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.

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.

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.

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.

Simultaneous study of the biodistribution of radio-yttrium complexed with EDTMP and citrate ligands in tumour-bearing rats.

The influence of the ligands ethylenediaminetetramethylene phosphonic acid (EDTMP) and citrate (CIT) on the biodistribution of radio-yttrium in rats bearing a DS-carcinosarcoma was compared. 88Y-EDTMP and 87Y-CIT were i.v. injected into the same animals. Faster blood clearance and higher renal excretion were observed for the EDTMP-ligand. Of high practical interest is the reduced liver uptake of radio-yttrium (by one order of magnitude) with the EDTMP complex. Since bone and tumour accumulation is only weakly influenced, high tumour-to-liver ratios (up to 14) were observed. We propose to use EDTMP or similar complex ligands for liver blocking when radionuclides like 90Y, 169Yb, 225Ac or other group 3 elements are to be applied in endoradionuclide therapy technique.

The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: synergism of tumor necrosis factor and interferon-gamma.

The influences of human tumor necrosis factor (TNF) (LuKII), recombinant human TNF-alpha, natural human interferon-gamma (HuIFN-gamma), recombinant HuIFN-gamma, and natural HuIFN-alpha were evaluated alone or in combination for their effects in vitro on colony formation by human bone marrow granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells incubated at 5% CO2 in lowered (5%) O2 tension. TNF (LuKII) and recombinant TNF-alpha caused a similar dose-dependent inhibition of colony formation from CFU-GM, BFU-E, and CFU-GEMM. Day 7 CFU-GM colonies were more sensitive than both day 14 CFU-GM colonies and day 7 CFU-GM clusters to inhibition by TNF. BFU-E colonies and CFU-GEMM colonies were least sensitive to inhibition with TNF. The suppressive effects of TNF (LuKII) and recombinant TNF-alpha were inactivated respectively with hetero-anti-human TNF (LuKII) and monoclonal anti-recombinant human TNF-alpha. The hetero-anti-TNF (LuKII) did not inactivate the suppressive effects of TNF-alpha and the monoclonal anti-recombinant TNF-alpha did not inactivate TNF (LuKII). The suppressive effects of TNF did not appear to be mediated via endogenous T lymphocytes and/or monocytes in the bone marrow preparation, and a pulse exposure of marrow cells with TNF for 60 min resulted in maximal or near maximal inhibition when compared with cells left with TNF for the full culture incubation period. A degree of species specificity was noted in that human TNF were more active against human marrow CFU-GM colonies than against mouse marrow CFU-GM colonies. Samples of bone marrow from patients with non-remission myeloid leukemia were set up in the CFU-GM assay and formed the characteristic abnormal growth pattern of large numbers of small sized clusters. These cluster-forming cells were more sensitive to inhibition by TNF than were the CFU-GM colonies and clusters grown from the bone marrow of normal donors. The sensitivity to TNF of colony formation by CFU-GM of patients with acute myelogenous leukemia in partial or complete remission was comparable with that of normal donors. When combinations of TNF and HuIFN were evaluated together, it was noted that TNF (LuKII) or recombinant TNF synergized with natural or recombinant HuIFN-gamma, but not with HuIFN-alpha, to suppress colony formation of CFU-GM, BFU-E, and CFU-GEMM from bone marrow of normal donors at concentrations that had no suppressive effects when molecules were used alone.(ABSTRACT TRUNCATED AT 400 WORDS)

The influence of isotopic and nonisotopic carriers on the biodistribution and biokinetics of M3+-citrate complexes.

The influence of carrier amounts of Fe, Ga, and Tm on the biodistribution of 67Ga-, 59Fe-, and 167Tm-citrate in mice was investigated. Our results suggest that 167Tm, unlike 67Ga and 59Fe, is not transported by transferrin in the blood. Of the three radioisotopes tested, 167Tm had the highest tumor/background ratio (10 h after the injection). The application of Fe carrier led to an enhancement of the elimination of 67Ga from the blood and muscles, resulting in a better tumor/background ratio.

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.