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Renal epithelioid angiomyolipoma (EAML) (epithelioid PEComa of the kidney), is a rare subtype of renal angiomyolipoma with the potential for aggressive behavior and a known diagnostically challenging entity. We present a renal EAML with unusual papillary architecture and tumor cells with abundant eosinophilic cytoplasm and cherry-red nucleoli with perinucleolar halos, strongly mimicking a fumarate hydratase (FH) deficient renal cell carcinoma (RCC). We herein report our findings and discuss the morphologic, immunohistochemical, and molecular pitfalls to consider in the differential of EAML, including with FH-deficient RCC and more recently described entities: TFEB-amplified RCC and other renal tumors with alterations in TSC1/2. Novel findings in this tumor include papillary morphology and a novel telomerase reverse transcriptase promoter rearrangement, which has not been previously reported in EAML.

Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of vorolanib/everolimus. Oral vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.

Augmentation cystoplasty is a surgical procedure used in the management of patients with neurogenic bladder. This procedure involves anastomosis of the bladder with gastrointestinal grafts, including portions of ileum, colon, or stomach. A rare but important complication of augmentation cystoplasty is the development of malignancy. The majority of malignancies arising in this setting have been described in case reports. A search for cases of non-urothelial carcinoma following augmentation cystoplasty was conducted through the urological pathology files of four major academic institutions. Ten cases were identified, including six cystoprostatectomy/cystectomy, two partial cystectomy, and two transurethral resection of bladder tumour specimens. The mean patient age at diagnosis was 47 years (range 27-87 years). The male:female ratio was 4:6. The tumours tended to present at an advanced stage; four cystoprostatectomy/cystectomy cases were categorised as pT3a, one was categorised as pT3b, and one was categorised as pT4a. Lymph node metastases were present in all cases which had lymph node excision (range 1-16 positive nodes per case). The majority of cases (90%) were predominantly characterised by a poorly differentiated adenocarcinoma with signet ring cell features. Other morphological features included mucinous features (30%), plasmacytoid features (20%), enteric/villous architecture (10%), and large cell undifferentiated morphology (10%). This is the largest study to date on the clinicopathological features of invasive non-urothelial carcinoma of the bladder following augmentation cystoplasty. The tumours are typically poorly differentiated adenocarcinoma, with diffuse signet ring cell features, aggressive, and present at high stage. Further molecular characterisation may provide additional insights into the pathogenesis of this entity.

To determine whether there are racial/ethnic disparities in patient experiences with care among lung cancer survivors, whether they are associated with mortality.A retrospective cohort study of lung cancer survivors 65 years old who completed a CAHPS survey 6 months after the date of diagnosis. We used data from the SEER-Consumer Assessment of Healthcare Providers Systems (SEER-CAHPS®) database from 2000 to 2013 to assess racial/ethnic differences in patient experiences with care multivariable Cox proportional hazards models to assess the association between patient experience with care scores mortality in each racial/ethnic group.Within our cohort of 2603 lung cancer patients, Hispanic patients reported lower adjusted mean score with their ability to get needed care compared to white patients (B: - 5.21, 95% CI: - 9.03, - 1.39). Asian patients reported lower adjusted mean scores with their ability to get care quickly (- 4.25 (- 8.19, - 0.31)), get needed care (- 7.06 (- 10.51, - 3.61)), get needed drugs (- 9.06 (- 13.04, - 5.08)). For Hispanic patients, a 1-unit score increase in their ability to get all needed care (HR: 1.02, 1.00-1.03) care coordination (1.06, 1.02-1.09) was associated with higher risk of mortality. Among black patients, a 1-unit score increase in their ability to get needed care (HR: 0.99, 95% CI 0.98-0.99) care coordination (0.97, 0.94-0.99) was associated with lower risk mortality.There are racial/ethnic disparities in lung cancer patient experiences with care that may impact mortality. Patient experiences with care are important risk factors of mortality for certain racial/ethnic groups.

