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Objective: To develop MR criteria for grades of chondromalacia patellae and to assess the accuracy of these grades.Design: Fat-suppressed T2-weighted double-echo, fat-suppressed T2-weighted fast spin echo, fat-suppressed T1-weighted, and gradient echo sequences were performed at 1.5 T for the evaluation of chondromalacia. A total of 1000 MR, 200 histologic, and 200 surface locations were graded for chondromalacia and statistically compared.Results: Compared with gross inspection as well as with histology the most accurate sequences were fat-suppressed T2-weighted conventional spin echo and fat suppressed T2-weighted fast spin echo, although the T1-weighted and proton density images also correlated well. The most accurate MR criteria applied to the severe grades of chondromalacia, with less accurate results for lesser grades.Conclusions: This study demonstrates that fat-suppressed routine T2-weighted and fast spin echo T2-weighted sequences seem to be more accurate than proton density, T1-weighted, and gradient echo sequences in grading chondromalacia. Good histologic and macroscopic correlation was seen in more severe grades of chondromalacia, but problems remain for the early grades in all sequences studied. [ABSTRACT FROM AUTHOR]

Objective: Since the thickness of cartilage is an important indicator of the status, progression and response to therapy of articular disorders, assessment of it is desirable. This study was undertaken to assess the accuracy, precision, and reliability of magnetic resonance (MR) measurements of articular cartilage.Methods: Fifteen cadaveric patellas were imaged in the axial plane at 1.5 T. Gradient echo and fat-suppressed FSE, T2-weighted, proton density, and T1-weighted sequences were performed. We measured each 5-mm section separately at three standardized positions, giving a total of 900 measurements. These findings were correlated with independently performed measurements of the corresponding anatomic sections. A hundred random measurements were also evaluated for reproducibility and interobserver variation.Results: Although all sequences were highly accurate (range r = 0.78-0.82), the T1-weighted images were the most accurate, with a mean difference of 0.25 mm and a correlation coefficient of 0.85. All sequences were also highly reproducible (mean difference between -0.09 and 0.05 mm) with little inter-observer variation (mean difference -0.04 and 0.11 mm). In an attempt to improve the accuracy of the MR measurements further, we retrospectively evaluated all measurements with discrepancies greater than 1 mm from the specimen. All these differences were attributable to focal defects causing exaggeration of the thickness on MR imaging.Conclusion: MR imaging is accurate, precise, and reliable as a basis for measuring articular cartilage and may potentially be usable to monitor progression of articular disorders. Care must be taken not to overestimate the thickness of areas with surface defects. [ABSTRACT FROM AUTHOR]

