Postherpetic granulomatous dermatitis occurring in the setting of immune checkpoint inhibitor therapy: A case report.

We report a case of a 72-year-old man presenting with a 2-month history of a persistent, painful rash of the chest, axilla, and back. He had a history of recently resolved varicella zoster virus reactivation in the same distribution of the current rash and metastatic malignant melanoma treated with nivolumab and ipilimumab. The histopathology was consistent with granulomatous dermatitis (GD), and a diagnosis of postherpetic isotopic response manifesting as GD was made. Given the paucity of reported cases of postherpetic GD in the setting of treatment with immune checkpoint inhibitors (ICIs), we discuss the clinicopathologic features of this case and potential mechanisms by which ICIs may contribute to the development of granulomatous disease.

Associations of practical, emotional, and physical problems with psychosocial distress among cancer patients.

OBJECTIVE: To better understand the relationship between cancer patient distress and psychosocial variables, including problem types, to improve ability to predict and address psychosocial need. METHODS: A variation of National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT) was administered and collected at four sites from an Integrated Network Cancer Program (INCP). The presence of moderate/severe distress was examined relative to patient demographics, disease characteristics, and psychosocial problems. RESULTS: Distress scores were positively correlated with all problem counts. For every count increase of practical, emotional, and physical problems, and for every cancer stage increase the odds of reporting a moderate/severe distress score was significantly higher. Relative to patients with one cancer treatment type, patients with three cancer treatment types were significantly less likely to report moderate/severe distress. CONCLUSION: Problem count could be a useful indicator for clinical intervention. Stage and number of treatment types may also be considered clinically relevant distress predictors.

Implications for Psychosocial ResearchThis study found that NCCN Distress Thermometer distress levels and problem counts are highly correlated in most cancer patients.In addition to distress level, problem count on NCCN Distress Thermometer should be considered a potential trigger for psychosocial intervention.NCCN Distress Thermometer problem count may be a more durable indicator of need for psychosocial intervention then distress level alone. Psychosocial problems are rarely transient, while distress level can fluctuate day-to-day.Future research should examine the role of psychosocial problems on continuous distress scores and the relative contribution of each set of problem types on distress.

Precision Therapy for Brain Tumors in Hereditary Syndromes.

OPINION STATEMENT: Nervous system tumors arising in the setting of monogenic, hereditary cancer predisposition syndromes are unique in that the initiating genetic event in tumor formation is known. This knowledge provides a powerful treatment approach if the alteration or pathway can be targeted with a therapeutic agent. A reasonable argument can be made for the use of targeted agents in these tumor patients, even though many of them have FDA approval only for other tumor types. It is our practice to use and employ targeted therapy when standard treatments have failed or represent an unattractive option. Over time, however, targeted therapies will likely become first-line options.

Preoperative relative cerebral blood volume analysis in gliomas predicts survival and mitigates risk of biopsy sampling error.

Appropriate management of adult gliomas requires an accurate histopathological diagnosis. However, the heterogeneity of gliomas can lead to misdiagnosis and undergrading, especially with biopsy. We evaluated the role of preoperative relative cerebral blood volume (rCBV) analysis in conjunction with histopathological analysis as a predictor of overall survival and risk of undergrading. We retrospectively identified 146 patients with newly diagnosed gliomas (WHO grade II-IV) that had undergone preoperative MRI with rCBV analysis. We compared overall survival by histopathologically determined WHO tumor grade and by rCBV using Kaplan-Meier survival curves and the Cox proportional hazards model. We also compared preoperative imaging findings and initial histopathological diagnosis in 13 patients who underwent biopsy followed by subsequent resection. Survival curves by WHO grade and rCBV tier similarly separated patients into low, intermediate, and high-risk groups with shorter survival corresponding to higher grade or rCBV tier. The hazard ratio for WHO grade III versus II was 3.91 (p = 0.018) and for grade IV versus II was 11.26 (p < 0.0001) and the hazard ratio for each increase in 1.0 rCBV units was 1.12 (p < 0.002). Additionally, 3 of 13 (23%) patients initially diagnosed by biopsy were upgraded on subsequent resection. Preoperative rCBV was elevated at least one standard deviation above the mean in the 3 upgraded patients, suggestive of undergrading, but not in the ten concordant diagnoses. In conclusion, rCBV can predict overall survival similarly to pathologically determined WHO grade in patients with gliomas. Discordant rCBV analysis and histopathology may help identify patients at higher risk for undergrading.

