 211 m in the 6MWT best separating responders from non-responders. Enhanced drug responsiveness after 3 years correlated with decline in walking endurance during this period (R = -0.634; P = 0.001). CONCLUSIONS: Initial walking impairment is a good predictor of therapeutic responsiveness to PR-fampridine. Valid predictors of patients' responsiveness to PR-fampridine are essential for patient stratification and optimization of multiple slcerosis treatment.

Prospective cohort study comparing transient EUS guided elastography to EUS-FNA for the diagnosis of solid pancreatic mass lesions.

BACKGROUND: Semiquantitative EUS-elastography has been introduced to distinguish between malignant and benign pancreatic lesions. This study investigated whether semiquantitative EUS-guided transient real time elastography increases the diagnostic accuracy for solid pancreatic lesions compared to EUS-FNA. PATIENTS AND METHODS: This single centre prospective cohort study included all patients with solitary pancreatic lesions on EUS during one year. Patients underwent EUS-FNA and semiquantitative EUS-elastography during the same session. EUS and elastography results were compared with final diagnosis which was made on the basis of tissue samples and long-term outcome. RESULTS: 91 patients were recruited of which 68 had pancreatic malignancy, 17 showed benign disease and 6 had cystic lesions and were excluded from further analysis. Strain ratios from malignant lesions were significantly higher (24.00; 8.01-43.94 95% CI vs 44.00; 32.42-55.00 95% CI) and ROC analysis indicated optimal cut-off of 24.82 with resulting sensitivity, specificity and accuracy of 77%, 65% and 73% respectively. B-mode EUS and EUS-FNA had an accuracy for the correct diagnosis of malignant lesions of 87% and 85%. When lowering the cut-off strain ratio for elastography to 10 the sensitivity rose to 96% with specificity of 43% and accuracy of 84%, resulting in the least accurate EUS-based method. This was confirmed by pairwise comparison. CONCLUSION: Semiquantitative EUS-elastography does not add substantial value to the EUS-based assessment of solid pancreatic lesions when compared to B-mode imaging.

[Hyperthyroid and acute tonsillitis in a 23-year-old woman]. / Hyperthyreose und akute Tonsillitis bei einer 23-jährigen Patientin.

A 23-year-old woman with preexisting Graves' disease who received thiamazole treatment presented with fever, dysphagia, hyperthyroidism and leukopenia. With suspicion of thyreotoxicosis accompanied by drug-induced agranulocytosis she was successfully managed by plasmapheresis, G­CSF administration and inhibition of periphereal conversion of thyroid hormones. In due course she underwent thyroidectomy. Thiamazole is frequently associated with drug-induced agranulocytosis. Long-term therapy with thiamazole requires critical evaluation and alternatives should be considered early. Plasmapheresis is an adequate treatment option to achieve normal thyroid hormonal status.

New Advances in the Treatment of Metastatic Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an extremely poor overall survival (OS) compared to other solid tumours. As the incidence of the disease is rising and the treatment options are limited, PDAC is projected to be the 2nd leading cause of cancer-related deaths in the United States by 2030. A majority of patients are not eligible for curative resection at the time of diagnosis, and those that are resected will often relapse within the first few years after surgery. SUMMARY: Until recently, the nucleoside analogue gemcitabine has been the standard of care for patients with non-resectable PDAC with only marginal effects on OS. In 2011, the gemcitabine-free FOLFIRINOX regimen (folinic acid, fluorouracil, irinotecan and oxaliplatin) showed a significant survival advantage for patients with metastatic PDAC in a phase III trial. In 2013, the Metastatic Pancreatic Adenocarcinoma Trial phase III trial with nano- formulated albumin-bound paclitaxel (nab-paclitaxel) in combination with gemcitabine also resulted in a significant survival extension compared to gemcitabine monotherapy. However, both intensified therapy regimens show a broad spectrum of side effects and patients need to be carefully selected for the most appropriate protocol. KEY MESSAGE: In this study, recent advances in the chemotherapeutic options available to treat metastatic PDAC and their implications for today's treatment choices are reviewed.

Cancer of unknown primary (CUP) through the lens of precision oncology: a single institution perspective.

PURPOSE: For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients. METHODS: In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. RESULTS: Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians' choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). CONCLUSION: CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients.