Talimogene Laherparepvec (OncoVEX mGMCSF ), an oncolytic virus, immune checkpoint inhibitor anti-programmed cell death protein 1 (anti-PD1), and BRAF inhibition (BRAFi), are all clinically approved for treatment of melanoma patients and are effective through diverse mechanisms of action. Individually, these therapies also have an effect on the tumor immune microenvironment (TIME). Evaluating the combination effect of these three therapies on the TIME can help determine when combination therapy is most appropriate for further study. In this study, we use a transgenic murine melanoma model (Tyr::CreER; BRAF CA/+ ; PTEN flox/flox ), to evaluate the TIME in response to combinations of BRAFi, anti-PD1, and OncoVEX mGMCSF . We find that mice treated with the triple combination BRAFi + anti-PD1 + OncoVEX mGMCSF have decreased tumor growth compared to BRAFi alone and prolonged survival compared to control. Flow cytometry shows an increase in percent CD8 + /CD3 + cytotoxic T Lymphocytes (CTLs) and a decrease in percent FOXP3 + /CD4 + T regulatory cells (Tregs) in tumors treated with OncoVEX mGMCSF compared to mice not treated with OncoVEX mGMCSF . Immunogenomic analysis at 30d post-treatment shows an increase in Th1 and interferon-related genes in mice receiving OncoVEX mGMCSF  + BRAFi. In summary, treatment with combination BRAFi + anti-PD1 + OncoVEX mGMCSF is more effective than any single treatment in controlling tumor growth, and groups receiving OncoVEX mGMCSF had more tumoral infiltration of CTLs and less intratumoral Tregs in the TIME. This study provides rational basis to combine targeted agents, oncolytic viral therapy, and checkpoint inhibitors in the treatment of melanoma., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: An imaging-based stratification tool is needed to identify melanoma patients who will benefit from anti Programmed Death-1 antibody (anti-PD1). We aimed at identifying biomarkers for survival and response evaluated in lymphoid tissue metabolism in spleen and bone marrow before initiation of therapy., Methods: This retrospective study included 55 patients from two institutions who underwent 18F-FDG PET/CT before anti-PD1. Parameters extracted were SUVmax, SUVmean, HISUV (SUV-based Heterogeneity Index), TMTV (total metabolic tumor volume), TLG (total lesion glycolysis), BLR (Bone marrow-to-Liver SUVmax ratio), and SLR (Spleen-to-Liver SUVmax ratio). Each parameter was dichotomized using the median as a threshold. Association with survival, best overall response (BOR), and transcriptomic analyses (NanoString assay) were evaluated using Cox prediction models, Wilcoxon tests, and Spearman's correlation, respectively., Results: At 20.7 months median follow-up, 33 patients had responded, and 29 patients died. Median PFS and OS were 11.4 (95%CI 2.7-20.2) and 28.5 (95%CI 13.4-43.8) months. TMTV (>25cm 3 ), SLR (>0.77), and BLR (>0.79) correlated with shorter survival. High TMTV (>25 cm3), SLR (>0.77), and BLR (>0.79) correlated with shorter survival, with TMTV (HR PFS 2.2, p = 0.02, and HR OS 2.5, p = 0.02) and BLR (HR OS 2.3, p = 0.04) remaining significant in a multivariable analysis. Low TMTV and TLG correlated with BOR (p = 0.03). Increased glucose metabolism in bone marrow (BLR) was associated with transcriptomic profiles including regulatory T cell markers (p < 0.05)., Conclusion: Low tumor burden correlates with survival and objective response while hematopoietic tissue metabolism correlates inversely with survival. These biomarkers should be further evaluated for potential clinical application.

Quantifiable measures of vascularity obtained from contrast enhanced color flow images were correlated with pathologic vascularity measurements in ten female patients with a solid breast mass. Each patient received Levovist Injection (Berlex Laboratories Inc., Montville, NJ). Color flow images pre- and post-contrast were obtained using an HDI 3000 unit (ATL, Bothell, WA) before removing the mass for pathologic vascularity assessments. Image-processing techniques were used to obtain both the ultrasound and pathologic vascularity measurements. Multiple linear regression found significant correlations for ultrasonic vascularity measurements post contrast and pathology (P = 0.02 and 0.06). No correlations were found between pre-contrast ultrasound and pathology. In conclusion, post-contrast ultrasonic flow measures provide a non-invasive measure of breast tumor neovascularity. However, the patient population is small, and until further patients are analyzed, these conclusions are preliminary.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification in distinct anatomic patterns. Early preosseous lesions in FOP are clinically and histologically indistinguishable from the lesions of aggressive juvenile fibromatosis (AJF). Although the genetic defect in FOP is unknown, bone morphogenetic proteins (BMPs) 2 and 4 are plausible candidates genes. To determine if there is a difference in BMP 2/4 expression in the early fibromatous lesions of the two conditions, we performed immunohistochemical studies with a monoclonal antibody to BMP 2/4 on the earliest detectable fibromatous lesions of FOP and compared them with histologically identical lesions resected from children who had AJF. Fibromatous cells from the early FOP lesions exhibited immunostaining for BMP 2/4, whereas histologically indistinguishable fibromatous cells from AJF lesions showed no evidence of BMP 2/4 immunostaining. It is incumbent on all physicians who treat patients with suspected fibromatosis to examine the toes to rule out FOP and to avoid unnecessary diagnostic biopsies because surgical trauma induces further bone formation in patients who have FOP. However, if diagnostic confusion still exists and a biopsy is performed, immunostaining with BMP 2/4 antibody may resolve the diagnostic dilemma between FOP and AJF before the appearance of heterotopic ossification is observed in the FOP lesions. Our data suggest that the BMP 2/4 subfamily of secreted proteins may be involved in the pathogenesis of the FOP lesions.