Mutations and epimutations in genes encoding the succinate dehydrogenase complex (SDHx) are associated with multiple tumour types in which identification of SDH-deficiency has significant management implications. Immunohistochemistry (IHC) for the succinate dehydrogenase B (SDHB) subunit can help to detect SDH-deficiency, which manifests as complete loss of staining in tumour cells. However, a subset of SDH-deficient tumours can show aberrant cytoplasmic SDHB-IHC staining patterns and be misinterpreted as 'retained', a diagnostic pitfall complicating interpretation. Herein, we characterise in detail aberrant SDHB-IHC staining patterns in SDH-deficient tumours.We identified 23 tumours from patients with known germline SDHx and/or molecularly confirmed SDHx pathogenic/likely-pathogenic variants in their tumour. Of these, eight (35%) showed significant SDHB-IHC staining: one SDHA-, one SDHB-, three SDHC- and three SDHD-mutated cases. In all eight cases, closer inspection revealed differences in intensity and intracellular distribution of SDHB-IHC staining in tumour cells compared to adjacent non-neoplastic cells: non-neoplastic cells showed intense cytoplasmic coarse granular staining; tumour cells in seven of eight cases showed weak to focally strong, cytoplasmic blush to fine granular staining, in 80% of cells. The remaining case in the initial block showed variably strong non-granular cytoplasmic staining with globular perinuclear accentuation throughout, only subtly distinct from the staining pattern of non-neoplastic cells. SDHB-IHC performed on two additional blocks in this latter case revealed significant intratumoral heterogeneity, including convincing areas of complete loss.When evaluating SDHB-IHC, care should be taken to distinguish true retained expression from aberrant cytoplasmic expression, which may be difficult to appreciate. Sometimes this may require additional molecular testing.

The information available on program websites concerning geriatric fellowships in internal medicine and family medicine is a crucial factor in generating applicants' interest in individual programs. Our study aimed to quantify the accessibility and quality of information available on accredited geriatric (family medicine and internal medicine) fellowship program websites and further analyze the implications of the results obtained. A list of geriatric (family medicine and internal medicine) fellowship programs was analyzed through quantified measures after being verified for accreditation. Certain criteria were evaluated for each of these programs, such as website accessibility and whether critical information was available on online program websites. These criteria were centered on academic, administrative, and application-based factors. Hundred and fifty eight Family Medicine and Internal Medicine geriatric fellowship programs were identified in total, of which only 150 were accredited by the Accreditation Council for Graduate Medical Education and considered for analysis. Of these, 20 (13.33%) programs had website links that were nonfunctional and only 145 programs had websites at all. On programs' websites, information regarding aspects such as contact information-including phone number or email for the program-were lacking. Other information regarding past and current fellows, research, and curriculum were also generally lacking. Geriatric Fellowship websites in Family Medicine and Internal Medicine can gain better traction from those interested in applying for their programs by updating information more often and providing more and better information concerning critical aspects of the programs themselves online.

BACKGROUND For biopsies with Gleason 3 + 3 = 6 or 3 + 4 = 7 prostate cancer, the Genomic Prostate Score (GPS; OncotypeDx) is designed to predict severe pathology at prostatectomy, and, in some cases, recommends reclassification of the National Comprehensive Cancer Network (NCCN) risk category. We hypothesized that certain histopathologic features that were not considered in the original design of the assay actually would be associated with the NCCN risk category change indicated by GPS testing. METHODS For patients with recommended NCCN risk category change, the biopsy cores used for GPS were re-reviewed for stromal reaction, chronic inflammation, and tumor nuclear polarization. RESULTS Of 520 patients from May 2011 to December 2018, GPS testing suggested NCCN risk reclassification in 131 (25%); 127 of these slides were available. Of these, the NCCN risk category increased from intermediate to high in 8, low to intermediate in 15, very low to low in 1, and decreased from intermediate to low in 32, and low to very low in 71. Biopsies with NCCN risk increase were associated with moderate or severe stromal reaction (p