[Overview of relevant clinical recommendations from the new S3 guidelines on acute and chronic pancreatitis]. / Überblick über relevante klinische Empfehlungen aus der neuen S3-Leitlinie "Akute und chronische Pankreatitis".

Acute pancreatitis is a primary sterile inflammation of the pancreas, which is characterized by an unphysiological enzyme activation. This leads to an inflammatory reaction with edema, vascular damage and cell decay. The first German interdisciplinary S3 guidelines on chronic pancreatitis were published in 2012. Under the auspices of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and with the participation of various societies and patient representatives, the guidelines were recently revised and extended, Comprehensive S3 guidelines on acute and chronic pancreatitis were compiled and agreed by consensus. This article presents the important clinical aspects on acute pancreatitis from these guidelines in a compact form and the recommendations are justified.

MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC).

BACKGROUND: Pain symptoms in the upper abdomen and back are prevalent in 80% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), where the current standard treatment is a systemic therapy consisting of at least doublet-chemotherapy for fit patients. Palliative low-dose radiotherapy is a well-established local treatment option but there is some evidence for a better and longer pain response after a dose-intensified radiotherapy of the primary pancreatic cancer (pPCa). Stereotactic body radiation therapy (SBRT) can deliver high radiation doses in few fractions, therefore reducing chemotherapy-free intervals. However, prospective data on pain control after SBRT of pPCa is very limited. Therefore, we aim to investigate the impact of SBRT on pain control in patients with mPDAC in a prospective trial. METHODS: This is a prospective, double-arm, randomized controlled, international multicenter study testing the added benefit of MR-guided adaptive SBRT of the pPca embedded between standard of care-chemotherapy (SoC-CT) cycles for pain control and prevention of pain in patients with mPDAC. 92 patients with histologically proven mPDAC and at least stable disease after initial 8 weeks of SoC-CT will be eligible for the trial and 1:1 randomized in 3 centers in Germany and Switzerland to either experimental arm A, receiving MR-guided SBRT of the pPCa with 5 × 6.6 Gy at 80% isodose with continuation of SoC-CT thereafter, or control arm B, continuing SoC-CT without SBRT. Daily MR-guided plan adaptation intents to achieve good target coverage, while simultaneously minimizing dose to organs at risk. Patients will be followed up for minimum 6 and maximum of 18 months. The primary endpoint of the study is the "mean cumulative pain index" rated every 4 weeks until death or end of study using numeric rating scale. DISCUSSION: An adequate long-term control of pain symptoms in patients with mPDAC is an unmet clinical need. Despite improvements in systemic treatment, local complications due to pPCa remain a clinical challenge. We hypothesize that patients with mPDAC will benefit from a local treatment of the pPCa by MR-guided SBRT in terms of a durable pain control with a simultaneously favorable safe toxicity profile translating into an improvement of quality-of-life. TRIAL REGISTRATION: German Registry for Clinical Trials (DRKS): DRKS00025801. Meanwhile the study is also registered at ClinicalTrials.gov with the Identifier: NCT05114213.

In vitro hematopoiesis following induction chemotherapy for acute leukemia.

The treatment of acute nonlymphocytic leukemia results in predictable bone marrow hypoplasia and eventual cellular repopulation. In order to study this postchemotherapy repopulation, assays for hematopoietic progenitor cells were performed on bone marrow samples obtained from seven patients with acute nonlymphocytic leukemia who had received similar chemotherapeutic induction regimens. Burst-forming units (erythrocyte), colony-forming units (megakaryocyte), colony-forming units (granulocyte-macrophage), and colony-forming units (granulocyte-erythrocyte-megakaryocyte-macrophage) were cloned from human bone marrow mononuclear cells 5 and/or 10 days following completion of chemotherapy. All patients were pancytopenic and had hypocellular marrows when studied. Assays were performed 7 to 30 days prior to complete remission. Colony-forming units (granulocyte-macrophage) were equivalent to control values 5 days following chemotherapy, while burst-forming units (erythrocyte) and colony-forming units (granulocyte-erythrocyte-megakaryocyte-macrophage) were not assayable at that time. Ten days following chemotherapy, colony-forming units (granulocyte-erythrocyte-megakaryocyte-macrophage) and colony-forming units (granulocyte-macrophage) were 200 and 250% of normal controls, respectively, while burst-forming units (erythrocyte) were 29% of control values. Colony-forming units (macrophage) were 10 to 15 times normal values 10 days following chemotherapy. In contrast to colonies from normal individuals, those grown from marrow obtained following chemotherapy were frequently macroscopic and were composed of thousands of cells. Patient marrow had larger proportions of progenitor cells in S phase of the cell cycle than did normal controls. These studies suggest the presence of a stem cell in human bone marrow which is resistant to chemotherapeutic agents and has a high capacity to regenerate hematopoietic progenitor cells. The period following completion of chemotherapy for acute nonlymphocytic leukemia appears suitable for the study of the hierarchical nature of human hematopoiesis.