Nickel-2,3,7,8,12,13,17,18-octaacetic acid-5,10,15,20-tetra-[3-carboranyl-methoxyphenyl]-porphyrin octamethylester (NiTCP) was given in a Cremophor EL, a polyethoxylated castor oil, and propylene glycol emulsion to BALB/c mice bearing transplanted s.c. KHJJ mammary carcinomas. A total dose of 244 microg NiTCP/gram body weight (gbw) (54 microg B/gbw) was given in 6 i.p. injections over a 32 hr period. Observations of behavior and changes in body weight and chemical and hematological blood tests indicated little or no toxicity from NiTCP over a period of 6-90 hr after injections. Boron concentrations near tumor margins were 160-180 microg B/g at 41-90 hr after the last injection. Tumor:normal brain boron concentration ratios reached approx. 10:1 and tumor:blood ratios reached approx. 250:1 after 4 days. There was no evidence of thrombocytopenia or other potentially important toxicities. Our findings place NiTCP among the leading candidates for pre-clinical experiments aimed toward improvement upon the compounds being tested for boron neutron-capture therapy of glioblastoma multiforme.

Proliferative periosteal disease was identified in 6 black lemurs (Eulemur macaco macaco) of 2 family groups. Bilaterally symmetric formation of periosteal new bone at the metaphyseal regions of major long bones was first detected at the stifle and tarsal areas and was detected later at the carpal areas. Bony changes were accompanied by progressive renal disease. The syndrome progressed for 6 to 16 months before the lemurs were euthanatized because of debility. Necropsy revealed changes confined to the skeleton and kidneys. Formation of new bone was detected at all affected joints, and chronic renal disease was evident in each lemur. A specific cause was not identified. Although indistinguishable histologically from hypertrophic osteoarthropathy, several important differences were apparent. Distribution of the periosteal new bone was in the metaphyseal rather than diaphyseal areas. Thoracic or gastrointestinal lesions, typically seen with hypertrophic osteoarthropathy, were not detected, and substantial renal disease was evident. A genetic component may be involved in the development of this condition.

Primary vaginal adenocarcinoma unrelated to intrauterine hormone exposure is very uncommon. We report a case of a 52-year-old woman who presented with primary vaginal adenocarcinoma that showed intestinal differentiation with prominent papillary formations and numerous papillary and villous features with prominent goblet cells. There was vaginal adenosis in the immediate vicinity of the tumor. To our knowledge, this is the first reported case of a primary vaginal adenocarcinoma of the intestinal type associated with adenosis in a patient unexposed to prenatal diethylstilbesterol.

A case of neurofibromatosis with a metastasizing malignant tumor is presented. The benign lesions were identified by light microscopy as neurofibromas containing granular cells typical of granular cell tumors. The malignant tumor was classified as a malignant granular cell tumor. Ultrastructural studies demonstrated common histogenetic and subcellular features of the benign and malignant tissues. The case is the first reported in which granular cells are seen in the lesions. The typical granular cell morphologic features of the malignant lesion support the concept of Schwann cell derivation of this group of tumors.

A 16-year-old girl with virilization and elevated serum alpha-fetoprotein (AFP) levels was found to have a Sertoli-Leydig cell tumor of the ovary. Immunoperoxidase studies using anti-AFP localized AFP in cells with the histologic appearance of Leydig cells. Serum AFP fell to undetectable levels after excision of the tumor. The patient is alive and well 1 year postexcision.

