The major mechanism for the repair of DNA double-strand breaks (DSBs) in mammalian cells is non-homologous end-joining (NHEJ), a process that involves the DNA-dependent protein kinase [1] [2], XRCC4 and DNA ligase IV [3] [4] [5] [6]. Rodent cells and mice defective in these components are radiation-sensitive and defective in V(D)J-recombination, showing that NHEJ also functions to rejoin DSBs introduced during lymphocyte development [7] [8]. 180BR is a radiosensitive cell line defective in DSB repair, which was derived from a leukaemia patient who was highly sensitive to radiotherapy [9] [10] [11]. We have identified a mutation within a highly conserved motif encompassing the active site in DNA ligase IV from 180BR cells. The mutated protein is severely compromised in its ability to form a stable enzyme-adenylate complex, although residual activity can be detected at high ATP concentrations. Our results characterize the first patient with a defect in an NHEJ component and suggest that a significant defect in NHEJ that leads to pronounced radiosensitivity is compatible with normal human viability and does not cause any major immune dysfunction. The defect, however, may confer a predisposition to leukaemia.

Object. A multidisciplinary team devised a protocol for long-term care of patients with skull base chordomas. In this study they describe their approach. Methods. Forty-two patients presented between 1986 and 1998 and were treated by maximum surgical cytoreduction and photon radiation therapy. Tumor volume—doubling time determined on the basis of magnetic resonance imaging, immunostaining, and cell proliferation (Ki67 labeling index [LI]) studies indicated growth rates of individual chordomas. The best outlook was associated with the greatest extent of tumor removal achieved during the first operation. There were no deaths associated with patients who underwent first-time surgery, but there was a 7.1% mortality rate associated with those who underwent subsequent operations. Cerebrospinal fluid leaks, additional cranial nerve palsies, and pharyngeal wound problems were the most difficult management problems encountered after second and subsequent surgeries. The time interval between operations was usually between 2 years and 3 years after the first surgery; very few patients required a second surgery, with a quiescent period in excess of 5 years. Life-table 5- and 10-year survival rates were 77% and 69%, respectively. Conclusions. The authors believe that this series of skull base chordomas provides new insights into the management of these lesions, particularly with regard to techniques that increase survival times and studies that aid in formulating prognoses.

SDH-B mutation carriers develop disease early and predominantly in extra-adrenal locations. Disease penetrance is incomplete. Metastatic disease is prominent but levels are less than previously reported. Clinical manifestations may include papillary renal cell carcinoma and macrovascular disease.

National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.

PurposePediatric Cushing’s disease (CD) is rare and there are limited data on the long-term outcomes. We assessed CD recurrence, body composition, pituitary function and psychiatric comorbidity in a cohort of pediatric CD patients.MethodsRetrospective review of 21 CD patients, mean age at diagnosis 12.1 years (5.7–17.8), managed in our center between 1986 and 2010. Mean follow-up from definitive treatment was 10.6 years (2.9–27.2).ResultsFifteen patients were in remission following transsphenoidal surgery (TSS) and 5 were in remission following TSS + external pituitary radiotherapy (RT). One patient underwent bilateral adrenalectomy (BA). CD recurrence occurred in 3 (14.3 %) patients: 2 at 2 and 6 years after TSS and 1 7.6 years post-RT. The BA patient developed Nelson’s syndrome requiring pituitary RT 0.6 years post-surgery. Short-term growth hormone deficiency (GHD) was present in 14 patients (81 % patients tested) (11 following TSS and 3 after RT) and 4 (44 % of tested) had long-term GHD. Gonadotropin deficiency caused impaired pubertal development in 9 patients (43 %), 4 requiring sex steroid replacement post-puberty. Four patients (19 %) had more than one pituitary hormone deficiency, 3 after TSS and 1 post-RT. Five patients (24 %) had long-term psychiatric co-morbidities (cognitive dysfunction or mood disturbance). There were significant long-term improvements in growth, weight and bone density but not complete reversal to normal in all patients.ConclusionsThe long-term consequences of the diagnosis and treatment of CD in children is broadly similar to that seen in adults, with recurrence of CD after successful treatment uncommon but still seen. Pituitary hormone deficiencies occurred in the majority of patients after remission, and assessment and appropriate treatment of GHD is essential. However, while many parameters improve, some children may still have mild but persistent defects.

