Study protocol for a prospective, multi-centered randomized controlled trial comparing pelvic fascia-sparing radical prostatectomy with conventional robotic-assisted prostatectomy: The PARTIAL trial.

BACKGROUND: Pelvic fascia-sparing robotic-assisted radical prostatectomy (PFS-RARP) is a novel approach that spares the endopelvic fascia ventral to the prostate. The preservation of more native structures compared to conventional robotic-assisted radical prostatectomy (RARP) may lead to faster recovery of urinary function, fewer penile changes, and decreased inguinal hernia sequelae, but may have a higher risk for positive surgical margins and poorer cancer control. However, high-level evidence is absent. The PARTIAL trial is a surgical randomized controlled trial (RCT) aiming to bridge this evidence gap (NCT05155501). METHODS: We describe a prospective RCT with a projected enrollment of 600 men randomized to PFS-RARP vs. RARP. The primary outcome is cancer control (positive surgical margins and prostate-specific antigen failure) and secondary outcomes include health-related quality of life pertaining to urinary and sexual function, decision regret, and adverse events (30-day complications, inguinal hernias, penile shortening, and Peyronie's disease). The anticipated duration of trial participation is 24 months. Study participation is incentivized with the use of innovative methodologies such as a novel, two-stage informed consent and a validated web-based interface to monitor patient-reported symptoms and empower individuals to improve their recovery. CONCLUSION: If PFS-RARP is non-inferior to RARP in terms of cancer control and has better functional outcomes, it should be the surgical standard of care for men with localized prostate cancer. Using the innovative two-stage consent process, completion of the trial will not only provide much needed evidence on one of the most common cancer surgeries but also insight on improving surgical RCT methodology. Trial status This trial is registered at ClinicalTrials.gov (NCT05155501; first posted on December 13, 2021); Institutional approval number: WCM IRB # 21-07023781, BRANY's initial approval event ID # 186333. The trial is not yet recruiting.

IgG4-Related Appendiceal Disease: A First Case Report Fulfilling All Pathological Diagnostic Criteria and With Concomitant S100-Positive Dendritic/Schwann Cell Hyperplasia.

IgG4-related disease is a recent entity that has been described in a wide variety of organ systems. A 46-year-old female presented with acute appendicitis accompanied by a mass-forming lesion, raising a concern for neoplasm, and therefore, hemicolectomy was performed. The lesion revealed a dense lymphoplasmacytic infiltrate accompanied by storiform fibrosis and obliterative phlebitis. The IgG4/IgG plasma cell ratio was >50%, and the number of IgG4-positive plasma cells was >100/high-power field. In order to assess the IgG4/IgG plasma cell ratio, MUM1 was employed instead of IgG to successfully estimate the plasma cell concentration. There was also a concomitant hyperplasia of S100-positive cell, which could represent dendritic or Schwannian origin and possibly play a pathophysiologic role. The hyperplasia was significant by itself that it may mimic a mass-forming lesion. This newly described entity of the past decade deserves increased recognition due to clinical implication and surgical morbidity. This is the first case of IgG4-related disease in the appendix to our knowledge that fully satisfied all the pathological diagnostic criteria. We would like to also highlight our innovative approach of evaluating the IgG4/IgG plasma cell.

A misleading frozen section in a lacrimal gland pleomorphic adenoma of a nine-year-old.

INTRODUCTION: Benign pleomorphic adenomas of the lacrimal gland usually present as a painless, slow growing mass in healthy adults and rarely present in childhood. This report describes a pediatric patient found to have a lacrimal gland pleomorphic adenoma that mimicked rhabdomyosarcoma on frozen section. REPORT: A nine-year-old African American male presented with two months of unilateral proptosis and was found to have a left orbital mass on computed topography. Through a lateral orbitotomy, the mass was excised, but noted to appear distinct from the lacrimal gland. An intraoperative frozen section demonstrated a myxoid matrix with scattered cells mimicking rhabdomyoblasts. Because this sample lacked additional elements, the diagnosis of rhabdomyosarcoma could not be excluded, especially considering the patient's age, short time course of symptoms, and the tumor's intraoperative appearance. Permanent sections of the whole lesion provided definitive diagnosis. CONCLUSIONS: In the rare pediatric presentations, pleomorphic adenomas of the lacrimal gland can be difficult to quickly and definitively differentiate from a rhabdomyosarcoma. The unusual age of presentation and the misleading frozen section appearance in this case demonstrate the intricacies of managing pediatric orbital tumors and highlight the importance of permanent sections for definitive diagnosis.

Five fraction image-guided radiosurgery for primary and recurrent meningiomas.