Prostatic adenocarcinoma and urothelial carcinoma typically demonstrate distinct morphologic and immunohistochemical features. However, high-grade prostate and urothelial carcinomas sometimes show significant morphologic and immunohistochemical overlap, which can result in misdiagnosis and mistreatment. This diagnostic dilemma is particularly acute in patients previously treated with radiation and/or hormone therapy for prostate cancer, who later present with high-grade carcinoma in the urinary bladder. To address the diagnostic utility of integrated immunohistochemical and molecular analysis in this setting, we evaluated 25 high-grade carcinomas of the bladder for which morphologic features were deemed indeterminate. Our analysis included immunohistochemistry for urothelial markers (GATA3, p63, uroplakin II), prostate markers (NKX3.1, prostate specific antigen, P501S), androgen receptor (AR) and ERG, along with molecular characterization using capture-based next generation DNA sequencing. Immunohistochemical findings were concordant with the final integrated diagnosis in 21 (84%) cases. However, in three (12%) cases, immunohistochemistry supported a diagnosis of urothelial carcinoma, but molecular analysis identified the correct diagnosis of prostate cancer based on the presence of a TMPRSS2-ERG fusion. One case remained unclassifiable even after this integrated analysis. Notably, in 1 of 21 cases, the presence of a TERT promoter mutation and the absence of a TMPRSS2-ERG fusion would typically favor a diagnosis of urothelial carcinoma, but the aggregate immunohistochemical and molecular findings instead supported a diagnosis of microsatellite unstable prostatic adenocarcinoma with deep deletion of MSH2 and MSH6. Our findings highlight the importance of considering prostatic origin in high-grade carcinoma of the urinary bladder of patients with a history of treated prostate cancer, even when the immunohistochemical findings favor urothelial carcinoma. In a subset of cases, an approach that integrates immunophenotypic and molecular data may help correctly assign site of origin and prevent misdiagnosis that can result from overreliance on any individual immunohistochemical or molecular result.

Objectives Tinnitus is the perception of sound in the absence of an external physical sound source, for some people it can severely reduce the quality of life. Acoustic residual inhibition (ARI) is a suppression of tinnitus following the cessation of a sound. The present study investigated the effect of ARI on brain activity measured using EEG. Design Thirty adult participants (mean age of 58 years) experiencing chronic tinnitus (minimum 2 years) participated. Participants were presented broad band noise at 10 dB above minimum masking level (1 min followed by 4 min of silence, 4 times) counterbalanced with a control treatment of broad band noise at threshold (1 min followed by 4 min of silence, 4 times) while 64-channel EEG was simultaneously recorded. Tinnitus loudness was measured using a 9-point tinnitus loudness rating scale. Results The ARI stimulation resulted in a self-reported reduction in tinnitus loudness in 17 of the 30 participants. Tinnitus rating reduced following stimulation but gradually returned to near baseline during 4 min of silence post sound exposure; successive sound exposures resulted in lower loudness ratings. No significant reductions in loudness rating were found with the control stimulation. The EEG showed increases in power spectral density, particularly in the alpha and gamma bands, during ARI compared to the control periods. Conclusions These results contribute to the understanding of ARI and tinnitus. We recommend that there be a closer examination of the relationship between onset and offset of sound in both tinnitus and nontinnitus control participants to ascertain if EEG changes seen with ARI relate to tinnitus suppression or general postsound activity.

Summary Invasive plasmacytoid urothelial carcinomas (PUCs) are an uncommon aggressive variant, which often shows immunohistochemical loss of E-cadherin, underlying its distinct discohesive histology. The marker P120 (well described in breast pathology as being a diagnostic tool alongside E-cadherin for lobular neoplasia) has not been evaluated in PUCs. Biopsies, transurethral resections, and cystectomies of PUCs were collected, and whole-slide immunohistochemical analysis of E-cadherin and P120 was applied. A subset of cases were also tested for CDH1 mutation. PUC cases were stratified into morphologic categories of classic, pleomorphic, or desmoplastic. For E-cadherin, 24 of 33 (73%) cases showed an abnormal staining pattern, consisting of complete absence of staining (17/24; 71%) or cytoplasmic staining (7/24; 29%). For P120, 24 of 33 (73%) cases showed an abnormal staining pattern, consisting of loss of membranous staining with cytoplasmic reactivity. Only 2 cases showed a discordant E-cadherin/P120 immunoprofile (94% concordance). Significant staining differences among the 3 morphologic categories were not found. CDH1 mutation was found in 4 of 8 (50%) of cases, with 3 of 4 (75%) cases showing matched molecular/immunoprofile reactivity. No cases with CDH1 mutation showed discordant pattern E-cadherin/P120 immunoreactivity. Our rate of aberrant E-cadherin immunoreactivity in PUCs (73%) is similar to a meta-analysis of published cases (74%). We also report an identical rate of aberrant P120 immunoreactivity in PUCs (73%). While PUC remains a histologic diagnosis, in a subset of cases showing a less appreciated pattern (such as desmoplastic) or confounding cytoplasmic E-cadherin reactivity, the utility of paired P120 staining may be a useful diagnostic tool.

