Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK.

Mutations in the TNF family of proteins have been associated with inherited forms of immune deficiency. Using an array-based sequencing assay, we identified an autosomal-dominant deficiency in TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) in a kindred with recurrent infection and impaired antibody responses to protein and polysaccharide vaccines. This mutation occurs in the sixth exon of TWEAK and results in the amino acid substitution R145C within the conserved TNF-homology domain of the full-length protein. TWEAK mutant protein formed high molecular weight aggregates under nonreducing conditions, suggesting an increased propensity for intermolecular interactions. As a result, mutant TWEAK associated with B-cell-activating factor (BAFF) protein and down-regulated the BAFF-mediated activation of the noncanonical NF-κB pathway through inhibition of p100 processing to p52, resulting in inhibition of BAFF-dependent B-cell survival and proliferation. As BAFF mediates T-cell-independent isotype switching and B-cell survival, our data implicate TWEAK as a disease-susceptibility gene for a humoral immunodeficiency.

Juvenile granulosa cell tumor in an adult woman during pregnancy: A case report and review of the literature.

Objective: To report a case of stage IIIB juvenile granulosa cell tumor (JGCT) complicating pregnancy in a 33 year-old (y.o.) woman. Methods: Retrospective review of the clinical data, imaging studies, and pathology reports of a case of JGCT diagnosed during pregnancy. Patient consent was obtained for review and presentation of the case. A literature review was conducted. Results: A 33 y.o., gravida 3, para 1 was incidentally found to have an 8 cm left ovarian mass on an anatomy scan at 22 weeks gestation. Four days later, she presented to labor and delivery triage with abdominal pain. An ultrasound revealed an 11 cm heterogeneous, solid mass in the left adnexa and free fluid at this level. The diagnosis of degenerating fibroid was made based on her clinical presentation and she was discharged. A follow up outpatient MRI revealed a 15 cm left ovarian mass consistent with a primary malignant ovarian neoplasm with moderate ascites and omental, left cul de sac, and probable paracolic gutter implantation. She re-presented 2 weeks later with an acute abdomen and was admitted for a gynecologic oncology consult. Pre-op tumor markers showed an elevated inhibin B. She underwent an exploratory laparotomy, left salpingo-oophorectomy, omental biopsy, and small bowel resection at 25 weeks gestation. Intra-op findings included a ruptured tumor and metastases. Tumor reductive surgery was completed to R0. Pathology revealed a JGCT, FIGO stage IIIB. The pathology and management were reviewed in collaboration with an outside institution. Chemotherapy was delayed until after delivery with monthly MRI surveillance. She underwent induction of labor at 37 weeks followed by an uncomplicated vaginal delivery. She received 3 cycles of bleomycin, etoposide, and cisplatin starting six weeks postpartum. Last known contact was over five years after the initial diagnosis with no evidence of recurrent disease. Conclusion: JGCTs account for 5% of granulosa cell tumors and 3% are diagnosed after age 30. JGCT is an uncommon neoplasm in pregnancy. 90% are stage I at diagnosis, but advanced stage tumors are aggressive often resulting in recurrence or death within 3 years of diagnosis. We present a surgically treated case with delay in chemotherapy until after delivery with a good outcome after 5 years of follow up.

CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome.

X-linked hyper-IgM syndrome (XHM) is a combined immune deficiency disorder caused by mutations in CD40 ligand. We tested CP-870,893, a human CD40 agonist monoclonal antibody, in the treatment of two XHM patients with biliary Cryptosporidiosis. CP-870,893 activated B cells and APCs in vitro, restoring class switch recombination in XHM B cells and inducing cytokine secretion by monocytes. CP-870,893 infusions were well tolerated and showed significant activity in vivo, decreasing leukocyte concentration in peripheral blood. Although specific antibody responses were lacking, frequent dosing in one subject primed T cells to secrete IFN-g and suppressed oocyst shedding in the stool. Nevertheless, relapse occurred after discontinuation of therapy. The CD40 receptor was rapidly internalized following binding with CP-870,893, potentially explaining the limited capacity of CP-870,893 to mediate immune reconstitution. This study demonstrates that CP-870,893 suppressed oocysts shedding in XHM patients with biliary cryptosporidiosis. The continued study of CD40 agonists in XHM is warranted.

