The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Creating a Narrative for Change: Health Promotion Students' Perspectives on the Power of Photovoice Research.

The use of Critical Race Theory, Photovoice, and Community-Based Participatory Research has helped uncover the root causes of issues such as systemic racism in the fields of public health and health promotion. Often, we see studies using traditional research methods to investigate potential causal factors of disparities in minoritized communities report only quantitative data. While these data are imperative for understanding the severity of disparities, quantitative-only approaches cannot address nor can they improve the critical root causes of these disparities. As a team of BIPOC graduate students in public health, we conducted a community-based participatory research project using Photovoice methodology to explore inequities in Black and Brown communities exacerbated during the COVID-19 pandemic. The participatory nature of this research revealed cumulative challenges across the social determinants of health in New Haven and Bridgeport, Connecticut. It allowed us to engage in local-level advocacy to promote health equity as our findings illuminated the need for community-led and community-engaged action. Health and racial inequities cannot be effectively addressed if public health research and programming do not collaborate with the community to build community capacity, empowerment, and trust. We describe our experiences doing community-based participatory research to investigate inequities and provide reflections on their value for public health students. As responses to health inequities and disparities become more politically polarized in the United States, it is critical for public health and health education students to use research methodologies that elevate communities that have been historically marginalized and neglected. Together, we can catalyze equitable change.

Genome-wide analysis of high-risk primary brain cancer pedigrees identifies PDXDC1 as a candidate brain cancer predisposition gene.

BACKGROUND: There is evidence for an inherited contribution to primary brain cancer. Linkage analysis of high-risk brain cancer pedigrees has identified candidate regions of interest in which brain cancer predisposition genes are likely to reside. METHODS: Genome-wide linkage analysis was performed in a unique set of 11 informative, extended, high-risk primary brain cancer pedigrees identified in a population genealogy database, which include from 2 to 6 sampled, related primary brain cancer cases. Access to formalin-fixed paraffin embedded tissue samples archived in a biorepository allowed analysis of extended pedigrees. RESULTS: Individual high-risk pedigrees were singly informative for linkage at multiple regions. Suggestive evidence for linkage was observed on chromosomes 2, 3, 14, and 16. The chromosome 16 region in particular contains a promising candidate gene, pyridoxal-dependent decarboxylase domain-containing 1 (PDXDC1), with prior evidence for involvement with glioblastoma from other previously reported experimental settings, and contains the lead single nucleotide polymorphism (rs3198697) from the linkage analysis of the chromosome 16 region. CONCLUSIONS: Pedigrees with a statistical excess of primary brain cancers have been identified in a unique genealogy resource representing the homogeneous Utah population. Genome-wide linkage analysis of these pedigrees has identified a potential candidate predisposition gene, as well as multiple candidate regions that could harbor predisposition loci, and for which further analysis is suggested.

Intravascular Lymphoma with Progressive CNS Hemorrhage and Multiple Dissections.

INTRODUCTION: Intravascular lymphoma (IVL) is an uncommon and often fatal disease characterized by intraluminal proliferation of lymphomatous cells within blood vessels. Because of a heterogeneous clinical presentation and lack of sensitive diagnostic protocols, diagnosis of IVL is most often made at autopsy. However, with early diagnosis and appropriate chemotherapy, the prognosis is greatly improved and complete remission is possible. In order to broaden the possible presentations of IVL, we present a patient with an atypical manifestation of biopsy-proven intravascular large B-cell lymphoma who suffered dissections of both intracranial and extracranial arteries in addition to progressive intracranial hemorrhages. Case Report. A 47-year-old woman presented with unilateral paresthesias. She developed progressive multifocal infarcts and hemorrhage with dissections of both intracranial and extracranial arteries, resulting in coma. Brain biopsy revealed IVL. She received aggressive chemotherapy and remains in complete remission with good neurologic recovery. CONCLUSION: IVL is known to exert its pathology on small arteries and capillaries, but is not known to cause dissections of large vessels. The diagnosis should be considered in cases with unexplained arterial dissections and progressive strokes. Early diagnosis with appropriate laboratory screening and tissue confirmation by biopsy can lead to greatly improved outcomes.

Retrospective clinical trial experimentally validates glioblastoma genome-wide pattern of DNA copy-number alterations predictor of survival.