Creation and Implementation of an Environmental Scan to Assess Cancer Genetics Services at Three Oncology Care Settings.

An environmental scan (ES) is an efficient mixed-methods approach to collect and interpret relevant data for strategic planning and project design. To date, the ES has not been used nor evaluated in the clinical cancer genetics setting. We created and implemented an ES to inform the design of a quality improvement (QI) project to increase the rates of adherence to national guidelines for cancer genetic counseling and genetic testing at three unique oncology care settings (OCS). The ES collected qualitative and quantitative data from reviews of internal processes, past QI efforts, the literature, and each OCS. The ES used a data collection form and semi-structured interviews to aid in data collection. The ES was completed within 6 months, and sufficient data were captured to identify opportunities and threats to the QI project's success, as well as potential barriers to, and facilitators of guideline-based cancer genetics services at each OCS. Previously unreported barriers were identified, including inefficient genetic counseling appointment scheduling processes and the inability to track referrals, genetics appointments, and genetic test results within electronic medical record systems. The ES was a valuable process for QI project planning at three OCS and may be used to evaluate genetics services in other settings.

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

Impact of neurofibromatosis type 1 in an adult community population.

Background: Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome with varying manifestations and severity. Adult NF1 patients often experience fragmented care, so we sought to characterize the health and demographic features of a community-based population of adults with NF1 and hypothesized that lack of a specialty clinic for adult NF1 patients correlates with unmet needs. Methods: Retrospective case-control study of all adult cases of NF1 among 4.06 million medical records in a Pacific Northwest population. 122 case charts were reviewed to ascertain NF1 disease features, comorbidities, and severity of disease. A 1:1 control cohort was selected by matching case/control by age, sex, and ZIP code to compare demographic features and health status. Results: Adult NF1 patients were less likely to have private insurance, be employed, and have children, but were equally likely to be married. One half of cases had disease features compromising health and well-being, and care involved 26 different specialties. Excluding neurofibromas, 43% of cases had cancer compared to 10% of controls [P < .0001, OR 5.38 (2.53-11.4)]. Only 27% of women ages 30-50 had undergone age-appropriate enhanced breast cancer surveillance. Behavioral health problems were found in 60% of NF1 patients compared to 37% of controls [P < .001, OR 2.61 (1.52-4.50)]. 93% of cases referred to a NF1 specialty center underwent a change in management upon establishing care. Conclusions: NF1 patients may benefit from coordinated management of care in a specialty center.

Adult pilocytic astrocytoma in the molecular era: a comprehensive review.

Adult pilocytic astrocytoma (PA) is less prevalent than pediatric PA and is associated with a worse prognosis. In a literature review, we found that 88.3% of the molecular alterations in adult PA are associated with MAPK pathway dysregulation. The most common alterations are fusions of BRAF. Understanding of the mechanisms underlying this pathway has evolved substantially, heralding advancements in specific targeted therapy. Here, we review clinical and molecular features of adult PA, characteristics predicting aggressive behavior and approaches to standard and investigational therapies. We highlight epigenetic profiling and integrated diagnosis as an essential component of classifying PA.

Brainstem ischemic syndrome in juvenile NF2.

OBJECTIVE: A new case of brainstem ischemic necrosis in a young woman with de novo neurofibromatosis type 2 (NF2) is reported, and given notable similarities to 7 prior cases of brainstem stroke in the literature, features defining a possible syndrome were sought. METHODS: Case review including detailed clinical assessment, neuroimaging analysis, genetic testing, and brain biopsy, followed by a multicase analysis. RESULTS: Brainstem ischemia in juvenile NF2 typically occurs in teenagers without previously known NF2 as an acute, monophasic presentation with restricted diffusion in the midbrain or pons following a recent hypoperfusion event, normal vascular imaging, obvious intracranial imaging features of NF2, typical inactivating NF2 alterations, biopsy showing necrosis without small vessel pathology, and subsequent aggressive NF2 lesion progression. CONCLUSIONS: Brainstem ischemia in juvenile NF2 is a rare syndrome of unclear etiology, possibly reflecting an unknown underlying vascular abnormality; a digenic effect is not excluded.