Binding of lysozyme to brush border membranes of rat kidney.

The binding of 125I-labelled egg-white lysozyme to isolated brush border membranes of rat kidney cortex was investigated. The lysozyme binding was reversible and saturable. The Scatchard plot revealed a one-component binding type with a dissociation constant of 7.8 microM and 15.6 nmol/mg membrane protein for the number of binding sites. The binding of the basic lysozyme could be reduced by basic amino acids such as L-lysine, L-ornithine or L-arginine, while neutral amino acids such as L-citrulline or L-alanine had no effect. The inhibitory effect of lysine was competitive.

Effect of arachnoiditis on pain threshold.

A model for studying the relationship between chronic arachnoiditis and pain sensitivity was developed. Thirty male ICR mice were randomly divided into three groups and the tail-flick test was done using an EMDIE-TF6 apparatus (Emdie Instrument Co., Montpelier, VA). Ten mice were injected intrathecally with 5.0 microL of a kaolin-metrizamide mixture and ten control mice were injected intrathecally with 5.0 microL of an electrolyte solution resembling CSF. A third group, (naive controls) were given no treatment. Six weeks later tail-flick tests were repeated. The kaolin-treated mice had significantly decreased tail-flick latencies (P less than .05) compared with the baseline; the controls had no significant change in tail-flick latency. Histologic examination revealed moderate to severe arachnoiditis in the kaolin-treated animals and no evidence of arachnoid abnormalities in the controls. This study suggests that arachnoiditis may be associated with decreased pain thresholds.

The acid and alkaline phosphatase activity in human cervical mucus of females using either a coil or combined therapy.

PIP: The effects of combination-type oral contraceptives and the Lippes loop on the biochemical components of the genital tract were analyzed in samples of cervical mucus obtained from a random sample of women (including student volunteers) at the Wayne County, Michigan, Family Planning Clinic. The mucoid samples from women without contraception, using Lippes loops, or combination-type oral contraceptives were checked for alkaline and acid phosphatase activity at 3 phases of the menstrual cycle: proliferative (Days 1-13), ovulatory (Days 13-17), and secretory (Days 17-35). A significant (p less than .01) midcycle rise in the amount of mucus was seen in the groups with oral contraceptives or with a coil. None of the groups demonstrated cyclic differences in acid and alkaline phosphatase activity though oral contraceptive users experienced a significant increase in level of activity in all 3 phases of the cycle. To achieve statistical significance, more observations under carefully controlled conditions must be obtained.^ieng

Application of MS and NMR to the structure elucidation of complex sugar moieties of natural products: exemplified by the steroidal saponin from Yucca filamentosa L.

An approach, using well characterized procedures, is presented that should be of general applicability for the structural elucidation of complex sugar moieties of natural products. The methods used are exemplified by the structure elucidation of a new gitogenin-based steroidal saponin that has a strong leishmanicidal activity similar to preparations used in clinical practice and has been isolated by bioactivity-guided fractionation of the ethanolic extract of Yucca filamentosa L. leaves. The saponin has been characterized as 3-O-((beta-D-glucopyranosyl-(1-->3)- beta-D-glucopyranosy-(1-->2))(alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->3))-beta-D-glucopyranosyl-(1-->4)-beta-D-galactopyranosyl)-25R,5alpha-spirostan-2alpha,3beta-diol.

The influence of EDTMP-concentration on the biodistribution of radio-lanthanides and 225-Ac in tumor-bearing mice. The ISOLDE Collaboration.