Aims Metanephric adenomas (MAs) are conventionally regarded as rare renal tumours with indolent behaviour; limited case reports have described MAs with aggressive features. Conventional MAs harbour hotspot BRAF V600E mutations. A BRAF V600E senescence pathway, mediated by cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16, has been proposed to confer MA benignity. Aside from BRAF, the molecular landscape in both conventional MAs and those with aggressive features has not been fully characterised. The aim of this study was to molecularly profile a series of MAs to investigate the correlation between genomic findings and clinical outcome. Methods and results We retrospectively examined the histomorphology and patient outcomes of 11 conventional MAs and one MA with aggressive features. Each was subjected to capture-based next-generation DNA sequencing of 479 cancer-related genes and immunohistochemical profiling. All tumours were positive for WT1 immunostaining and BRAF V600E mutation. One conventional MA contained an additional somatic BRCA2 pathogenic mutation. The MA with aggressive features had a biphasic appearance: one component was epithelial, with areas morphologically consistent with conventional MA; the second component was sarcomatous, with areas of solid and angiosarcomatous growth. Differential profiling of the two populations revealed identical BRAF, EIF1AX and TERT promoter hotspot mutations in the epithelial and sarcomatous components. Deep deletion of CDKN2A and MYC amplification were identified only in the sarcomatous component. Conclusions Although the vast majority of MAs show indolent behaviour, rare pathogenic alterations can occur in conventional MAs in addition to BRAF. Molecular profiling of a case with aggressive clinical and pathological features shows genetic evidence for malignant evolution in MAs.

Background Molecular testing of prostate cancer biopsies with Gleason pattern 4 suggests the expansile cribriform pattern is more aggressive than the glomerulation pattern. These two extreme patterns have not been compared at prostatectomy. We hypothesized that at prostatectomy the expansile cribriform pattern would be associated with histopathologic and molecular features of aggressiveness and with greater risk of biochemical recurrence (BCR) than the glomerulation pattern. Methods In a retrospective cohort study, radical prostatectomy reports with expansile cribriform pattern or glomerulation pattern were analyzed for percentage of total pattern 4, extraprostatic extension (EPE), positive lymph nodes, seminal vesicle invasion (SVI), and intraductal carcinoma (IDC). Cases with pattern 5 or with both expansile cribriform and glomerulations patterns present were excluded. The electronic medical record was reviewed for BCR-free survival and for Decipher test results. Results Of 1020 radical prostatectomies from July 2015 to July 2018, 110 (11%) had either expansile cribriform or glomerulation pattern present. The expansile cribriform group was associated with more histopathologic features of aggressiveness, with higher average total percentage pattern 4 (43.7 vs 27.0, P = .002), a trend of greater extensive EPE (32.7% vs 17.2%, P = .06), a trend toward statistical significance of higher rate of SVI (11.5% vs 3.4%, P = .1), greater positive lymph nodes (9.6% vs 0%, P = .02), and a higher percentage of cases with or suspicious for IDC (23.1% vs 8.6%, P = .04). The risk of BCR was 4.4 (1.3-15.4) fold greater for the expansile cribriform group vs the glomerulations group (P = .02). For the 38 patients who underwent Decipher testing, the expansile cribriform group had a high-risk assay category mean score whereas the glomerulations group had an average risk assay category mean score (0.61 vs 0.47, P = .02). Conclusions In a comparison of prostatectomy cases with expansile cribriform pattern to those with glomerulation pattern, the expansile cribriform pattern was associated with more histopathologic features of aggressiveness, greater risk of biochemical failure, and higher scores with a molecular classifier (Decipher) test. These findings underscore the importance of reporting the types of pattern 4 and supports the argument that men with expansile cribriform likely require more aggressive management.