If a sufficient concentration of the stable isotope 10B is introduced into a neoplasm, radiation therapy can be effected by short-range heavy charged particles from the disintegration of 10B by slow neutrons. Brain tumors were irradiated postoperatively by Hatanaka and co-workers in Japan using a 1 to 2 hour intraarterial infusion of 10B-enriched Na2B12H11SH (Na210B12H11SH) before exposure of the tumor-bearing area of the brain to slow neutrons from a 100 kilowatt nuclear reactor. The clinical outcome of such boron neutron capture therapy has been favorably impressive in some patients, but its efficacy in brain tumors needs improvement. In our study, a terminally ill patient with malignant astrocytoma was infused intravenously with Na210B12H11SH for 25 hours. The postmortem distribution of 10B in unfixed, frozen, tumor-bearing brain and spinal cord tissues was studied by comparing representative cryostat sections of these specimens with neutron-induced heavy charged particle radiographs of the same sections. Preferential accumulation of 10B was observed in the tumor, with relatively little accumulation of 10B in the parenchyma of the central nervous system.

The differential expression of the ras oncogene product p21 in the primary tumor, regional nodes, and distant metastatic sites in patients with disseminated breast cancer was examined to define the biologic and clinical significance of the ras oncogene in the progression of breast cancer. The avidin-biotin peroxidase complex method was used on formalin-fixed, paraffin-embedded tissues from 16 patients with metastatic disease. The primary antibody used in this protocol was RAP-5, an anti-p21 murine monoclonal IgG2a. p21 antigen staining was similar in the primary tumor and regional nodes from the same patient (P less than 0.05), but the staining of distant metastases was more variable. Expression of ras p21 was consistently increased in invasive components of the primary tumor as compared with intraductal tumor. In addition, a high level of p21 expression was seen in tumor emboli in lymphatics and blood vessels as compared with contiguous tumor in parenchymal tissue. Although p21 staining is present in aggressive primary breast cancers and most metastatic sites, our findings indicate that markedly enhanced p21 expression is associated with the earlier stages (invasion and dissemination) of aggressive breast cancers.

The major neoplastic transformation-inducing genes of human solid tumors are members of the ras oncogene family. We used an immunohistochemical assay to assess expression of both the unaltered and the mutated ras oncogene protein (p21) in normal and neoplastic prostatic cells. With the concentration of monoclonal antibody used in this study, epithelial and stromal cells from subjects with normal prostates and from 19 patients with benign prostatic hyperplasia were negative for p21 antigen. This antigen was detected in 2 of 6 prostates with Grade I carcinoma, 4 of 6 with Grade II, and all of 17 with higher grades. A semiquantitative immunohistochemical method demonstrated that expression of the p21 antigen in a carcinoma strongly correlated with nuclear anaplasia and was inversely related to the degree of glandular differentiation. However, markedly anaplastic tumors were often more heterogeneous in expression of p21 and contained areas of low staining for the antigen. Comparison of p21 antigen with tumor carcinoembryonic antigen and prostate-specific antigen demonstrated that ras p21 was the only phenotypic marker that correlated with histologic tumor grade. Thus, ras oncogene p21 may represent a new class of biologically relevant tumor markers and may be a useful adjunct to histopathologic examination in determining the prognosis of patients with prostate cancer.

Following infection with 10(3) cells of Cryptococcus neoformans, progressive multiplication occurred in all tissues for 7 to 28 days. Thereafter, most mice gained control of the infection so that 3 to 6 months after inoculation, tissues were usually sterile or contained only small numbers of cryptococci. Survivors challenged 1 to 4 months after infection with 10(3) cells lived longer than controls and had an increased survival rate. Pretreatment with bacterial endotoxin also resulted in protection against cryptococcal challenge. Endotoxin-protected animals showed no ability to limit the infection until circulating antibody could be demonstrated. Histologic studies revealed an increased cellular infiltration in the brains of specifically protected and endotoxin-protected mice 1 to 2 weeks after challenge. However, control of cryptococcal multiplication could be correlated with the presence of antibody but could not be correlated with the enhanced cellular response. Although protection against cryptococcal challenge appears to be antibody-dependent, it is unclear whether protective antibody is to be found in plasma or is tissue-bound.