PURPOSE: Benign tumors that arise from the meninges can be difficult to treat due to their potentially large size and proximity to critical structures such as cranial nerves and sinuses. Single fraction radiosurgery may increase the risk of symptomatic peritumoral edema. In this study, we report our results on the efficacy and safety of five fraction image-guided radiosurgery for benign meningiomas. MATERIALS/METHODS: Clinical and radiographic data from 38 patients treated with five fraction radiosurgery were reviewed retrospectively. Mean tumor volume was 3.83 mm(3) (range, 1.08-20.79 mm(3)). Radiation was delivered using the CyberKnife, a frameless robotic image-guided radiosurgery system with a median total dose of 25 Gy (range, 25-35 Gy). RESULTS: The median follow-up was 20 months. Acute toxicity was minimal with eight patients (21%) requiring a short course of steroids for headache at the end of treatment. Pre-treatment neurological symptoms were present in 24 patients (63.2%). Post treatment, neurological symptoms resolved completely in 14 patients (58.3%), and were persistent in eight patients (33.3%). There were no local failures, 24 tumors remained stable (64%) and 14 regressed (36%). Pre-treatment peritumoral edema was observed in five patients (13.2%). Post-treatment asymptomatic peritumoral edema developed in five additional patients (13.2%). On multivariate analysis, pre-treatment peritumoral edema and location adjacent to a large vein were significant risk factors for radiographic post-treatment edema (p = 0.001 and p = 0.026 respectively). CONCLUSION: These results suggest that five fraction image-guided radiosurgery is well tolerated with a response rate for neurologic symptoms that is similar to other standard treatment options. Rates of peritumoral edema and new cranial nerve deficits following five fraction radiosurgery were low. Longer follow-up is required to validate the safety and long-term effectiveness of this treatment approach.

Histopathologic effects of hypofractionated robotic radiation therapy on malignant and benign prostate tissue.

We describe the first histopathologic analysis of prostatic tissue following hypofractionated robotic radiation therapy. A 66 year-old man presented with stage II, low risk adenocarcinoma of the prostate and underwent elective conformal hypofractionated radiation therapy. His pretreatment evaluation revealed T1c adenocarcinoma, Gleason's grade 3 + 3 = 6 and a prostate specific antigen (PSA) level of 4.87 ng/ml. Hypofractionated radiation therapy (37.5 Gy in five daily fractions of 7.5 Gy) was completed on an Internal Review Board approved protocol. One year later, he developed progressive urinary retention. Transurethral prostatic resection was performed to alleviate obstructive symptoms. Bilobar hypertrophy was observed without evidence of stricture. Histolopathologic analyses of resected prostate tissues revealed changes consistent with radiation treatment, including cellular changes, inflammation, glandular atrophy and hyperplasia. There was no evidence of residual cancer, fibrosis or necrosis. The patient's postoperative course was uneventful with post-treatment PSA of 0.5 ng/ml and residual grade 1 stress incontinence.

Increased inhibitor of differentiation 4 (id4) expression in glioblastoma: a tissue microarray study.

BACKGROUND: The inhibitor of differentiation/DNA binding protein family (Id1-4) is involved in cell cycle control, tumorigenesis and angiogenesis through the negative regulation of helix-loop-helix transcription factors. Of these proteins, Id4 is known to play an important role in neural stem cell differentiation, and deregulation has been implicated in glial neoplasia. However, the expression and significance of Id4 in astrocytomas has not been fully addressed. Herein we report the differential expression of Id4 in astrocytomas of various grades using tissue microarrays (TMA) and immunohistochemistry (IHC). DESIGN: The GBM TMA was constructed from 53 archival cases at Georgetown University Hospital and a TMA with normal brain controls and grades II-III astrocytoma was obtained from Cybrdi (Rockville, MD). TMA sections were stained with Id4 antibody and the slides were scored according to the percentage of staining astrocytic nuclei (<9% -, 10-50% +, >51% ++). The Fisher Exact test was used to test for statistical significance. RESULTS: Nuclear staining for Id4 was seen in 73.58% GBMs, 25% grade III, and 12.5% grade II astrocytomas; staining was absent in normal brain tissue. There was a statistically significant difference between GBM and grades II, III astrocytoma (p <0.01). Significant Id4 expression was not detected in normal brain. CONCLUSIONS: Our study confirms the frequent upregulation of Id4 expression in GBM, which lends support to its role in tumorigenesis, possibly in the transformation of low to high-grade astrocytoma (i.e. GBM). Further studies are warranted to determine the precise role of Id4 in glial neoplasia and its potential use in targeted therapy for GBM.

Atypical teratoid rhabdoid tumor (AT/RT) in adults: review of four cases.