Low-Grade Gemistocytic Morphology in H3 G34R-Mutant Gliomas and Concurrent K27M Mutation: Clinicopathologic Findings.

Mutations in histone H3 are key molecular drivers of pediatric and young adult high-grade gliomas. Histone H3 G34R mutations occur in hemispheric high-grade gliomas and H3 K27M mutations occur in aggressive, though histologically diverse, midline gliomas. Here, we report 2 rare cases of histologically low-grade gliomas with gemistocytic morphology and sequencing-confirmed histone H3 G34R mutations. One case is a histologically low-grade gemistocytic astrocytoma with a G34R-mutation in H3F3A. The second case is a histologically low-grade gemistocytic astrocytoma with co-occurring K27M and G34R mutations in HIST1H3B. Review of prior histone H3-mutant gliomas sequenced at our institution shows a divergent clinical and immunohistochemical pattern in the 2 cases. The first case is similar to prior histone H3 G34R-mutant tumors, while the second case most closely resembles prior histone H3 K27M-mutant gliomas. These represent novel cases of sequencing-confirmed histone H3 G34R-mutant gliomas with low-grade histology and add to the known rare cases of G34R-mutant tumors with gemistocytic morphology. Although K27M and G34R mutations are thought to be mutually exclusive, we document combined K27M and G34R mutations in HIST1H3B and present evidence suggesting the K27M-mutation drove tumor phenotype in this dual mutant glioma.

Survival in patients with brain metastases from breast cancer: the importance of HER-2 status.

BACKGROUND: Brain metastases (BM) are the most common intracranial tumors in adults. To the authors' knowledge, established prognostic factors for survival after the diagnosis of BM in breast cancer patients do not take into account HER-2 status, which may have increasing relevance in the trastuzumab therapy era. METHODS: The authors identified 83 patients with breast cancer and new parenchymal BM diagnosed between January 1, 2001 and December 31, 2005 who were treated at Massachusetts General Hospital. Survival was estimated using the Kaplan-Meier method and curves were compared using the log-rank test. A Cox proportional hazards model was used to determine independent predictors of survival. RESULTS: The median overall survival from the time of BM was 8.3 months. On univariate analysis, HER-2-positive patients were found to have prolonged survival after BM compared with HER-2-negative patients (17.1 months vs 5.2 months). Patients with triple negative disease had a median survival of 4.0 months, compared with 11.2 months for all other patients. Additional predictors of improved survival on univariate analysis included

Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults.

We conducted a phase II study of the combination of temozolomide and angiogenesis inhibitors for treating adult patients with newly diagnosed glioblastoma. Patients who had stable disease following standard radiation therapy received temozolomide for 5 days in 28-day cycles, in combination with daily thalidomide and celecoxib. Patients were treated until tumor progression or development of unacceptable toxicity. Four-month progression-free survival (PFS) from study enrollment was the primary end point, and overall survival (OS) was the secondary end point. In addition, we sought to correlate response with O(6)-methylguanine-DNA methyltransferase promoter methylation status and serum levels of angiogenic peptides. Fifty patients with glioblastoma were enrolled (18 women, 32 men). Median age was 54 years (range, 29-78) and median KPS score was 90 (range, 70-100). From study enrollment, median PFS was 5.9 months (95% confidence interval [CI]: 4.2-8.0) and 4-month PFS was 63% (95% CI: 46%-75%). Median OS was 12.6 months (95% CI: 8.5-16.4) and 1-year OS was 47%. Of the 47 patients evaluable for best response, none had a complete response, five (11%) had partial response, four (9%) had minor response, 22 (47%) had stable disease, and 16 (34%) had progressive disease. Analysis of serial serum samples obtained from 47 patients for four angiogenic peptides failed to show a significant correlation with response or survival for three of the peptides; higher vascular endothelial growth factor levels showed a trend toward correlation with decreased OS (p=0.07) and PFS (p=0.09). The addition of celecoxib and thalidomide to adjuvant temozolomide was well tolerated but did not meet the primary end point of improvement of 4-month PFS from study enrollment.

