Abstract:Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radio-chemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm Phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. Methods: The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by eight cycles of cisplatin, lomustine and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated. Primary endpoint was the rate of toxicityrelated treatment terminations after four chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% percent showed classic and desmoplastic-nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in Non-WNT/Non-SHH. Four cycles of chemotherapy were feasible in the majority (n=21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate (EFS) was 66.6% at the time of databank lock. Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first four chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen.Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation N-O-D-17-00180R1Dear Prof. Wen, many thanks for the opportunity to, for the second time, re-submit our above mentioned manuscript to NeuroOncology with major revisions.Below, you will find our point-to-point answer to all reviewer comments. Please be aware that there are two open questions where we will need the feedback of the acting editor and the reviewer, respectively.We declare that our manuscript, or any part of it, has not been previously published or submitted concurrently to any other journal, and that all co-authors have read and approved the revised version of the manuscript. We further declare that we agree to pay for full color reproduction.We hope that the revisions will now qualify the manuscript for publication in Neuro-Oncology. We will however be happy to address further questions, if indicated. . This hypothesis results in an exploratory and descriptive feasibility design, focusing on the rate of toxicity-related treatment terminations after 4 cycles of adjuvant chemotherapy. The statistical approach of this study therefore did not contain a formal H0/...

Background. CUPISCO is an ongoing randomized phase II trial (NCT03498521) comparing molecularly-guided therapy versus platinum-based chemotherapy in patients newly diagnosed with 'unfavorable' cancer of unknown primary (CUP). Patients and Methods. Patients with an unfavorable CUP diagnosis, as defined by the European Society of Medical Oncology (ESMO), and available cancer tissue for molecular sequencing are generally eligible. Potential CUP patients entering screening undergo a review involving reference histopathology and clinical work-up by a central Eligibility Review team (ERT). Patients with "favorable" CUP, a strongly suspected primary site of origin, lack of tissue, or unmet inclusion criteria are excluded. Results. As of April 30, 2020, 628 patients had entered screening and 346 (55.1%) were screen failed. Screen fails were due to technical reasons (N=89), failure to meet inclusion/exclusion criteria not directly related to CUP diagnosis (N=89) and other reasons (N=33). 124 (35.8%) patients were excluded because unfavorable adeno-or poorly differentiated CUP could not be confirmed by the ERT. These cases were classified into 3 groups ineligible due to (i) histologic subtype, such as squamous and neuroendocrine, or favorable CUP; (ii) evidence of a possible primary tumor or (iii) non-carcinoma histology. Conclusions. Experience with CUPISCO has highlighted challenges with standardized screening in an international clinical trial and the difficulties in diagnosing unfavorable CUP. Re-confirmation of unfavorable CUP by an ERT in a clinical trial can result in many reasons for screen failures. By sharing this experience, we aim to foster understanding of diagnostic challenges and improve diagnostic pathology and clinical CUP algorithms. Implications for Practice:: A high unmet need exists for improved treatment of cancer of unknown primary (CUP); however, study in a trial setting is faced with the significant challenge of definitively distinguishing CUP from other cancer types. Here we report on our experience of this challenge so far in the ongoing CUPISCO trial, which compares treatments guided by patients' unique genetic signatures versus standard chemotherapy. The data presented will aid future decision-making regarding diagnosing true CUP cases; this will have far-reaching implications in the design, execution and interpretation of

Background. Carcinoma of unknown primary origin (CUP) accounts for 2%-5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm. Materials and Methods. Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture-based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed deathligand 1 (PD-L1) positivity were determined. Results. A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabyte of DNA; 34 patients (11.6%) had a TMB greater or equal to 16 mutations per megabyte. Three patients (1%) had high MSI, and 42 (14%) displayed high PD-L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 or 303 specimens; 19.6% had a score of >16%. Conclusions. Thirty-two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD-L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP-informed treatment. Clinical trial identification number. NCT03498521 The Oncologist 2020;9999:• • Implications for Practice: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, like programmed death-ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling-informed treatment.

Numerous energetic coordination complexes (MnII, FeII, CoII, NiII, CuII, ZnII, and AgI) using 1-methyl-tetrazole as the ligand were synthesized and tuned by different counteranions (e.g. NO3−, ClO4−, picrate, and styphnate). They show great potential for mechanical or optical initiation systems.

The synthesis of the new hybrid guanidine ligands DMEGdmap, DMEGdeae, TMGdmab, DMEGdmab, TMGdeab and DMEGdeab is reported. These ligands were combined with zinc chloride, and the six obtained new complexes were structurally characterised by X-ray crystallography and NMR spectroscopy. Further six new zinc chloride complexes were obtained from the hybrid guanidine ligands TMGdmae, DMEGdmae, TMGdeae, TMGdmap, TMGdeap and TEGdeap. Each of the twelve com- [a]