BACKGROUND: Histopathologic examination (HPE) of tumor tissue obtained by invasive biopsy is the standard for cancer diagnosis but is resource-intensive and has been associated with procedural risks. The authors demonstrate that immunocytochemistry (ICC) profiling of circulating ensembles of tumor-associated cells (C-ETACs) can noninvasively provide diagnostic guidance in solid organ cancers. METHODS: The clinical performance of this approach was tested on blood samples from 30,060 individuals, including 9416 individuals with known cancer; 6725 symptomatic individuals with suspected cancer; and 13,919 asymptomatic individuals with no prior diagnosis of cancer. C-ETACs were harvested from peripheral blood and profiled by ICC for organ-specific and subtype-specific markers relevant to the cancer type. ICC profiles were compared with HPE diagnoses to determine concordance. RESULTS: The presence of malignancy was confirmed by the detection of C-ETACs in 91.8% of the 9416 individuals with previously known cancer. Of the 6725 symptomatic individuals, 6025 were diagnosed with cancer, and 700 were diagnosed with benign conditions; C-ETACs were detected in 92.6% of samples from the 6025 individuals with cancer. In a subset of 3509 samples, ICC profiling of C-ETACs for organ-specific and subtype-specific markers was concordant with HPE findings in 93.1% of cases. C-ETACs were undetectable in 95% of samples from the 700 symptomatic individuals who had benign conditions and in 96.3% of samples from the 13,919 asymptomatic individuals. CONCLUSIONS: C-ETACs were ubiquitous (>90%) in various cancers and provided diagnostically relevant information in the majority (>90%) of cases. This is the first comprehensive report on the feasibility of ICC profiling of C-ETACs to provide pan-cancer diagnostic guidance with accuracy comparable to that of HPE. Cancer Cytopathol 2020;0:1-13.

Mutations in succinate dehydrogense-B (SDHB) and the von Hippel-Lindau (VHL) genes result in an increased risk of developing chromaffin tumours via a common aetiological pathway. The aim of the present retrospective study was to compare the clinical phenotypes of disease in subjects developing chromaffin tumours as a result of SDHB mutations or VHL disease. Thirty-one subjects with chromaffin tumours were assessed; 16 subjects had SDHB gene mutations and 15 subjects had a diagnosis of VHL. VHL-related tumours were predominantly adrenal phaeochromocytomas (22/26; 84.6%), while SDHB-related tumours were predominantly extraadrenal paragangliomas (19/25; 76%). Median age at onset of the first chromaffin tumour was similar in the two cohorts. Tumour size was significantly larger in the SDHB cohort in comparison with the VHL cohort (PZ0.002). Multifocal disease was present in 9/15 (60%) of the VHL cohort (bilateral phaeochromocytomas) and only 3/16 (19%) of the SDHB cohort, while metastatic disease was found in 5/16 (31%) of the SDHB cohort but not in the VHL cohort to date. The frequency of symptoms, hypertension and the magnitude of catecholamine secretion appeared to be greater in the SDHB cohort. Renal cell carcinomas were a feature in 5/15 (33%) of the VHL cohort and 1/16 (6%) of the SDHB cohort. These data indicate that SDHB-related tumours are predominantly extra-adrenal in location and associated with higher catecholamine secretion and more malignant disease, in subjects who appear more symptomatic. VHL-related tumours tend to be adrenal phaeochromocytomas, frequently bilateral and associated with a milder phenotype.

One patient died of a pulmonary embolus; the patients harboring mesenchymal chondrosarcomas died at 20 and 36 months, respectively, after treatment. Of the remaining patients, 93% were alive 5 years postsurgery and had a projected 10-year survival rate of 84% (mean survival time 9.3 years). These data emphasize the very slow progression of this tumor compared with skull base chordoma.