Primary Leptomeningeal Oligodendroglioma, IDH-Mutant, 1p/19q-Codeleted.

We present a case of a 43-year-old woman with a history of headaches and blurry vision. Ophthalmologic examination identified papilledema. MR imaging demonstrated a right parietal region mass with patchy areas of contrast enhancement and focal calcifications. Intraoperative examination and exploration revealed an extra-axial mass with no apparent parenchymal involvement. Microscopic examination revealed solid sheets of tumor cells with clear cell cytologic features and no discernable intra-parenchymal tumor component. Molecular studies demonstrated the presence of IDH1 IDH1 c.395G>A p.R132H and CIC c.601C>T p.R281W mutations and 1p/19q codeletion. The radiographic features, gross appearance, and microscopic and molecular characteristics of the mass support the diagnosis of primary leptomeningeal oligodendroglioma, IDH-mutant, 1p/19-codeleted. This case represents one of a very few reported instances of molecularly-defined solitary, primary, intracranial oligodendroglioma, without definitive involvement of the brain parenchyma.

Diffusion and perfusion imaging in subacute neurotoxicity following high-dose intravenous methotrexate.

Methotrexate (MTX) is a widely used chemotherapeutic agent that can cause acute, subacute, and chronic neurological complications. Subacute MTX neurotoxicity is manifest by abrupt onset of focal cerebral dysfunction occurring days to weeks after MTX administration, usually in children. We describe the neuroimaging features of an adult patient with primary CNS lymphoma who presented with transient aphasia and right hemiparesis 12 days after receiving intravenous high-dose MTX (8 g/m2) chemotherapy. Imaging within 1 h of symptom onset showed bilateral symmetrical restricted diffusion involving white matter of the cerebral hemispheres. CT angiogram and dynamic susceptibility MRI showed no evidence of vasospasm or perfusion defect. MRI five days later showed near-complete resolution of the abnormalities. MRI 3(1/2) months later showed normal diffusion but new hyperintense T2-weighted signal changes in the subcortical white matter corresponding to previous areas of restricted diffusion. The absence of vascular or perfusion abnormalities suggests that transient cytotoxic edema in white matter may explain the syndrome of subacute MTX neurotoxicity.

Physiologic and radiographic evidence of the distal edge of the proton beam in craniospinal irradiation.

PURPOSE: Fatty replacement of bone marrow resulting from radiation therapy can be seen on T1-weighted magnetic resonance (MR) images. We evaluated the radiographic appearance of the vertebral bodies in children treated with proton craniospinal irradiation (CSI) to illustrate the distal edge effect of proton radiotherapy. METHODS AND MATERIALS: The study cohort consisted of 13 adolescents aged 12-18 years who received CSI with proton radiotherapy at Massachusetts General Hospital. Ten of these patients had reached maximal or near-maximal growth. Proton beam radiation for these 10 patients was delivered to the thecal sac and exiting nerve roots only, whereas the remaining 3 patients had a target volume that included the thecal sac, exiting nerve roots, and entire vertebral bodies. Median CSI dose was 27 [range, 23.4-36] cobalt gray equivalent (CGE) given in 1.8-CGE fractions. Magnetic resonance images of the spine were obtained after completion of radiotherapy. RESULTS: Magnetic resonance images of patients who received proton radiotherapy to the thecal sac only demonstrate a sharp demarcation of hyperintense T1-weighted signal in the posterior aspects of the vertebral bodies, consistent with radiation-associated fatty marrow replacement. Magnetic resonance images of the patients prescribed proton radiotherapy to the entire vertebral column had corresponding hyperintense T1-weighted signal involving the entire vertebral bodies. CONCLUSION: The sharp delineation of radiation-associated fatty marrow replacement in the vertebral bodies demonstrates the rapid decrease in energy at the edge of the proton beam. This provides evidence for a sharp fall-off in radiation dose and supports the premise that proton radiotherapy spares normal tissues unnecessary irradiation.