Modeling of genomic profiles from the Cancer Genome Atlas (TCGA) by using recently developed mathematical frameworks has associated a genome-wide pattern of DNA copy-number alterations with a shorter, roughly one-year, median survival time in glioblastoma (GBM) patients. Here, to experimentally test this relationship, we whole-genome sequenced DNA from tumor samples of patients. We show that the patients represent the U.S. adult GBM population in terms of most normal and disease phenotypes. Intratumor heterogeneity affects ≈ 11 % and profiling technology and reference human genome specifics affect <1% of the classifications of the tumors by the pattern, where experimental batch effects normally reduce the reproducibility, i.e., precision, of classifications based upon between one to a few hundred genomic loci by >30%. With a 2.25-year Kaplan-Meier median survival difference, a 3.5 univariate Cox hazard ratio, and a 0.78 concordance index, i.e., accuracy, the pattern predicts survival better than and independent of age at diagnosis, which has been the best indicator since 1950. The prognostic classification by the pattern may, therefore, help to manage GBM pseudoprogression. The diagnostic classification may help drugs progress to regulatory approval. The therapeutic predictions, of previously unrecognized targets that are correlated with survival, may lead to new drugs. Other methods missed this relationship in the roughly 3B-nucleotide genomes of the small, order of magnitude of 100, patient cohorts, e.g., from TCGA. Previous attempts to associate GBM genotypes with patient phenotypes were unsuccessful. This is a proof of principle that the frameworks are uniquely suitable for discovering clinically actionable genotype-phenotype relationships.

Pathologic remodeling in human neuromas: insights from clinical specimens.

BACKGROUND: Neuroma pathology is commonly described as lacking a clear internal structure, but we observed evidence that there are consistent architectural elements. Using human neuroma samples, we sought to identify molecular features that characterize neuroma pathophysiology. METHODS: Thirty specimens-12 neuromas-in-continuity (NICs), 11 stump neuromas, two brachial plexus avulsions, and five controls-were immunohistochemically analyzed with antibodies against various components of normal nerve substructures. RESULTS: There were no substantial histopathologic differences between stump neuromas and NICs, except that NICs had intact fascicle(s) in the specimen. These intact fascicles showed evidence of injury and fibrosis. On immunohistochemical analysis of the neuromas, laminin demonstrated a consistent double-lumen configuration. The outer lumen stained with GLUT1 antibodies, consistent with perineurium and microfascicle formation. Antibodies to NF200 revealed small clusters of small-diameter axons within the inner lumen, and the anti-S100 antibody showed a relatively regular pattern of non-myelinating Schwann cells. CD68+ cells were only seen in a limited temporal window after injury. T-cells were seen in neuroma specimens, with both a temporal evolution as well as persistence long after injury. Avulsion injury specimens had similar architecture to control nerves. Seven pediatric specimens were not qualitatively different from adult specimens. NICs demonstrated intact but abnormal fascicles that may account for the neurologically impoverished outcomes from untreated NICs. CONCLUSIONS: We propose that there is consistent pathophysiologic remodeling after fascicle disruption. Particular features, such as predominance of small caliber axons and persistence of numerous T-cells long after injury, suggest a potential role in chronic pain associated with neuromas.

Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis.

Astroblastoma (AB) is a rare CNS tumor demonstrating abundant astroblastomatous pseudorosettes. Its molecular features have not been comprehensively studied and its status as a tumor entity is controversial. We analyzed a cohort of 27 histologically-defined ABs using DNA methylation profiling, copy number analysis, FISH and site-directed sequencing. Most cases demonstrated mutually exclusive MN1 rearrangements (n = 10) or BRAFV600E mutations (n = 7). Two additional cases harbored RELA rearrangements. Other cases lacked these specific genetic alterations (n = 8). By DNA methylation profiling, tumors with MN1 or RELA rearrangement clustered with high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) and RELA-fusion ependymoma, respectively. In contrast, BRAFV600E-mutant tumors grouped with pleomorphic xanthoastrocytoma (PXA). Six additional tumors clustered with either supratentorial pilocytic astrocytoma and ganglioglioma (LGG-PA/GG-ST), normal or reactive cerebrum, or with no defined DNA methylation class. While certain histologic features favored one genetic group over another, no group could be reliably distinguished by histopathology alone. Survival analysis between genetic AB subtypes was limited by sample size, but showed that MN1-rearranged AB tumors were characterized by better overall survival compared to other genetic subtypes, in fact, significantly better than BRAFV600E-mutant tumors (P = 0.013). Our data confirm that histologically-defined ABs are molecularly heterogeneous and do not represent a single entity. They rather encompass several low- to higher-grade glial tumors including neuroepithelial tumors with MN1 rearrangement, PXA-like tumors, RELA ependymomas, and possibly yet uncharacterized lesions. Genetic subtyping of tumors exhibiting AB histology, particularly determination of MN1 and BRAFV600E status, is necessary for important prognostic and possible treatment implications.