Utility of ultrasound and MRI in prenatal diagnosis of placenta accreta: a pilot study.

OBJECTIVE: The purpose of this study was to evaluate transabdominal pelvic ultrasound and MRI for the prenatal diagnosis of placenta accreta. MATERIALS AND METHODS: A historical cohort pilot study was performed at our institution to identify women at risk of placenta accreta who had undergone both prenatal ultrasound and MRI. Findings at ultrasound and MRI were compared with the final diagnosis, which was established with clinical findings at delivery and pathologic examination of specimens. Volume measurements were made of low-signal-intensity intraplacental bands on T2-weighted MR images. Risk factors for placental insufficiency were recorded. RESULTS: Thirteen patients at risk of placenta accreta underwent both sonography and MRI. Nine of these patients had abnormal placentation. With ultrasound, abnormal placentation was correctly identified in six of nine patients (67%) and the absence of accreta in two of four patients (50%). With MRI, abnormal placentation was correctly identified in seven of nine patients (78%) and the absence of accreta in three of four patients (75%). The volumes of low-signal-intensity bands were significantly different in the patients with abnormal placentation and those without placenta accreta (p = 0.047), and band volumes were significantly different among patients with accreta, increta, and percreta (p < 0.0005). CONCLUSION: The accuracy of MRI may improve if volumes of low-signal-intensity bands are calculated, MRI is performed before 30 weeks' gestation, and risk factors for placental insufficiency are recognized.

Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrent-only epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to first-line platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor (VEGF): A Gynecologic Oncology Group Study.

PURPOSE: To compare progression-free survival (PFS), overall survival (OS) and toxicities of thalidomide versus tamoxifen and to evaluate serum vascular endothelial growth factor (VEGF) in biochemical-recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube carcinoma (EOC/PPC/FTC). METHODS: Biochemical recurrence was defined as a rising CA-125 exceeding twice the upper limit of normal without evidence of disease as defined by RECIST 1.0 criteria. Women with FIGO stages III and IV, histologically confirmed EOC/PPC/FTC who were free of disease following first-line chemotherapy were randomized to oral thalidomide 200mg daily with escalation to a maximum of 400 mg or tamoxifen 20mg orally twice daily for up to 1 year, progression or adverse effect prohibited further treatment. VEGF was quantified by ELISA in pre and post-treatment serum. RESULTS: Of the 139 women randomized, 138 were eligible. Interim analysis showed that thalidomide did not reduce the recurrence rate relative to tamoxifen, and the trial was closed. Thalidomide versus tamoxifen was associated with a similar risk of progression (HR = 1.31, 95% confidence interval [CI] = 0.93-1.85), an increased risk of death (HR = 1.76, 95% CI = 1.16-2.68) and more grades 3 and 4 toxicities (55% versus 3%). The most common grades 3 and 4 toxicities were constitutional (12%), somnolence (12%), pulmonary (9%), venous thromboembolism (VTE) (6%) and peripheral neurologic (6%) for thalidomide, with VTE (1.4%) and gastrointestinal (1.4%) for tamoxifen. Serum VEGF was not associated with clinical characteristics, treatment, PFS or OS. CONCLUSION: Thalidomide was not more effective than tamoxifen in delaying recurrence or death but was more toxic. VEGF was not prognostic in this cohort.

Canine prostate: contrast-enhanced US-guided radiofrequency ablation with urethral and neurovascular cooling--initial experience.