High-resolution gamma spectroscopy was applied to measure simultaneously the biodistribution of carrier-free radionuclides of several lanthanides (141Ce, 145Sm, 149Gd, 167Tm) and 225Ac in tumor-bearing nude mice. Mixtures of the radiotracers were injected in solutions containing different concentrations of EDTMP (ethylenediaminetetramethylenephosphonic acid). The strong dependence of liver uptake on the ionic radius of the radio-lanthanides was confirmed for all tracers used. The ratios of radioactivity concentrated in tumour that concentrated in liver are strongly influenced by the EDTMP concentration, reaching values close to 10 for Tm, 3 for Sm, and 1 for Ac. The optimal EDTMP concentrations, giving highest tumor-to-liver ratios of enrichment, were between 1 and 10 mM for 100 microL injected volume for the animal model used in this experiment. In radionuclide therapy using EDTMP as ligands, close control of ligand concentration will be necessary.

The effects of continuous combined transdermal oestrogen-progestogen treatment on bleeding patterns and the endometrium in postmenopausal women.

Fifty postmenopausal women requiring hormone replacement therapy for the treatment of climacteric symptoms were recruited in six centers. All patients received a new combined norethisterone acetate (NETA)/oestradiol (E2)-TTS, (Estragest TTS, Ciba-Geigy Ltd), delivering 0.25 mg NETA and 50 micrograms E2 per day, continuously for 12 calendar months. Bleeding occurred in 38 (76%) of the 50 patients at any time during the 1 year treatment. The percentage of patients without bleeding increased gradually each month, from 24% in the second month to a relatively stable level of approximately 80% in month 7 and thereafter. Twenty-seven patients (54%) did not complete the whole trial period; 15 of which discontinued the treatment within the first few months due to irregular bleeding. In patients who remained in the trial, a clear decrease in the frequency and intensity of the bleeding was observed with time. Bleeding was mostly light or consisted of spotting only. None of the post-trial biopsies showed proliferation or hyperplasia of the endometrium. The treatment resulted in a substantial decrease of climacteric symptoms (Kupperman index) within 4 months and was well tolerated. It was concluded that the continuous NETA/E2-TTS treatment is an effective and safe alternative for the treatment of climacteric symptoms in selected patients.

[Scintigraphic use of 87Y during 90Y therapy of bone metastases]. / Szintigraphische Verwendung von 87Y bei der 90Y-Therapie von Knochenmetastasen.

Carrier-free 87Y is produced by cyclotron irradiation of Rb. It decays with a half-life of 80.3 h, transforming via 87mSr to stable 87Sr with the emission of gamma lines of 0.48 and 0.39 MeV. Experience in 6 patients shows good scan quality and correspondence between 99mTc-DPD and 87Y images useful in 90Y-citrate therapy for bone metastases. 87Y offers new possibilities of studying biological kinetics in 90Y therapy. To avoid contamination this should only be used in departments with possibilities of radioactive waste storage and controlled disposal.

Intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a rare disease occurring mainly during the last trimester of pregnancy. Pruritus, often accompanied by excoriation of the skin but without other skin lesions, and elevated concentrations of bile acids are characteristic for this disorder. We present a 30-year-old woman with pruritus, elevated bile acids, ASAT and ALAT in the 22nd week of pregnancy. Treatment with ursodeoxycholic acid resulted in complete disappearance of the pruritus and normalisation of the bile acids, ASAT and ALAT. A healthy child was born at term. In the differential diagnosis of liver function abnormalities during pregnancy, ICP should be included. ICP responds very well to treatment with ursodeoxycholic acid, with no detrimental effects for mother and child.

Production of terbium-152 by heavy ion reactions and proton induced spallation.

Terbium-152 (Tb-152) is of potential value as a radiotracer for radiolanthanides in positron emission tomography. We report the production of Tb-152 by heavy ion reactions at the ANU Tandem accelerator, and by the spallation method at the CERN proton accelerator using the on-line ISOLDE separator, obtaining microcurie and millicurie yields, respectively. After purification, a phantom image in PET is obtained which shows the feasibility of using Tb-152 for monitoring the kinetics of Tb-149 and other radiolanthanides. However, the current availability of this radioisotope will be restricted to major nuclear physics research centres.

[Campylobacter infections in pregnancy]. / Campylobacter-infecties in de zwangerschap.

In two pregnant women aged 39 and 35, who presented with fever and diarrhoea, Campylobacter was cultured from a blood sample. They were treated with antibiotics. One had a healthy neonate, in the other intrauterine foetal death had occurred. Campylobacter species have increasingly been recognized as possible causes of septic abortion, premature labour and neonatal sepsis. Early recognition and treatment of maternal Campylobacter infection may reduce the risk of serious foetal or neonatal complications.