The contribution of the rs55705857 G allele to familial cancer risk as estimated in the Utah population database.

BACKGROUND: IDH1/2 mutated glioma has been associated with a germline risk variant, the rs55705857 G allele. The Utah Population Database (UPDB), a computerized genealogy of people in Utah, is a unique resource to evaluate cancer risk in related individuals. METHODS: One hundred and two individuals with IDH1/2 mutant or 1p/19q co-deleted glioma were genotyped and linked to the UPDB. DNA came from blood (21), tumor tissue (43), or both (38). We determined congruence between somatic and germline samples and estimated the relative risk for developing cancer to first and second-degree relatives of G and A allele carriers at rs55705857. RESULTS: Somatic (glioma) DNA had 85.7% sensitivity (CI 57.2-98.2%) and 95.8% specificity (CI 78.9-99.89%) for germline rs55705857 G allele. Forty-one patients were linked to pedigrees in the UPDB with at least three generations of data. First-degree relatives of rs55705857 G allele carriers were at significantly increased risk for developing cancer (RR = 1.72, p = 0.045, CI 1.02-2.94), and specifically for oligodendroglioma (RR = 57.61, p = 0.017, CI 2.96-320.98) or prostate cancer (RR = 4.10, p = 0.008, CI 1.62-9.58); relatives of individuals without the G allele were not at increased risk. Second-degree relatives of G allele carriers also had significantly increased risk for developing cancer (RR = 1.50, p = 0.007, CI 1.15-2.01). CONCLUSIONS: Tumor DNA may approximate genotype at the rs55705857 locus. We confirmed this locus confers an increased risk of all cancers and especially of oligodendroglioma. No increased cancer or brain tumor risk is seen in family members of individuals without the high-risk G allele.

Gliosarcoma: Neuroimaging and Immunohistochemical Findings.

BACKGROUND AND PURPOSE: Gliosarcoma (GSC) is an intra-axial lesion which often abuts a dural margin and is composed of glial and mesenchymal elements. This lesion is considered a variant of isocitrate dehydrogenase (IDH)-wild type glioblastoma (GBM). The purpose of this study is to evaluate the imaging and molecular features of GSC in a large patient cohort. METHODS: Pathology-proved GSC cases were collected from our quaternary care center spanning the last 16 years and IDH status was documented. Older GSC cases without prior immunohistochemical testing underwent tissue block staining to obtain IDH status. When available, p53, phosphate and tensin (PTEN), MIB-1, EGFR amplification, and MGMT methylation were recorded and imaging findings tabulated. Logistic regression analyses were performed to determine correlation of molecular markers and imaging characteristics. RESULTS: A total of 25 cases were identified (21 de novo, 4 post-treatment). All lesions contacted a dural, pial, or ependymal surface and were negative for an IDH R132H mutation, including postradiation GSC. In total, 16 of 16 cases showed nonamplification of EGFR/CEP7, 2 of 16 demonstrated MGMT methylation, and multiple lesions demonstrated p53 and PTEN mutations. Imaging features included areas of nodular thickening in necrotic lesions which appeared to abut the site of dural contact. There was no significant correlation of molecular markers with imaging characteristics. CONCLUSION: GSC was IDH(-) in all cases, supporting the current understanding of this lesion being a wild-type GBM variant. Additional molecular markers demonstrated no significant correlation with imaging findings in this cohort.

Myopathy in the York Platelet Syndrome: An Underrecognized Complication.

York Platelet Syndrome (YPS) is a calcium channelopathy caused by gain of function in STIM1, a gene which acts as a calcium sensor. It is characterized by platelet abnormalities and muscle weakness. Medical literature emphasizes the hematologic aspects of the cases with few data of the neuromuscular and neuropathologic evaluation. We present a patient with YPS whose myopathy was the most prominent aspect. She presented around 2 years of age with proximal weakness and easy bruisability. YPS was diagnosed in the infant at 16 months of age at the National Institutes of Health. Muscle biopsy demonstrated a severe chronic myopathy. Rimmed vacuoles and tubular aggregates were noted. Although YPS is rare, the combination of a congenital myopathy with thrombocytopenia may facilitate the diagnosis and enable further insights into the disease.

