Diagnosis of Cholangiocarcinoma (CCA) is difficult, thus a noninvasive approach towards (i) assessing and (ii) monitoring the tumor-specific mutational profile is desirable to improve diagnosis and tailor treatment. Tumor tissue and corresponding ctDNA samples were collected from patients with CCA prior to and during chemotherapy and were subjected to deep sequencing of 15 genes frequently mutated in CCA. A set of ctDNA samples was also submitted for 710 gene oncopanel sequencing to identify progression signatures. The blood/tissue concordance was 74% overall and 92% for intrahepatic tumors only. Variant allele frequency (VAF) in ctDNA correlated with tumor load and in the group of intrahepatic CCA with PFS. 63% of therapy naive patients had their mutational profile changed during chemotherapy. A set of 76 potential progression driver genes was identified among 710 candidates. The molecular landscape of CCA is accessible via ctDNA. This could be helpful to facilitate diagnosis and personalize and adapt therapeutic strategies.

This document presents the recommendations developed by the IOC Medical and Scientific Commission and several international federations (IF) on the protection of athletes competing in the heat. It is based on a working group, meetings, field experience and a Delphi process. The first section presents recommendations for event organisers to monitor environmental conditions before and during an event; to provide sufficient ice, shading and cooling; and to work with the IF to remove regulatory and logistical limitations. The second section summarises recommendations that are directly associated with athletes’ behaviours, which include the role and methods for heat acclimation; the management of hydration; and adaptation to the warm-up and clothing. The third section explains the specific medical management of exertional heat stroke (EHS) from the field of play triage to the prehospital management in a dedicated heat deck, complementing the usual medical services. The fourth section provides an example for developing an environmental heat risk analysis for sport competitions across all IFs. In summary, while EHS is one of the leading life-threatening conditions for athletes, it is preventable and treatable with the proper risk mitigation and medical response. The protection of athletes competing in the heat involves the close cooperation of the local organising committee, the national and international federations, the athletes and their entourages and the medical team.

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Synergistic effects of immunotherapy with pembrolizumab or drugs targeting DNA damage e.g. olaparib could be used to overcome the limitations of radioligand therapy (RLT) with Lu-177 prostate specific membrane antigen (PSMA) in metastasized castrate resistant prostate cancer (mCRPC) patients. Here, we present two patients receiving such combination / sequential therapies. Methods: RLT was performed at 6-8 week intervals after they either exhausted or were considered unfit for all approved conventional treatment. Patient 1 was on pembrolizumab for his squamous cell carcinoma of the skin whereas patient 2 received RLT sequentially 4 weeks after a 3 months monotherapy with olaparib. Results: Both patients tolerated RLT without any significant hematotoxicity.Patient 2 showed radiological and biochemical response whereas patient 1 achieved PSA stabilization after 3 therapy cycles. Conclusion: These cases indicate that RLT in combination with pembrolizumab or sequentially after olaparib might be well tolerated in single patients.

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Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of the elderly, with high metastatic potential and poor prognosis. In particular, the primary resistance to immune checkpoint inhibitors (ICI) in metastatic (m)MCC patients represents a challenge not yet met by any efficient treatment modality. Herein, we describe a novel therapeutic concept with short-interval, low-dose 177Lutetium (Lu)-high affinity (HA)-DOTATATE [177Lu]Lu-HA-DOTATATE peptide receptor radionuclide therapy (SILD-PRRT) in combination with PD-1 ICI to induce remission in patients with ICI-resistant mMCC. We report on the initial refractory response of two immunocompromised mMCC patients to the PD-L1 inhibitor avelumab. After confirming the expression of somatostatin receptors (SSTR) on tumor cells by [68Ga]Ga-HA-DOTATATE-PET/CT (PET/CT), we employed low-dose PRRT (up to six treatments, mean activity 3.5 GBq per cycle) at 3–6 weeks intervals in combination with the PD-1 inhibitor pembrolizumab to restore responsiveness to ICI. This combination enabled the synergistic application of PD-1 checkpoint immunotherapy with low-dose PRRT at more frequent intervals, and was very well tolerated by both patients. PET/CTs demonstrated remarkable responses at all metastatic sites (lymph nodes, distant skin, and bones), which were maintained for 3.6 and 4.8 months, respectively. Both patients eventually succumbed with progressive disease after 7.7 and 8 months, respectively, from the start of treatment with SILD-PRRT and pembrolizumab. We demonstrate that SILD-PRRT in combination with pembrolizumab is safe and well-tolerated, even in elderly, immunocompromised mMCC patients. The restoration of clinical responses in ICI-refractory patients as proposed here could potentially be used not only for patients with mMCC, but many other cancer types currently treated with PD-1/PD-L1 inhibitors.

BackgroundThe aims of this study were to establish shear wave elastography of the pancreas by comparing measurements in patients with type 1 diabetes (T1D) and healthy volunteers and to consider whether this method could contribute to the screening or prevention of T1D.MethodsThis pilot study included 15 patients with T1D (10 men, 5 women) and 15 healthy volunteers (10 men, 5 women) as controls. Measurements were performed with a Siemens Acuson S3000 (Siemens Healthcare, Erlangen, Germany) using a 6C1 convex transducer and the Virtual Touch™ tissue quantification (VTQ) method.ResultsThe mean shear wave velocity of the head of the pancreas was 1.0 ± 0.2 m/s (median: 1.1 m/s) for the study group and likewise 1.0 ± 0.2 m/s (median: 0.9 m/s) for the control group. Velocities of 1.2 ± 0.2 m/s (median: 1.2 m/s) were measured in the body of the pancreas in both groups. There was a significant difference between the values obtained in the tail of the pancreas: patients 1.1 ± 0.1 m/s (median: 1.0 m/s) versus controls 0.9 ± 0.1 m/s (median: 0.8 m/s) (p = 0.0474). The mean value in the whole pancreas of the study group was not significantly above that of the control group: 1.1 ± 0.1 m/s (median: 1.0 m/s) versus 1.0 ± 0.1 m/s (median: 1.0 m/s) (p = 0.2453).ConclusionsSonoelastography of the pancreas revealed no overall difference between patients with T1D and healthy volunteers. Patients with T1D showed higher values only in the tail segment. Future studies need to determine whether specific regional differences can be found in a larger study population.