PURPOSE: To prospectively evaluate in a canine model contrast material-enhanced ultrasonography (US) for guiding and monitoring radiofrequency (RF) ablation of the entire prostate, with urethral and vascular cooling to protect the surrounding structures. MATERIALS AND METHODS: After approval by the institutional animal use and care committee, an RF electrode was used to ablate the entire prostate in 15 dogs. During ablation, pulse-inversion harmonic US was performed by using an endocavitary probe after an intravenous bolus injection (0.04 mL/kg) and infusion (0.015 muL/kg/min) of a US contrast agent. In group 1 (n = 4), no cooling protection was used during ablation. In group 2 (n = 5), urethral and bladder protection was provided by inserting a 12-F catheter infused with cold saline (8 degrees C +/- 4 [standard deviation]) at a rate of 100 mL/min. In group 3 (n = 6), further protection of the neurovascular bundles (NVBs) was provided by infusing cold saline (8 degrees C +/- 4) into the iliac arteries at a rate of 50 mL/min by means of catheterization of the femoral artery. Pathologic findings among the three groups were compared by using the Wilcoxon rank sum test. RESULTS: The average volumes of prostate ablation achieved in the three groups were 96.6%, 91.9%, and 92%. Contrast-enhanced pulse-inversion harmonic US allowed visualization and monitoring of urethral and NVB blood flow during the ablation. Without protection, damage to the urethra and the NVB was demonstrated at both US and pathologic examination. There was highly significant difference in urethral damage between groups with and the group without urethral cooling (P = .002), while intraarterial cooling demonstrated a nonsignificant trend toward a decreased NVB damage (P = .069). CONCLUSION: Contrast-enhanced US can guide RF ablation of the entire prostate. Infusion of cold saline provides effective protection for the urethra during such procedures. The application of intraarterial cooling did not provide a significant improvement in the protection of the NVB in this small study.

Ovarian preservation in stage I low-grade endometrial stromal sarcomas.

OBJECTIVE: To examine the impact of ovarian preservation in a case-control study of women with stage I low-grade endometrial stromal sarcomas. METHODS: Patients with low-grade endometrial stromal sarcomas were identified at 5 institutions from 1976 to 2002. Cases were defined as patients who retained ovarian function; each case was matched to 2 control patients who underwent bilateral salpingo-oophorectomy (BSO). Immunostaining for estrogen and progesterone receptors was performed. Data were examined with Student t, chi(2), Cox regression, and Kaplan-Meier analyses. RESULTS: Twelve premenopausal patients with low-grade endometrial stromal sarcomas who did not undergo BSO were matched to 24 controls. Of the 36 patients in the entire cohort, disease recurred in 14 (39%). Recurrences were identified in the pelvis, abdomen, lung, or lymphatics in both cases and controls. Disease recurred in 4/12 (33%) case patients, compared with 10/24 (42%) control patients (P = .63). When case patients were compared with controls, no differences in progression-free (91.3 months versus 68.6 months, P = .44) or overall survival (median survival not yet reached versus 406 months, P = .82) were identified. This study had 13% power to detect the observed difference in median disease-free survival. After controlling for use of adjuvant therapy and BSO, older age remained the only independent poor prognostic factor for progression-free survival (P = .008). Twenty-two available tumors demonstrated positivity for both estrogen and progesterone receptors. CONCLUSION: Bilateral salpingo-oophorectomy did not appear to affect time to recurrence or overall survival. Retention of ovarian function may be an option for premenopausal women with low-grade endometrial stromal sarcomas.

Quantitative computed tomography perfusion of prostate cancer: correlation with whole-mount pathology.

