Langerhans Cell Histiocytosis of the Head and Neck: Experience at a Rural Tertiary Referral Center.

OBJECTIVES: Retrospectively analyze head and neck Langerhans Cell Histiocytosis at a rural tertiary referral center and compare results with previously published data. METHODS: Electronic health record review was performed from 2003 to 2019. Patients with biopsy proven LCH with primary head and neck involvement were included. Demographics, presentation, imaging characteristics, treatment modality, delay in diagnosis (DD, ≥60 days), and outcomes were analyzed and reported. RESULTS: Twenty-four patients were included. The most common presenting symptoms were otorrhea (n = 6) and scalp pain or swelling (n = 6). All patients had bony involvement. The most common site was facial or skull lesions (n = 20). Most skull lesions (75%) demonstrated CNS risk. Six patients were treated with primary surgery, 15 with primary chemotherapy, and 3 with surgery plus adjuvant chemotherapy. Nine patients experienced relapse of disease with median time to documented relapse of 11.4 months; all were treated with salvage chemotherapy to achieve complete remission (median follow-up: 72 months). Patients most likely to relapse were those with multisystem disease (5/7, 71.4%), temporal bone lesions (4/7, 57.1%), and DD (7/12, 58.3%). Of the 9 total patients who experienced relapse, 78% had a delay in diagnosis. CONCLUSIONS: LCH is a complex disease process in which diagnosis can be delayed if not considered in the differential. Within the head and neck, the skull, including isolated temporal bone involvement, is the most common site of involvement. Treatment modality does not appear to have an influence on relapse rates. Relapse was more likely to occur in the first year after treatment and close monitoring is required.

Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade.

POLE mutations are a major cause of hypermutant cancers, yet questions remain regarding mechanisms of tumorigenesis, genotype-phenotype correlation, and therapeutic considerations. In this study, we establish mouse models harboring cancer-associated POLE mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation in vivo, independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of POLE mutations into three groups based on clinical phenotype and mutagenicity. Cancers driven by these mutations displayed striking resemblance to the human ultrahypermutation and specific signatures. Furthermore, Pole-driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in intertumoral and intratumoral heterogeneity. Checkpoint blockade did not prevent Pole lymphomas, but rather likely promoted lymphomagenesis as observed in humans. These observations provide insights into the carcinogenesis of POLE-driven tumors and valuable information for genetic counseling, surveillance, and immunotherapy for patients. SIGNIFICANCE: Two mouse models of polymerase exonuclease deficiency shed light on mechanisms of mutation accumulation and considerations for immunotherapy.See related commentary by Wisdom and Kirsch p. 5459.

Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.

Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.

Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue.

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

A Rare Initial Presentation of Primary Diffuse Leptomeningeal PNET in a 10-Year-Old-Male.

Primary leptomeningeal primitive neuroectodermal tumors (PNETs) are extremely rare childhood central nervous system malignancies harboring a very poor prognosis. There is no consensus treatment for these tumors to date. We report a case of a 10-year-old male who presented with mental status change, hydrocephalus, intracranial and spinal diffuse leptomeningeal enhancement without a primary mass upon cranial imaging and a negative initial biopsy until five months into his presentation. He responded significantly well to initial chemotherapy and radiotherapy.

Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Sodium thiosulfate is an antioxidant shown in preclinical studies in animals to prevent cisplatin-induced hearing loss with timed administration after cisplatin without compromising the antitumour efficacy of cisplatin. The primary aim of this study was to assess sodium thiosulfate for prevention of cisplatin-induced hearing loss in children and adolescents. METHODS: ACCL0431 was a multicentre, randomised, open-label, phase 3 trial that enrolled participants at 38 participating Children's Oncology Group hospitals in the USA and Canada. Eligible participants aged 1-18 years with newly diagnosed cancer and normal audiometry were randomly assigned (1:1) to receive sodium thiosulfate or observation (control group) in addition to their planned cisplatin-containing chemotherapy regimen, using permuted blocks of four. Randomisation was initially stratified by age and duration of cisplatin infusion. Stratification by previous cranial irradiation was added later as a protocol amendment. The allocation sequence was computer-generated centrally and concealed to all personnel. Participants received sodium thiosulfate 16 g/m2 intravenously 6 h after each cisplatin dose or observation. The primary endpoint was incidence of hearing loss 4 weeks after final cisplatin dose. Hearing was measured using standard audiometry and reviewed centrally by audiologists masked to allocation using American Speech-Language-Hearing Association criteria but treatment was not masked for participants or clinicians. Analysis of the primary endpoint was by modified intention to treat, which included all randomly assigned patients irrespective of treatment received but restricted to those assessable for hearing loss. Enrolment is complete and this report represents the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00716976. FINDINGS: Between June 23, 2008, and Sept 28, 2012, 125 eligible participants were randomly assigned to either sodium thiosulfate (n=61) or observation (n=64). Of these, 104 participants were assessable for the primary endpoint (sodium thiosulfate, n=49; control, n=55). Hearing loss was identified in 14 (28·6%; 95% CI 16·6-43·3) participants in the sodium thiosulfate group compared with 31 (56·4%; 42·3-69·7) in the control group (p=0·00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the sodium thiosulfate group compared with the control group (odds ratio 0·31, 95% CI 0·13-0·73; p=0·0036). The most common grade 3-4 haematological adverse events reported, irrespective of attribution, were neutropenia (117 [66%] of 177 participant cycles in the sodium thiosulfate group vs 145 [65%] of 223 in the control group), whereas the most common non-haematological adverse event was hypokalaemia (25 [17%] of 147 vs 22 [12%] of 187). Of 194 serious adverse events reported in 26 participants who had received sodium thiosulfate, none were deemed probably or definitely related to sodium thiosulfate; the most common serious adverse event was decreased neutrophil count: 26 episodes in 14 participants. INTERPRETATION: Sodium thiosulfate protects against cisplatin-induced hearing loss in children and is not associated with serious adverse events attributed to its use. Further research is needed to define the appropriate role for sodium thiosulfate among emerging otoprotection strategies. FUNDING: US National Cancer Institute.

