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.

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.

[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.

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.

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.

[Autoimmune pancreatitis]. / Autoimmunpankreatitis.

Autoimmune pancreatitis is a relatively rare form of chronic pancreatitis which is characterized by a lymphoplasmatic infiltrate with a storiform fibrosis and often goes along with painless jaundice and discrete discomfort of the upper abdomen. Clinically we distinguish between two subtypes, which differ in terms of their histology, clinical picture and prognosis. Type 1 autoimmune pancreatitis is the pancreatic manifestation of the IgG4-associated syndrome which also involves other organs. About one third of the patients can only be diagnosed after either histological prove or a successful steroid trail. Type 2 is IgG4-negative with the histological picture of an idiopathic duct centric pancreatitis and is to higher degree associated with inflammatory bowel disease. A definitive diagnosis can only be made using biopsy. Usually both forms show response to steroid treatment, but in type 1 up to 50 % of the patients might develop a relapse. The biggest challenge and most important differential diagnosis remains the discrimination of AIP from pancreatic cancer, because also AIP can cause mass of the pancreatic head, lymphadenopathy and ductal obstruction. This article summarizes recent advances on epidemiology, clinical presentation, diagnostic strategy, therapy and differential diagnosis in this relatively unknown disease.

Microwave-supported preparation of (68)Ga bioconjugates with high specific radioactivity.

The generator-produced positron-emitting (68)Ga (T(1/2) = 68 min) is of potential interest for clinical PET. (68)Ga as a metallic cation is suitable for complexation reactions with chelators, naked or conjugated, with peptides or other macromolecules. Large (68)Ga generator eluate volumes, metal traces from the generator column material, or reaction reagents, however, disturb a fast, reliable, and quantitative labeling procedure. In this paper we describe a simple technique, based on anion exchange, aiming first, to increase the (68)Ga concentration, second to purify it from competing impurities, and third to obtain a fast and quantitative (68)Ga-labeled peptide conjugate that can be applied in humans without further purification. Within 5 min one can obtain from the original 6 mL generator eluate a 200 microL (68)Ga preparation (volume reduction by a factor 30) that is suitable for direct and quantitative labeling of peptide conjugates. DOTATOC (DOTA-D-Phe(1)-Tyr(3)-octreotide, DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was used as a test tracer for comparing the labeling properties of the different (68)Ga preparations. In combination with microwave heating, peptide conjugates of 0.5-1 nmol quantities could be labeled within 10 min with the full (68)Ga activity of a generator. Further purification of the (68)Ga-labeled peptide conjugate was no longer required since the nuclide incorporation was quantitative. The specific radioactivity (with respect to the peptide) was improved by a factor approximately 100 compared to the previously applied techniques using the original generator eluate. The commercial (68)Ge/(68)Ga generator from Obninsk in combination with this system for purification and concentration with an integrated microwave-supported labeling technology resulted in a kitlike technology for (68)Ga-tracer production. The first automated prototype using this technology is being tested.

Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab.

This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10(6) Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 micro g unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%+/-4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%+/-2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with (149)Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach.

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.

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.

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.

Impact of moxifloxacin versus clarithromycin on normal oropharyngeal microflora.

A multiple-dose, randomized, double-blind, controlled, cross-over trial was performed in 12 healthy male subjects in order to investigate the effect of a 7-day treatment with moxifloxacin (400 mg orally, once daily) versus clarithromycin (500 mg orally, twice daily) on the normal oropharyngeal microflora. Moxifloxacin caused significant reductions in levels of alpha-streptococci and Neisseria cocci during the treatment period, while the numbers of gram-negative anaerobic bacteria increased markedly during moxifloxacin administration. Clarithromycin administration caused a suppression of micrococci and corynebacteria, while no significant changes were recorded in the anaerobic microflora. No new colonizing moxifloxacin-resistant strains were isolated during the investigation period.

Comparative effects of moxifloxacin and clarithromycin on the normal intestinal microflora.

Twelve healthy male subjects age range 24-40 y participated in the investigation. The trial was divided into 2 35-d periods. The 2 treatment regimens were: (i) 1 x 400 mg moxifloxacin tablet in the morning and 1 placebo tablet in the evening for 7 d; and (ii) 1 x 500 mg clarithromycin tablet in the morning and 1 x 500 mg clarithromycin tablet in the evening for 7 d. Each subject received firstly I treatment regimen and secondly the other treatment regimen. The wash-out period was 6 weeks between the two treatment regimens. Moxifloxacin caused significant decreases of enterococci and enterobacteria during the administration period while the numbers of staphylococci, streptococci, Bacillus and Candida were not affected. No impact on peptostreptococci, lactobacilli, Veillonella, Bacteroides or fusobacteria was observed, while bifidobacteria and clostridia decreased during moxifloxacin administration. The microflora was normalized after 35 d. Clarithromycin caused significant reduction of Escherichia coli while the numbers of enterococci, Enterobacter, Citrobacter, Klebsiella and Pseudomonas increased markedly. No significant changes in the numbers of staphylococci, streptococci, Bacillus and Candida were noticed. In the anaerobic microflora bifidobacteria, lactobacilli and clostridia were suppressed, while no changes in peptostreptococci, Veillonella, Bacteroides and fusobacteria were found. The microflora was normalized in all volunteers after 35 d.

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.

[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.