PURPOSE: Microvessel density within the prostate is associated with presence of cancer, disease stage, and disease-specific survival. We evaluated multidetector computed tomography (CT) to estimate prostate perfusion and localize prostate cancer. PATIENTS AND METHODS: Ten subjects were evaluated with contrast enhanced CT before radical prostatectomy with the Mx8000IDT 16-slice scanner. Following baseline pelvic scan, 100 cc of Optiray 300 was administered intravenously (4 cc per second). Repeated dynamic scans through the prostate were obtained at 20, 30, 40, 50, and 60 seconds following initiation of contrast injection. Computed tomography perfusion was compared with pathologic findings of Gleason score and tumor volume on whole-mount prostatectomy specimens. RESULTS: Conventional adenocarcinoma (Gleason score, 6-10) was present in all subjects, including one who also demonstrated a mucinous variant of prostate cancer. Visible focal CT enhancement was noted in 1 patient with a high-volume tumor and a Gleason score of 10. A positive correlation between local estimates of CT perfusion and percent of prostate volume occupied by tumor in each sextant was found for half of the subjects (Pearson correlation coefficient, 0.3-0.95; mean, 0.48) but statistically significant correlation (P < 0.05; Pearson coefficient, 0.9-0.95) was present in only the 2 subjects with the highest Gleason scores (8 and 10) and the highest tumor volume (> or = 50% in > or = 1 sextant region). CONCLUSION: Visible enhancement of prostate cancer during dynamic CT is present in a minority of subjects. Correlation between quantitative CT perfusion and tumor location is statistically significant only in subjects with localized high-volume, poorly differentiated prostate cancer.

Loss of WWOX expression in gastric carcinoma.

PURPOSE: WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene that maps to the common fragile site FRA16D on chromosome 16q23.3-24.1. To investigate the role of the WWOX gene in the development of gastric carcinoma, we examined a large series of primary adenocarcinomas and nine gastric cancer cell lines for the expression of Wwox. EXPERIMENTAL DESIGN: Loss of heterozygosity, reverse-transcription-PCR, and immunohistochemistry were used to assess the role of WWOX in stomach cancer. A total of 81 primary gastric adenocarcinoma were analyzed. RESULTS: Loss of heterozygosity was observed in 31% of the cases and loss of Wwox protein expression was found in 65% of gastric adenocarcinoma primary specimens and 33% of gastric cancer cell lines. In addition, we found a high correlation between Wwox and Fhit protein expression. CONCLUSIONS: Our results indicate that alterations of the WWOX gene may be involved quite frequently in gastric tumorigenesis. Our data could be used in future studies to develop diagnostic and targeted therapy of stomach cancer.

Primary renal sclerosing epithelioid fibrosarcoma: report of 2 cases with EWSR1-CREB3L1 gene fusion.

We report the first 2 genetically confirmed cases of primary renal sclerosing epithelioid fibrosarcoma (SEF), occurring in a 17-year-old boy and a 61-year-old woman. In both cases, the tumors demonstrated the typical epithelioid clear cell morphology associated with extensive hyalinizing fibrosis, raising the differential diagnosis of solitary fibrous tumor, metanephric stromal tumor, and the sclerosing variant of clear cell sarcoma of the kidney. Both neoplasms demonstrated diffuse immunoreactivity for MUC4, a highly specific marker for SEF, and both demonstrated evidence of rearrangement of both the EWSR1 and CREB3L1 genes, which have recently been shown to be fused in this entity. Both neoplasms presented with metastatic disease. Primary renal SEF represents yet another translocation-associated sarcoma now shown to arise primarily in the kidney.

Adjacent parenchymal abnormalities in peripheral bronchogenic carcinoma: correlation of thin-section CT with histology.

