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.

Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial.

BACKGROUND: Approvals of cancer therapeutics are primarily disease entity specific. Current molecular diagnostic approaches frequently identify actionable alterations in rare cancers or rare subtypes of common cancers for which the corresponding treatments are not approved and unavailable within clinical trials due to entity-related eligibility criteria. Access may be negotiated with health insurances. However, approval rates vary, and critical information required for a scientific evaluation of treatment-associated risks and benefits is not systematically collected. Thus clinical trials with optimized patient selection and comprehensive molecular characterization are essential for translating experimental treatments into standard care. PATIENTS AND METHODS: Continuous ReAssessment with Flexible ExTension in Rare Malignancies (CRAFT) is an open-label phase II trial for adults with pretreated, locally advanced, or metastatic solid tumors. Based on the evaluation by a molecular tumor board, patients are assigned to combinations of six molecularly targeted agents and a programmed death-ligand 1 (PD-L1) antagonist within seven study arms focusing on (i) BRAF V600 mutations; (ii) ERBB2 amplification and/or overexpression, activating ERBB2 mutations; (iii) ALK rearrangements, activating ALK mutations; (iv and v) activating PIK3CA and AKT mutations, other aberrations predicting increased PI3K-AKT pathway activity; (vi) aberrations predicting increased RAF-MEK-ERK pathway activity; (vii) high tumor mutational burden and other alterations predicting sensitivity to PD-L1 inhibition. The primary endpoint is the disease control rate (DCR) at week 16; secondary and exploratory endpoints include the progression-free survival ratio, overall survival, and patient-reported outcomes. Using Simon's optimal two-stage design, 14 patients are accrued for each study arm. If three or fewer patients achieve disease control, the study arm is stopped. Otherwise, 11 additional patients are accrued. If the DCR exceeds 7 of 25 patients, the null hypothesis is rejected for the respective study arm. CONCLUSIONS: CRAFT was activated in October 2021 and will recruit at 10 centers in Germany. TRIAL REGISTRATION NUMBERS: EudraCT: 2019-003192-18; ClinicalTrials.gov: NCT04551521.

Severe coronary sinus dilatation after a modification of the classic Fontan operation: successful resolution with a revision Fontan operation.

Two patients with functional single ventricle and a left superior vena cava, which drained to the coronary sinus, are presented. Each had undergone a Fontan modification that incorporated the coronary sinus into the Fontan pathway. Each developed severe right atrial and coronary sinus dilatation. Revision of a Fontan with an intraatrial lateral tunnel and an extracardiac conduit resulted in improved functional capacity of the patients.

Mg(2+) modulates voltage-dependent activation in ether-à-go-go potassium channels by binding between transmembrane segments S2 and S3.

Extracellular Mg(2+) directly modulates voltage-dependent activation in ether-à-go-go (eag) potassium channels, slowing the kinetics of ionic and gating currents (Tang, C.-Y., F. Bezanilla, and D.M. Papazian. 2000. J. Gen. Physiol. 115:319-337). To exert its effect, Mg(2+) presumably binds to a site in or near the eag voltage sensor. We have tested the hypothesis that acidic residues unique to eag family members, located in transmembrane segments S2 and S3, contribute to the Mg(2+)-binding site. Two eag-specific acidic residues and three acidic residues found in the S2 and S3 segments of all voltage-dependent K(+) channels were individually mutated in Drosophila eag, mutant channels were expressed in Xenopus oocytes, and the effect of Mg(2+) on ionic current kinetics was measured using a two electrode voltage clamp. Neutralization of eag-specific residues D278 in S2 and D327 in S3 eliminated Mg(2+)-sensitivity and mimicked the slowing of activation kinetics caused by Mg(2+) binding to the wild-type channel. These results suggest that Mg(2+) modulates activation kinetics in wild-type eag by screening the negatively charged side chains of D278 and D327. Therefore, these residues are likely to coordinate the bound ion. In contrast, neutralization of the widely conserved residues D284 in S2 and D319 in S3 preserved the fast kinetics seen in wild-type eag in the absence of Mg(2+), indicating that D284 and D319 do not mediate the slowing of activation caused by Mg(2+) binding. Mutations at D284 affected the eag gating pathway, shifting the voltage dependence of Mg(2+)-sensitive, rate limiting transitions in the hyperpolarized direction. Another widely conserved residue, D274 in S2, is not required for Mg(2+) sensitivity but is in the vicinity of the binding site. We conclude that Mg(2+) binds in a water-filled pocket between S2 and S3 and thereby modulates voltage-dependent gating. The identification of this site constrains the packing of transmembrane segments in the voltage sensor of K(+) channels, and suggests a molecular mechanism by which extracellular cations modulate eag activation kinetics.