Background Talimogene laherparepvec (T-VEC) is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and to produce granulocyte-macrophage colony-stimulating factor to enhance systemic antitumor immune responses. The safety and efficacy of T-VEC in treatment of advanced melanoma has been demonstrated as monotherapy and in combination with the checkpoint inhibitors (CPI) pembrolizumab and ipilimumab. Additionally, T-VEC monotherapy has demonstrated tolerable safety for intrahepatic injection (Hecht GICS 2018). Atezolizumab (atezo) is a humanized monoclonal antibody that promotes antitumor immunity by targeting programmed cell death ligand-1 (PD-L1) and is approved for metastatic triple negative breast cancer (mTNBC). We hypothesize that T-VEC in combination with a CPI may be effective in mTNBC and CRC in addition to melanoma. This phase 1b, multicenter study (clinicaltrials.gov identifier: NCT03256344) evaluates the safety of intrahepatic injection of T-VEC in combination with intravenous (IV) atezo in patients (pts) with mTNBC or colorectal cancer (CRC) with liver metastases (LMs). Here we report early safety data in the TNBC cohort. Methods Key eligibility criteria included age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG PS 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable LM suitable for injection. T-VEC (≤ 4mL) was injected by image-guided intralesional injection: 106 PFU/mL day 1, 108 PFU/mL every 21 days thereafter; atezo 1,200 mg IV was given on day 1 and every 21 days thereafter. The primary objective of this study is to evaluate incidence of dose limiting toxicity (DLT) for safety of T-VEC injection into LMs in combination with IV atezo, by tumor type. The DLT analysis set included DLT-evaluable pts who were on treatment for at least 6 weeks from the initial dose of study treatment and received at least 2 doses of T-VEC and 2 doses of atezo in combination or have a DLT during the DLT evaluation period. Key secondary objectives include objective response rate, durable response rate, progression-free survival, and overall survival of the combination therapy, by tumor type. Results Thirty-two pts were enrolled in two parallel cohorts (8 TNBC, 24 CRC). Of the 8 TNBC pts, 4 were evaluable for DLT at the time of this analysis. Of the 4 pts that were not DLT-evaluable, 1 never received study drug, 1 received atezo monotherapy, and 2 received intrahepatic T-VEC and IV atezo but stopped study drugs for unconfirmed progression before the DLT evaluation period was completed. No DLTs were reported in the TNBC cohort. In the 7 TNBC pts who received at least one dose of the study drug, the most common treatment-emergent adverse events (TEAEs) in terms of the subject incidence were pyrexia (71.4%), chills (42.9%), and rash (42.9%). In the 7 TNBC pts who received at least one dose of study drug, T-VEC related AEs in more than one pt were pyrexia (n=3) and chills (n=2). Atezo related AEs in more than one pt were pyrexia (n=5), chills and rash (n=3 each), and fatigue, arthralgia, pain, and pruritus (n=2 each). Study drug-related serious adverse events (SAEs) occurred in 3 (42.9%) pts, including Grade (G) 3 hypersensitivity related to atezo, G3 orthostatic hypotension related to T-VEC and atezo, and G1 pyrexia related to T-VEC and atezo. Procedure-related SAEs occurred in 1 (14.3%) pt, of G3 hepatic hematoma and G3 abdominal infection, but these were not related to the study drugs. One confirmed partial response in the TNBC cohort has been seen thus far. Conclusion T-VEC intrahepatic injection in combination with IV atezo at standard doses has thus far been demonstrated as feasible and tolerable with no DLTs observed in the TNBC cohort to date. Citation Format: Joel Randolph Hecht, Arlene Chan, Jean-Francois Baurain, Miguel Martin, Federico Longo-Munoz, Kevin Kalinsky, Steven Raman, Chunxu Liu, Edward Cha, Emily Chan. Preliminary safety data of intrahepatic talimogene laherparepvec and intravenous atezolizumab in patients with triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-19.