Parameningeal rhabdomyosarcoma in a patient with Costello syndrome.

Costello syndrome, a rare entity with multiple congenital anomalies, has been associated with a high incidence of benign and malignant tumors, particularly rhabdomyosarcoma. Although the head and neck is the most common site for rhabdomyosarcomas in children, only one other case in the literature has been reported of a head and neck rhabdomyosarcoma in a Costello patient. The authors describe a 3-year-old with a parameningeal infratemporal fossa rhabdomyosarcoma. Management is discussed with particular attention to the difficulties encountered due to the congenital heart abnormalities associated with the syndrome.

Effects of amifostine on clonogenic mesenchymal progenitors and hematopoietic progenitors exposed to radiation.

PURPOSE: To determine the radiation sensitivities of mesenchymal progenitors and hematopoietic progenitors, and to determine the in vitro effects of amifostine on hematopoietic and mesenchymal progenitors exposed to radiation. METHODS: Radiosensitivity of mesenchymal progenitor cells was determined by exposing marrow low-density cells to radiation at doses of 100 to 800 cGy. Mesenchymal cell colonies were established by plating 2.5 x 10(5) marrow low-density cells in long-term marrow culture medium (LTCM). The size, frequency, and cellular composition of the mesenchymal progenitor cells were scored after 14 days of incubation. Mesenchymal progenitor cells were subdivided into progenitors forming fibroblast and adipocyte mixed colonies (CFU-FA), and pure fibroblast colonies (CFU-F). Hematopoietic progenitors were assessed by methylcellulose-based assay. RESULTS: Radiation at 100 cGy caused a mild decrease in CFU-F and CFU-FA derived colonies by 12% and 13%, respectively; 200 cGy decreased CFU-F by 36% and CFU-FA by 52%; 400 cGy decreased CFU-F by 50% and CFU-FA by 86%; and 600 cGy decreased CFU-F by 24%, with total absence of CFU-FA. Pretreatment with amifostine protected 100% of CFU-F at 100 and 200 cGy, 84% at 400 cGy, 46% at 600 cGy, and 14% at 800 cGy. With CFU-FA colonies amifostine pretreatment provided only minimal radioprotection. For hematopoietic progenitors radiation at 100 cGy reduced CFU-GM by 74% but had no significant effect on CFU-GEMM and BFU-E. Radiation at 200 cGy decreased CFU-GEMM by 72%, BFU-E by 54%, and CFU-GM by 84%; 400 cGy further decreased CFU-GEMM by 83%, BFU-E by 81%, and CFU-GM by 93%. Pretreatment with amifostine resulted in twofold stimulation of CFU-GEMM and BFU-E colonies. All BFU-E colonies were protected up to 200 cGy. For CFU-GEMM amifostine pretreatment resulting in 68% at 200 cGy and 31% at 400 cGy. For CFU-GM colonies it was 54% at 100 cGy, 32% at 200 cGy, and 12% at 400 cGy. CONCLUSIONS: Mesenchymal progenitor cell subpopulations are differentially sensitive to radiation. Amifostine protects both mesenchymal and hematopoietic progenitors against radiation injury, though the level of protection appears to be dependent upon the sensitivities of these progenitor cells to radiation. Amifostine is a potent stimulant of BFU-E and CFU-GEMM progenitor colonies.