Atypical teratoid/rhabdoid (AT/RT) tumor is a rare, highly malignant tumor of the central nervous system (CNS) most commonly found in children less than 5 years of age. Although the vast majority of cases are diagnosed in young children, there have been isolated case reports in adults. Since its histological appearance can be confused with other tumors, especially in adults, separating AT/RT from other neoplasms may be difficult. In many instances, a reliable diagnosis is not possible without demonstrating the lack of nuclear INI1 protein expression by immunohistochemical methods. The patients (three males and one female) ranged in age from 23 to 42 years (mean age, 32 years). Radiographically, two tumors were localized in the right fronto-parietal region, one was frontal and the other was found in the left temporal lobe. Varying degrees of hydrocephalus and heterogeneous enhancement were present on MRI. In all cases, diagnosis during intraoperative consultation and preliminary diagnosis was different from the final diagnosis after immunohistochemical analysis. Immunohistochemical staining showed that the tumor cells were positive for vimentin and reacted variably for keratin, epithelial membrane antigen (EMA), synaptophysin, neurofilament protein, CD34, and smooth muscle actin (SMA). All were negative for GFAP, S-100, desmin and CD99. Three of the four cases lacked nuclear expression of INI1. One patient is alive with no evidence of disease 17 years after the diagnosis. In adult examples of AT/RT, the diagnosis requires a high index of suspicion, with early tissue diagnosis and a low threshold for investigation with INI1 immunohistochemistry to differentiate this entity from other morphologically similar tumors. Although the prognosis is dismal in pediatric population, long term survival is possible in adult AT/RT cases after surgery and adjuvant radiotherapy and chemotherapy.

CD79a is heterogeneously expressed in neoplastic and normal myeloid precursors and megakaryocytes in an antibody clone-dependent manner.

CD79a, a component of the B-cell antigen receptor complex, can also be expressed in certain non-B-cell malignancies. The reported frequency of CD79a expression in acute myeloid leukemias (AML) ranges from 0% to 90%. We evaluated 39 bone marrow biopsy specimens (29 AML and 10 normal cases) using 5 different commercially available anti-CD79a monoclonal antibody (MoAb) clones. Of 7 acute promyelocytic leukemia (APL) cases, 6 (86%) stained for CD79a with clones HM47/A9 (Novocastra, Newcastle Upon Tyne, England) and HM57 (DAKO, Carpinteria, CA) but were negative with clones 11E3 (Novocastra), and JCB117 (DAKO). Half of 6 acute megakaryoblastic leukemia (AMKL) cases and normal megakaryocytes in 14 (67%) of 21 cases were immunoreactive using clone 11D10 (Novocastra). Approximately one third of non-APL/non-AMKL AML and myeloid precursors in normal marrow specimens stained with clones HM57 and 11D10. This heterogeneity of CD79a expression in AML, megakaryocytes, and myeloid precursors is MoAb clone-dependent, likely owing to different epitope detection, and may be of diagnostic usefulness.

Oligodendroglioma with neurocytic differentiation versus atypical extraventricular neurocytoma: a case report of unusual pathologic findings of a spinal cord tumor.

Differentiating oligodendroglioma from extraventricular neurocytoma by conventional light microscopy alone can present a diagnostic challenge. We report pathologic findings of an unusual spinal cord tumor from a 33-year-old male patient which showed hybrid features of oligodendroglioma and extraventricular neurocytoma. Magnetic resonance imaging (MRI) showed an enhancing intramedullary mass in the cervicothoracic region (C7 through T6). Histologic examination revealed a clear cell neoplasm containing ganglion-like cells and calcifications, prompting the differential diagnosis of oligodendroglioma and extraventricular neurocytoma. The immunohistochemical analysis disclosed neural differentiation of the neoplastic cells with strong synaptophysin and neurofilament staining consistent with extraventricular neurocytoma, as well as strong S-100 and glial fibrillary acidic protein (GFAP) expression. Molecular studies with fluorescent in situ hybridization (FISH) revealed chromosome 1p/(partial) 19q deletions, a finding commonly observed in oligodendroglioma. The proliferation index (using antibody MIB1) of the tumor was approximately 30%. The morphologic findings and these results strengthen the hypothesis that these tumors may share a common progenitor cell, which has also been observed by others. Because there are differences in patient management and long-term prognosis, it is important to attempt to distinguish between oligodendroglioma and neurocytoma. This unusual case and similar rare reported cases support the need to reclassify tumors showing pathologic features common to both neurocytoma and oligodendroglioma as a unique entity, while the effort continues to identify the cell of origin.

Chronic idiopathic myelofibrosis terminating in extramedullary anaplastic plasmacytoma.