Our purpose is to correlate thin section CT of peripheral bronchogenic carcinomas with histologically detected lymphatic or vascular invasion. Retrospective 3-year database search revealed 186 surgical resections for primary bronchogenic carcinoma, of which 58 had available preoperative imaging performed at our institution. Cases with prior surgery, nonconfirmatory pathology, remote imaging, or central location were excluded, resulting in a study population of 42 patients, 25 men, 17 women, with a mean age of 69 years. Imaging with 1-3 mm collimation was performed within a mean of 32 days prior to surgery. Histologic diagnoses included adenocarcinoma (n = 24, 57%), squamous cell carcinoma (n = 13, 31%), large cell carcinoma (n = 4, 10%), and small cell carcinoma (n = 1, 2%), with a mean tumor size of 27 mm. Three radiologists blindly and independently recorded bronchovascular thickening, septal and nonseptal opacities, and the extent of each beyond tumor margins: 1) <5 mm, 2) 5-10 mm, and 3) >10 mm. Lymphangio-invasion was correlated with imaging findings, tumor size, and histology. Adjacent parenchymal abnormalities were recorded in 40 (95%) of 42 masses, with isolated nonseptal opacities representing the most frequent abnormality in 21 (50%), followed by bronchovascular thickening in 16 (38%), and septal opacities in 12 (29%). Lymphangio-invasion was present in 16 (38%) of cases. The frequency of lymphangio-invasion was highest (53%) in cases with 2 or more positive findings, and extension beyond 10mm from the tumor margin. This trend did not achieve statistical significance by ROC analysis. Lymphangio-invasion was positively correlated with tumor size, P =.03, but not histology.In conclusion, parenchymal abnormalities beyond tumor margins shown by CT may be due to lymphangio-invasion but imaging findings did not reliably distinguish cases with and without lymphangio-invasion.

Vascular endothelial growth factor (VEGF) expression in locally advanced prostate cancer: secondary analysis of radiation therapy oncology group (RTOG) 8610.

BACKGROUND: Angiogenesis is a key element in solid-tumor growth, invasion, and metastasis. VEGF is among the most potent angiogenic factor thus far detected. The aim of the present study is to explore the potential of VEGF (also known as VEGF-A) as a prognostic and predictive biomarker among men with locally advanced prostate cancer. METHODS: The analysis was performed using patients enrolled on RTOG 8610, a phase III randomized control trial of radiation therapy alone (Arm 1) versus short-term neoadjuvant and concurrent androgen deprivation and radiation therapy (Arm 2) in men with locally advanced prostate carcinoma. Tissue samples were obtained from the RTOG tissue repository. Hematoxylin and eosin slides were reviewed, and paraffin blocks were immunohistochemically stained for VEGF expression and graded by Intensity score (0-3). Cox or Fine and Gray's proportional hazards models were used. RESULTS: Sufficient pathologic material was available from 103 (23%) of the 456 analyzable patients enrolled in the RTOG 8610 study. There were no statistically significant differences in the pre-treatment characteristics between the patient groups with and without VEGF intensity data. Median follow-up for all surviving patients with VEGF intensity data is 12.2 years. Univariate and multivariate analyses demonstrated no statistically significant correlation between the intensity of VEGF expression and overall survival, distant metastasis, local progression, disease-free survival, or biochemical failure. VEGF expression was also not statistically significantly associated with any of the endpoints when analyzed by treatment arm. CONCLUSIONS: This study revealed no statistically significant prognostic or predictive value of VEGF expression for locally advanced prostate cancer. This analysis is among one of the largest sample bases with long-term follow-up in a well-characterized patient population. There is an urgent need to establish multidisciplinary initiatives for coordinating further research in the area of human prostate cancer biomarkers.

Adrenocortical Carcinoma: Complete Surgical Resection After 18 Years.

Adrenal cortical carcinoma (ACC) is a rare neoplasm often associated with an aggressive biological behavior. Complete surgical resection is the mainstay of therapy for ACC and offers the best chance for prolonged disease-free survival. We present an unusual case of a long-standing adrenal mass, well documented over a period of at least 18 years, without the development of metastatic disease, and ultimately proven to represent ACC after successful surgical resection. Physicians should be aware that ACC can present with a wide spectrum of biological behavior, from very aggressive to more indolent disease.

Cryptococcosis of the upper genital tract.

Upper genital tract infection by Cryptococcus neoformans has not previously been reported. We describe such a case, in order to alert clinicians to the existence of this rare infection. A 34-year-old woman with AIDS presented with chronic menorrhagia, fever, anemia, and thrombocytopenia. Despite blood transfusions and hormonal therapy, her vaginal bleeding could not be controlled and she became hemodynamically unstable. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed, at which time granulomatous peritonitis and prominent myometrial blood vessels were found. Histologic examination revealed cryptococcal infection of all upper genital organs. This case demonstrates that disseminated cryptococcosis may involve the upper genital tract in women, and may be associated with profuse vaginal bleeding.

