Citations

A 23-year-old gentleman presented to the emergency department with new onset neurological dysfunction and painful oral and genital ulcers. Biopsies of the lesions noted non-specific inflammatory changes. MRI of the brain revealed a large mass-like lesion involving the pons, medulla, midbrain and surrounding cerebral tissue with T2 signal enhancement that was not amenable for biopsy. Both the ulcer biopsy results and the MRI findings could be attributed to either central nervous system (CNS) lymphoma or CNS Behçet's disease. A diagnosis of CNS Behçet's disease was thought to be most likely based on the clinical presentation and MRI findings. He was treated with high-dose immunosuppression and made a significant recovery.

Background: The results of surgical treatment for femoroacetabular impingement have been increasingly reported, and more advanced intra-articular disease has been identified as an important predictive factor of outcome. Yet, the reliability of arthroscopic hip disease classification has not been well defined. Purpose/Hypothesis: To determine the intraobserver and interobserver reliability of the Beck classification of labral and articular cartilage disease (anterior-superior acetabular rim) encountered in hip arthroscopy. Secondly, we identified the sources of poor reliability that may be improved with future disease classification schemes. Our hypothesis was that the Beck classification of labral and chondral lesions would demonstrate substantial reliability, while the differentiation of early forms of disease would be a common source of disagreement. Study Design: Cohort study; Level of evidence, 3. Methods: Four experienced hip arthroscopists reviewed standardized arthroscopic videos of 40 cases. Arthroscopic findings at the anterior-superior acetabular rim were classified using the Beck classification of labral and articular cartilage disease. Repeat classification of videos was performed at least 2 weeks later. The reliability of arthroscopic classification was defined using the average weighted Cohen κ values and agreement rates. Results: Arthroscopic classification of labral disease using the Beck classification demonstrated moderate to substantial interobserver reliability (average κ = .62; range, .48-.78) and an overall agreement rate of 81.7%. Intraobserver reliability showed a similar level of reliability (average κ = .65; agreement rate, 80.6%). The differentiation between labral degeneration and labral detachment was a common source of disagreement. Similarly, the Beck classification of articular cartilage disease had moderate to substantial interobserver reliability (average κ = .65; range, .49-.78) and overall agreement rate of 57.5%. Intraobserver reliability showed a slightly better level of reliability (average κ = .80; agreement rate, 77.5%). The differentiation between articular cartilage malacia and debonding was a common source of disagreement. Conclusion: The arthroscopic classification of acetabular rim disease with the Beck classification has substantial interobserver reliability. This level of reliability is similar to previously reported arthroscopic disease classifications in the knee and shoulder and seems appropriate for future outcome reporting. Future classifications that eliminate common sources of disagreement may further improve the reliability.

PurposeThe optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT).Patients and MethodsWe analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database.ResultsOf 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival.ConclusionIn this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation.

Abstract Introduction: Invasive transitional cell carcinoma of the urinary bladder (InvTCC) kills >14,000 people yearly in the US. Folate receptors (FRs, especially FRα) are being targeted for imaging and therapy across multiple cancer types. This work was performed to define FR expression and uptake in InvTCC, with comparison to normal bladder; and to determine the antitumor activity and toxicity of folate-targeted vinblastine in dogs with naturally-occurring InvTCC where the cancer closely mimics human InvTCC. Canine InvTCC metastasizes frequently, and only 35% of dogs have remission with chemotherapy. Methods: Immunohistochemistry (IHC, mab343, PU17, FRβmab) was performed in InvTCC, bladder tissues adjacent to InvTCC in humans, and in bladder from normal dogs. Folate uptake was determined ex vivo by folate binding assay, and in vivo in dogs with InvTCC by nuclear scintigraphy (99mTc based FR targeted imaging agent). A dose escalation study of folate-targeted vinblastine (EC0905, IV weekly) was performed in dogs with biopsy-confirmed, FR-positive, measurable InvTCC. Toxicity (VCOG criteria) was assessed by CBCs, serum chemistry profiles, urinalyses, physical exams, and dog owner observations. The MTD was defined as the highest dose at which 0 of 6 dogs had grade 4 toxicity and ≤1 of 6 dogs had grade 3 toxicity. Tumor response was assessed by ultrasonography (with detailed bladder mapping) and radiography. Results: FR expression (IHC, PU17) was noted in the majority of canine samples including 56 of 74 (76%) primary tumors, 7 of 12 (58%) nodal metastases, and 10 of 21 (48%) lung metastases, as well as in normal urothelium. Typically, >50% of tumor cells were positive. FR expression was cytoplasmic in 18, membrane in 6, and in both sites in 32 InvTCC cases. Scintigraphy (n= 12 dogs) revealed folate uptake in primary and metastatic lesions. The MTD of EC0905 in dogs was 0.25 mg/kg IV weekly. At doses above the MTD, gastrointestinal upset and myelosuppression occurred. No urologic toxicity was noted. Tumor responses included partial remission (≥50% reduction in tumor volume) in 5 dogs and stable disease (<50% change in tumor volume) in 5 dogs. In human InvTCC, IHC results with PU17 were similar to those in dogs with 29 of 36 (78%) primary tumors, 12 of 15 (80%) nodal metastases, and 5 of 5 tissues adjacent to InvTCC being positive. Immunoreactivity to mab343 was less frequent (22% of primary tumors, 33% of nodal metastases). FRβ was expressed in 3 of 14 (21%) InvTCC cases. Ex vivo folate binding to human and canine InvTCC was detected, although binding varied from case to case and did not always correlate with IHC. Conclusions: Folate-targeted therapy holds promise for the treatment of InvTCC. FR expression was detected in human and canine InvTCC, and folate-targeted vinblastine had excellent antitumor activity against canine InvTCC where the cancer closely mimics human InvTCC. In addition to FRα, FRβ may be important in InvTCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-5. doi:1538-7445.AM2012-LB-5