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

Chromophobe renal cell carcinoma (ChRCC) is a relatively rare subtype of RCC with a characteristic histologic appearance. Most ChRCC are slow growing, but sarcomatoid differentiation and metastases can occur, indicative of aggressive behavior and poor prognosis. Herein, we characterize ten ChRCC with aggressive components, defined as sarcomatoid change and/or metastasis. Immunohistochemistry and next-generation sequencing was performed on available formalin-fixed paraffin-embedded tissue, with differential profiling of conventional and aggressive components. All ten cases showed a conventional component of renal tumor morphologically consistent with ChRCC: three had sarcomatoid change, four had metastases, and three had both sarcomatoid change and metastases. In the primary conventional components, a typical ChRCC IHC pattern (CK7+, CD117+ and CAIX-) was observed in 8/10 cases; 2 cases had rare CK7 staining. In the aggressive components, CD117 and/or CK7 was lost in 7/10 cases; 3 cases showed loss of both. Two of 10 cases showed significant CAIX staining in the aggressive component. All 7 cases that had molecular profiling performed showed characteristic chromosomal losses reported for ChRCC, though two cases showed additional complex copy number alterations in the aggressive component only. Recurrent TP53 mutations (TP53m) were also seen; however surprisingly, the conventional and aggressive components had no shared TP53m: a TP53m was private to aggressive components in 2 cases; to the conventional component in 1 case; and in 4 cases, components demonstrated different TP53m. Of the 21 pathogenic alterations identified in 7 tumors, only a PTEN splicing alteration was shared between both components in one case. In conclusion, ChRCC can have IHC staining patterns and molecular profile that differ between conventional and aggressive components. Interpretation of stains on metastases or small biopsies to determine histologic subtype can be misleading. The lack of shared pathogenic mutations between the two components supports a model in which aggressive ChRCC can have convergent subclones with different TP53m.

532 Background: ICIs form the backbone of treatment for mUC. However, only a minority of pts benefit and additional biomarkers of ICI response are needed. Methods: In our institution, we identified mUC pts treated with ICI monotherapy who had next generation sequencing (NGS). Somatic alterations present in ≥10% of pts ( ARID1A, CCND1, CDKN2A, CDKN2B, ERBB2, FGF3, FGF4, FGF19, FGFR3, KDM6A, MDM2, MLL2, PIK3CA, RB1, TERTp, TP53, TSC1), as well as DNA-damage response (DDR) alterations and tumor mutational burden (TMB) were analyzed as biomarkers. These biomarkers were individually evaluated in separate multivariate models while accounting for clinical factors including age, BMI, ECOG PS, primary tumor location, histology, hemoglobin, neutrophil to lymphocyte ratio and albumin. Multivariate cox regression and logistic regression models were used to measure hazard ratios (HR) and odds ratios (OR) for overall survival (OS), progression-free survival (PFS) and observed response rate (ORR). Results: Among 152 mUC ICI-treated pts, 107 had NGS data (FoundationOne, UCSF500, Strata), including 85 with TMB data. For the 107 pts with NGS, median age was 70 yrs, majority were male (69, 64%), Caucasian (70, 65%), had pure urothelial histology (57, 53%), and had first-line ICI (55, 51%). ORR was 35%, median PFS was 3.9 mos (95% CI: 2.6-7.5 mos), and median OS was 17.4 mos (95% CI: 14.1-30.6 mos). Biomarkers associated with improved outcomes to ICI, independent of relevant clinical factors, included alterations in ARID1A and DDR, as well as high TMB (>10 Mut/Mb). Inferior outcomes were seen in pts with CDKN2B, KDM6A, FGF3, FGF4, and FGF19 alterations (Table). Conclusions: In this large retrospective multivariate analysis controlling for clinical factors in ICI-treated mUC pts, we found multiple biomarkers associated with improved or inferior outcomes. These hypothesis-generating findings can inform clinical decision making and trial design for mUC pts treated with ICIs, and should be validated in larger cohorts. [Table: see text]