Giant Cell Tumor of the Lateral Skull Base: Diagnostic and Management Options.

Giant cell tumor of bone (GCTB) is a rare, benign, osteolytic neoplasm that most commonly occurs in early adulthood and often involves the long bones of the body. Although GCTB largely affects the epiphyses of long bones, several reports of GCTB involvement of the cranial and facial bones exist in the literature. In addition to reviewing other reported cases of GCTBs of the lateral skull base in the literature, the authors report here on the clinical presentation, radiographic findings, and neurosurgical management of a patient found to have a GCTB of the middle and infratemporal fossae, which was treated by aggressive en bloc resection of the lateral skull base.

Pathologic Remodeling of Endoneurial Tubules in Human Neuromas.

BACKGROUND: Laminins are extracellular matrix proteins that participate in endoneurial tubule formation and are important in the regeneration of nerves after injury. They act as scaffolds to guide nerves to distal targets and play a key role in neurite outgrowth. Because there is evidence that laminin architecture affects nerve regeneration, we evaluated endoneurial tubules by examining the laminin structure in clinical samples from patients with nerve injuries. METHODS: In a retrospective review of eight nerve injury cases, we evaluated nerve histology in relation to clinical history and injury type. The immunohistochemical delineation of the laminin structure in relationship with the neuroma type was performed. RESULTS: Five cases of upper-trunk stretch injuries-four from childbirth injury and one from a motorcycle accident-and three cases of nerve laceration leading to neuroma formation were examined. In the upper-trunk stretch injuries, avulsed nerves demonstrated no neuroma formation with a linear laminin architecture and a regular Schwann cell arrangement, but increased fibrous tissue deposition. For neuromas-in-continuity after a stretch injury, laminin immunohistochemistry demonstrated a double-lumen laminin tubule, with encapsulation of the Schwann cells and axonal processes. Nerve laceration leading to stump neuroma formation had a similar double-lumen laminin tubule, but less severe fibrosis. CONCLUSIONS: In nerve injuries with regenerative capacity, endoneurial tubules become pathologically disorganized. A double-lumen endoneurial tubule of unclear significance develops. The consistency of this pattern potentially suggests a reproducible pathophysiologic process. Further exploration of this pathophysiologic healing may provide insight into the failure of programmed peripheral nerve regeneration after injury.

Undifferentiated Nonrhabdomyosarcoma Soft Tissue Sarcoma of the Orbit.

A 6-month-old boy presented with recurrent, poorly differentiated orbital sarcoma diagnosed as nonrhabdomyosarcoma soft tissue sarcoma, as pathologic and immunohistochemical evaluation was inconsistent with rhabdomyosarcoma or other specific sarcoma subtypes. He responded favorably to a treatment regimen for poorly differentiated sarcomas.

Adjuvant radiotherapy for atypical meningiomas.

OBJECTIVE The aim of this paper was to evaluate outcomes in patients with atypical meningiomas (AMs) treated with surgery alone compared with surgery and radiotherapy at initial diagnosis, or at the time of first recurrence. METHODS Patients with pathologically confirmed AMs treated at the University of Utah from 1991 to 2014 were retrospectively reviewed. Local control (LC), overall survival (OS), Karnofsky Performance Status (KPS), and toxicity were assessed. Outcomes for patients receiving adjuvant radiotherapy were compared with those for patients treated with surgery alone. Kaplan-Meier and the log-rank test for significance were used for LC and OS analyses. RESULTS Fifty-nine patients with 63 tumors were reviewed. Fifty-two patients were alive at the time of analysis with a median follow-up of 42 months. LC for all tumors was 57% with a median time to local failure (TTLF) of 48 months. The median TTLF following surgery and radiotherapy was 180 months, compared with 46 months following surgery alone (p = 0.02). Excluding Simpson Grade IV (subtotal) resections, there remained an LC benefit with the addition of radiotherapy for Simpson Grade I, II, and III resected tumors (median TTLF 180 months after surgery and radiotherapy compared with 46 months with surgery alone [p = 0.002]). Patients treated at first recurrence following any initial therapy (either surgery alone or surgery and adjuvant radiotherapy) had a median TTLF of 26 months compared with 48 months for tumors treated at first diagnosis (p = 0.007). There were 2 Grade 3 toxicities and 1 Grade 4 toxicity associated with radiotherapy. CONCLUSIONS Adjuvant radiotherapy improves LC for AMs. The addition of adjuvant radiotherapy following even a Simpson Grade I, II, or III resection was found to confer an LC benefit. Recurrent disease is difficult to control, underscoring the importance of aggressive initial treatment.