Contrast enhanced ultrasound for radio frequency ablation of canine prostates: initial results.

PURPOSE: We determined the feasibility of contrast enhanced ultrasound for radio frequency ablation of the entire prostate as a method of minimally invasive treatment for prostate cancer in a canine model. MATERIALS AND METHODS: Approval of the Institutional Animal Use and Care committee was obtained. Initially 5 dogs (group 1) were tested using variable power (5 to 30 W), time (4 to 12 minutes), bolus (0.01 to 0.04 ml/kg) and infusion (3 to 11 ml per minute at 0.015 microl/kg) injections of an ultrasound contrast agent with conventional grayscale power Doppler and pulse inversion harmonic imaging to establish optimal parameters. Subsequently 4 dogs (group 2) underwent entire prostate ablation using parameters based on group 1. The size of the thermal lesions and residual viable tissue was measured with ImageJ software (National Institutes of Health, Bethesda, Maryland) on ultrasound and pathological study. Linear regression and Student's t test were used for statistical analysis. RESULTS: A bolus of 0.04 ml/kg, an infusion of 11 ml per minute at 0.015 microl/kg and the contrast enhanced pulse inversion harmonic imaging mode were ranked best for guiding ablation. Thermal lesion volume was proportional to ablation power and time. There was no significant difference in measured thermal lesion size in group 1 between ultrasound and pathological findings (mean +/- SD 1.51 +/- 0.74 and 1.46 +/- 0.74 cm3, p = 0.56) or in residual viable tissue in group 2 (0.43 +/- 0.043 and 0.41 +/- 0.291 cm3, p = 0.21). The average volume of prostate ablation achieved in group 2 was 96.3%. CONCLUSIONS: Contrast enhanced pulse inversion harmonic imaging is able to guide, monitor and control radio frequency ablation of the entire prostate.

Atypical polypoid adenomyoma mimicking cervical adenocarcinoma.

Atypical polypoid adenomyoma (APA) of the uterus is a rare, benign lesion. Histologically, it is composed of a glandular and squamous cell proliferation with architectural complexity and cytologic atypia of glands, and a hypercellular smooth muscle stroma. APA is difficult to distinguish from well-differentiated adenocarcinoma of the uterus. In the case presented, the diagnosis of APA was confused pathologically, radiographically, and clinically with a cervical adenocarcinoma. A review of the English literature is presented.

Evaluation of colposcopically directed cervical biopsies yielding a histologic diagnosis of CIN 1,2.

OBJECTIVE: To determine the prognostic value of the diagnostic category CIN 1,2. MATERIALS AND METHODS: Computerized pathology records of patients with CIN 1,2 at colposcopically directed biopsy followed by treatment with excision were examined, and we compared the diagnostic biopsy with the final tissue diagnosis. Two pathologists who were blinded to the final diagnosis reviewed the original biopsies independently. The ability of the referee pathologist to predict CIN 2 or 3 lesions and interobserver consistency are described. RESULTS: Sixty-nine cases of biopsies with CIN 1,2 were reviewed. Nineteen of these patients were lost to follow-up. Of the 46 cases with either an excisional biopsy or hysterectomy, 12 cases (26.1%) demonstrated CIN 2 or greater. Pathologist A and B correctly predicted the high-grade lesions in 66.7% and 58.3% of cases reviewed. Pathologist A and B agreed with each other in 33 of the 46 cases (71.1%). CONCLUSIONS: 1) CIN 1,2 on a colposcopic biopsy is associated with a high-grade lesion in 26.1% of the cases. 2) Experienced gynecologic pathologists can identify these high-grade lesions on review in only two thirds of the cases. 3) CIN 1,2 is a useful diagnostic category to prevent undertreatment.