Moyamoya phenomenon after radiation for optic glioma.

The role of radiotherapy in the management of patients with optic pathway glioma is controversial. In a series of patients with optic pathway glioma treated at The Hospital for Sick Children in Toronto, five children were encountered who developed moyamoya phenomenon after radiotherapy. A retrospective review of the medical records was undertaken in order to assess the relationship between optic pathway glioma, neurofibromatosis type 1 (NF1), radiation therapy, and moyamoya disease. Forty-seven patients with optic pathway glioma were operated on at The Hospital for Sick Children between 1971 and 1990. The moyamoya phenomenon did not occur in any of the 19 patients not receiving radiotherapy. Among the 28 patients who received radiotherapy, five developed moyamoya disease (two of 23 without NF1 and three of five with NF1). There was a statistically significant relationship between radiotherapy and moyamoya disease when the analysis was stratified according to the presence of NF1 (Mantel-Haensel chi-squared test 15.23, p < 0.01). The high incidence of moyamoya disease (three of five cases, or 60%) in patients with NF1 who have undergone radiotherapy suggests a synergistic relationship that should be considered when formulating a treatment plan for NF1 patients with optic pathway glioma.

Spinal hemangioblastoma, syrinx, and hydrocephalus in a two-year-old child.

A two-year-old child presented with an acute inability to bear weight. Radiological investigation revealed a large cervicothoracolumbar syrinx of no known cause. During investigation, acute communicating hydrocephalus developed, which required a shunt. At surgery, a small thoracic spinal cord hemangioblastoma was discovered and excised. Complete recovery with collapse of the syrinx followed. The clinical features of this rare childhood tumor and its associated effects are discussed.

Fracturas lineales del craneo com factor de riesgo de hematoma intracraneal

Un total de 61 pacientes con traumatismo craneano y fractura lineal del cráneo fue admitido al Servicio de Neurocirugía del Hospital Santo Tomás, durante el año de 1985. Escogimos para este estudio los pacientes con alteración en el nivel de conciencia, para cuya determinación utilizamos la Escala de Coma de Glasgow. la incidencia del hematoma intracreaneal en los pacientes con fractura lineal fue de 67% en los caos en que la Escala demostró que era < ou = 9 y de 25% demostró que era de > ou = 10. La mortalidad fue de 85% en los casos con Escala de Coma de Glasgow de < ou = 9 y de 4%, en los casos de > ou 10

c-myc amplification and expression in newly established human osteosarcoma cell lines.

Three cell lines were isolated from a patient with osteosarcoma of the femur. These lines were obtained from the primary neoplasm before (HTLA145) and after (HTLA161) chemotherapy and from a metastasis of the lung (HTLA195) in the same patient. The three cell lines exhibited a similar morphology in culture and formed tumors in nude mice which demonstrated a histopathology similar to that which had been observed in the patient. High expression of the genes coding for the alpha-1 and alpha-2 chain of collagen Type I was found in vitro and in s.c. tumors growing in nude mice. The c-myc protooncogene was amplified in all three cell lines and extensive expression of c-myc was found in vitro and in vivo. No heterogeneity in regard to c-myc expression in vivo was detected by in situ localization in tumors growing in nude mice.