Dramatic radiographic response resulting in cerebrospinal fluid rhinorrhea associated with sunitinib therapy in recurrent atypical meningioma: case report.

Sunitinib is a multiple tyrosine kinase inhibitor with antiangiogenic, cytostatic, and antimigratory activity for meningiomas. A recent clinical trial of sunitinib for treatment of recurrent Grade II and III meningiomas suggested potential efficacy in this population, but only 2 patients exhibited significant radiographic response with tumor volume reduction. The authors illustrate another such case and discuss a complication related to this dramatic tumor volume reduction in aggressive skull base meningiomas. The authors describe the case of a 39-year-old woman who had undergone repeat surgical interventions and courses of radiotherapy over the previous 11 years for recurrent cranial and spinal meningiomas. Despite 4 operations over the course of 4 years on her right petroclival meningioma with cavernous sinus and jugular fossa extensions, she had progressive neurological deficits and tumor recurrences. The specimen histology progressed from WHO Grade I initially to Grade II at the time of the third recurrence. The lesion was then irradiated 3 times using stereotactic radiosurgery for further recurrences. More recently, the tumor size increased rapidly on imaging, in association with progressive neurological symptoms arising from brainstem compression and vasogenic edema. Institution of sunitinib therapy yielded a dramatic radiographic response, with marked reduction in the tumor volume and reduction of brainstem vasogenic edema within a few weeks of initiation of treatment. The significant radiographic response of tumor in the clival region was also associated with CSF rhinorrhea from a dural breach created by resolution of the invasive skull base meningioma, which necessitated withholding the sunitinib medication. To address the leak, the authors undertook surgical exploration and transsphenoidal packing using an autologous fat graft and a vascularized pedicled nasoseptal flap. The patient has done well during follow-up of 3 months after packing, with no evidence of recurrent CSF leak, and the medication was subsequently restarted. Prior clinical data and the dramatic radiographic response in this patient suggest that sunitinib holds promising therapeutic potential in carefully selected patients with recurrent atypical meningiomas where conventional strategies have been exhausted. There is a potential risk of associated CSF rhinorrhea, especially in more invasive skull base lesions showing dramatic radiographic response.

Hypothalamic-Optochiasmatic Pilocytic Astrocytoma Associated with Occipital and Sacral Spinal Cavernomas: A Mere Coincidence or a True Association?

BACKGROUND: The co-occurrence of cerebral gliomas and cavernous angiomas is rarely encountered in clinical practice. All reported cases with such association have occurred within the brain with none involving the spinal cord. CASE DESCRIPTION: The authors report the case of a hypothalamic-optochiasmatic pilocytic astrocytoma coexisting with right occipital and sacral spinal cavernomas. This 30-year-old man had an 8-year history of chronic lower back pain. Spinal magnetic resonance imaging (MRI) demonstrated an 8.2-cm expansile multilobulated heterogeneously enhancing intradural mass within the sacral spinal canal, extending into the bilateral S1 and left S2 foramina. Brain MRI depicted a 2.9-cm lobulated heterogeneously enhancing sellar-suprasellar solid and cystic mass expanding the sella and displacing the infundibulum to the right, with a normal-appearing pituitary gland inside the sella, and an extensive supratentorial and infratentorial superficial hemosiderosis. L5-S4 laminectomy and pterional craniotomy were performed for the resection of these lesions. Histopathologic examination revealed a sacral spinal cavernoma and a suprasellar hypothalamic-optochiasmatic pilocytic astrocytoma. CONCLUSION: The coexistence of hypothalamic-optochiasmatic pilocytic astrocytoma and occipital and sacral spinal cavernomas has not been reported previously. Especially for radiologically atypical suprasellar lesions, hypothalamic-optochiasmatic glioma should be included in the differential diagnosis of masses that can expand the sella. Besides previously postulated hypotheses of viral-induced or angiogenic factor-induced glial growth, we hypothesize that neoplastic origins of hypothalamic-optochiasmatic glioma might be due to the irritative mechanisms resulting from the frequent bleeds occurring from the spinal or cranial cavernoma.