Abstract Background: Estrogen receptors are over-expressed in around 70% of breast cancer cases. The genetic changes that occur during aromatase inhibitor (AI) treatment are not well understood and may differ depending upon the patient's response phenotype. Methods: We performed whole genome sequencing (WGS) of matched blood, pre-treatment, and post-treatment biopsy samples from 22 estrogen receptor positive breast cancer patients treated with neoadjuvant aromatase inhibitors. For 5 cases, we performed the whole genome sequencing (WGS) on patients’ matched normal, two pre AI-treatment, and two post AI-treatment DNA isolates from biopsy samples. We validated all putative coding and non-coding somatic mutations using deep sequencing. By comparing the validated somatic mutations from pre- and post- AI treatment biopsy samples, we were able to determine the alterations in the tumor genomes. In every case we defined the clonal architecture of each pair of pre-treatment and post-treatment biopsy samples by comparing the variant allele frequencies from thousands of validated somatic mutations. Results: Comparisons of the two pre AI-treatment biopsy samples from the same patient indicates that the variant allele frequencies of mutations showed high concordances in all 5 cases, 0.74 to 0.95 range of correlation coefficient. Only a small percentage of somatic mutations were detected in one pre-treatment sample and not the other (4.65% overall). In comparing the somatic variations between pre-treatment and matched post-treatment biopsy samples in 22 cases, we found that patients with good clinical response to AI treatment retained known driver mutations only in their pre-treatment tumors. Conversely, those patients with poor clinical response presented new driver mutations in their post-treatment samples. Furthermore, the variant allele frequency for most mutated genes decreased in post AI treatment samples for patients with good AI treatment response; on the contrary, the variant allele frequency increased for patients with poor clinical response. Conclusions: From WGS of matched normal, pre-treatment, and post-treatment biopsy samples, we identified new driver genes mutated in patients with poor clinical response, while patients with good clinical response had lost mutated driver genes in their post-treatment biopsy samples. The genetic landscape revealed by WGS of pre-treatment and post-treatment biopsy samples reveals mutational repertoires are remodeled by AI therapy. This finding suggests deep sequencing of AI treated samples will be necessary to reveal the complete complement of mutations present in a patient's tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-423. doi:1538-7445.AM2012-LB-423

Background Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. Methods Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). Results Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less ‘ BRCA1 -like’ than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more ‘ BRCA1 -like’ than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p.Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. Conclusions Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.

Abstract Bladder cancer is the 4th most commonly diagnosed cancer in the United States. Because superficial bladder cancer (SBC) recurs in about 60% of cases, standard treatment involves tumor resection followed by intravesical therapies to prevent recurrence, as well as lifelong periodic cystoscopy. There is an urgent need for better intravesical therapies to prevent both the recurrence and progression of SBC. The Mammalian Target Of Rapamycin (mTOR) complex is upregulated in many bladder cancer tumors. We have targeted both the mTORc1 and mTORc2 complexes with drugs that inhibit both complexes. We used PP242 and a second inhibitor, OSI-027, which is currently in a phase I clinical trial for solid tumors (NCT00698243). Our in vitro model targets cell proliferation in three bladder cancer cell line (HT1376, T24 and UM-UC-3). Both drugs are effective in inhibiting the growth of bladder cancer cell lines with IC50 values between 0.6 and 18µM. In comparison with rapamycin, both drugs demonstrate effects on downstream targets of both the mTORc1 and mTORc2 pathways including 4EBP1 and pAkt. Receptor tyrosine kinases are another therapeutic target for bladder cancer. Lapatinib which targets EGFR and Her3, in combination with OSI-027 forms a highly synergistic treatment that inhibits bladder cancer cell line growth. Downstream molecular targets of the combination therapy, including the apoptosis markers PARP and caspase 3, were evaluated by Western blots. Our in vitro data suggests that a combination of dual mTOR inhibitors with RTK inhibitors may provide a novel effective therapeutic treatment for bladder cancer. Future studies of the in vivo efficacy of these drug combinations in a mouse model are planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 896. doi:1538-7445.AM2012-896