Chronic idiopathic myelofibrosis (CIMF) is a chronic myeloproliferative disorder (CMPD) with progressive fibrosis and extramedullary hematopoiesis. Similar to other CMPDs, the stem cell in CIMF has the potential to differentiate into myeloid or lymphoid lineages, and thus CIMF can culminate in acute leukemia of myeloid or, rarely, lymphoid lineage. We describe an unusual case of CIMF terminating in extramedullary anaplastic plasmacytoma. The patient was a 61-year-old male with an 11-year history of CIMF. His course was complicated by rapidly growing abdominal and inguinal lymphadenopathy. Lymph node biopsy revealed a diffuse undifferentiated infiltrate in the background of extramedullary hematopoiesis. Flow cytometric and immunohistochemical analysis demonstrated plasma cell-related antigens (CD138, CD38, cytoplasmic kappa light chain), epithelial membrane antigen and CD43 in the tumor cells. The myeloid, B-cell or T-cell markers were negative. A clonal immunoglobulin heavy chain gene rearrangement was identified by polymerase chain reaction. The plasma cell origin was further confirmed by electron microscopic examination, which revealed stacks of rough endoplasmic reticulum. Monoclonal gammopathy may occur in CIMF, and rare cases of simultaneous plasma cell myeloma and CIMF have been reported in the literature. However, to the best of our knowledge, this is the first report of CIMF terminating in extramedullary anaplastic plasmacytoma.

A preliminary transcriptome map of non-small cell lung cancer.

We constructed a genome-wide transcriptome map of non-small cell lung carcinomas based on gene-expression profiles generated by serial analysis of gene expression (SAGE) using primary tumors and bronchial epithelial cells of the lung. Using the human genome working draft and the public databases, 25,135 nonredundant UniGene clusters were mapped onto unambiguous chromosomal positions. Of the 23,056 SAGE tags that appeared more than once among the nine SAGE libraries, 11,156 tags representing 7,097 UniGene clusters were positioned onto chromosomes. A total of 43 and 55 clusters of differentially expressed genes were observed in squamous cell carcinoma and adenocarcinoma, respectively. The number of genes in each cluster ranged from 18 to 78 in squamous cell carcinomas and from 20 to 165 in adenocarcinomas. The size of these clusters varied from 1.8 Mb to 65.5 Mb in squamous cell carcinomas and from 1.6 Mb to 98.1 Mb in adenocarcinomas. Overall, the clusters with genes over-represented in tumors had an average of 3-4-fold increase in gene expression compared with the normal control. In contrast, clusters of genes with reduced expression had about 50-65% of the gene expression level compared with the normal. Examination of clusters identified in squamous cell lung cancer suggested that 9 of 15 clusters with overexpressed genes and 13 of 28 clusters with underexpressed genes were concordant with previously reported cytogenetic, comparative genomic hybridization or loss of heterozygosity studies. Therefore, at least a portion of the gene clusters identified via the transcriptome map most likely represented the transcriptional or genetic alterations occurred in the tumors. Integrating chromosomal mapping information with gene expression profiles may help reveal novel molecular changes associated with human lung cancer.

Somatic VHL gene deletion and point mutation in MEN 2A-associated pheochromocytoma.

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome that includes pheochromocytoma. Germline mutations in RET are responsible for MEN 2 but the precise pathogenetic mechanisms of tumorigenesis are unknown. We have recently identified possible mechanisms of tumor formation in patients with MEN 2A-related pheochromocytoma. Two of nine tumors investigated, however, did not reveal either of these mechanisms. In the present study, we therefore searched for other possible mechanisms underlying the pathogenesis of MEN 2A-related pheochromocytoma. Hereditary pheochromocytoma also occurs in patients with von Hippel-Lindau (VHL) disease, a syndrome consisting of tumors caused by inactivation of the VHL tumor suppressor gene. A subset of sporadic pheochromocytomas have somatic mutations in RET or VHL, suggesting that both genes contribute to pheochromocytoma pathogenesis in a subset of tumors. It is unknown, however, whether VHL gene alterations would be associated with tumorigenesis in hereditary, MEN 2-related pheochromocytoma. We therefore investigated four pheochromocytomas from patients with MEN 2A and RET germline mutations for the presence of allelic deletion and/or somatic mutation of the VHL gene. LOH analysis using the polymorphic markers D3S1038 and D3S1110 that map to the VHL gene locus 3p25/26, revealed evidence for somatic VHL gene deletion in all four MEN 2A-related pheochromocytomas. Mutation analysis of the VHL gene showed frameshift mutations in two tumors and a splice acceptor mutation in one tumor. The remaining tumor did show LOH but not mutation of the VHL gene. These results suggest that somatic genetic alterations of the VHL gene may play a role in the tumorigenesis of some MEN 2A-related pheochromocytomas.