41 Background: KRAS mutation accounts for ~37% of colorectal cancer (CRC), with KRAS G12C occurring in ~3% of CRC tumors. KRAS G12C mutation is associated with poorer prognosis in terms of real-world progression-free survival (rwPFS) and overall survival (OS) compared to other KRAS mutations and KRAS wild-type. As KRAS G12C mutated metastatic CRC (mCRC) is recognized as a discrete potentially druggable target, there is a need to further describe this patient population. This retrospective cohort study provides real-world clinicopathological and molecular characteristics, treatment patterns, and outcomes (OS, rwPFS) in patients with KRAS G12C mutated mCRC. Methods: Adult (≥18 years old) patients diagnosed between 01 January 2009 and 01 February 2019 with KRAS G12C mutated mCRC were assessed from three US academic centers in AACR Project GENIE: Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and Vanderbilt-Ingram Cancer Center. Patient characteristics and treatment patterns were reported, and median OS and rwPFS by line of therapy (LOT) were estimated with the Kaplan-Meier method, including exploratory analyses by co-mutation profile. Results: Among 71 mCRC patients, median age at initial diagnosis was 52.1 years, 59% were women, 83% were White, and 68% had initial stage 4 disease. Co-mutations with an oncogenic, likely oncogenic, or predicted oncogenic OncoKB annotation were assessed, and the most commonly observed were APC in 79% of patients, TP53 in 63%, and PIK3CA in 20%. Only 8% of patients had high tumor mutational burden (>10 mut/Mb), and no patients had microsatellite instability-high among those measured (n=48). Most patients (71%) had evidence of surgical resection in the metastatic setting. Nearly all (93%) patients had received systemic therapy: 15 (23%) had only one LOT, 20 (30%) had only two LOTs, and 31 (47%) had three or more. Most patients received oxaliplatin- or irinotecan-based regimens in the first two LOTs. Median OS from the start of first LOT was 33.5 months (95% CI: 26.9, 37.1), 20.7 months (95% CI: 6.4, 23.2) from start of second LOT, and 15.8 months (95% CI: 3.1, 23.4) from start of third LOT. Median rwPFS from start of first LOT was 20.9 months (95% CI: 8.4, 32.0), 4.0 months (95% CI: 2.2, 9.7) from start of second LOT, and 3.1 months (95% CI: 1.1, 7.2) from start of third LOT. Patients with FBXW7 co-mutation had shorter OS and patients with PIK3CA co-mutation had longer rwPFS, compared to those with KRAS G12C alone. Conclusions: In this select patient cohort with KRAS G12C mutated mCRC from US academic centers, outcomes, particularly rwPFS, were poor in later lines of therapy. Frontline OS and rwPFS were longer than in other similar studies, which may be attributable to the young median age and high proportion of surgical resection in the metastatic setting observed in this cohort.

Papillary renal cell carcinoma (PRCC) is well-recognized as a morphologically and molecularly heterogenous group of kidney tumors with variable clinical behavior. Our goal was to analyze a unique histologic pattern of PRCC we have observed in routine practice to evaluate for potential clinical significance or distinct molecular signature. We identified 42 cases of PRCC showing a morphologically distinct architecture characterized by numerous epithelial-lined cysts containing the papillary tumor (herein called "microcysts"), which are typically separated by fibrous stroma. Of the initial 42 case test set with microcystic features, 23 (55%) were stage pT3a or higher. Most tumors had strong and diffuse cytoplasmic immunoreactivity for CK7 (93%, 37/40) and AMACR (100%, 40/40). Fumarate hydratase staining was retained in all cases tested (39/39). We performed next-generation sequencing on 15 of these cases with available tissue and identified chromosomal alterations commonly reported in historically "type 1" PRCC, notably multiple chromosomal gains, particularly of chromosomes 7 and 17, and MET alterations. However, alterations in pathways associated with more aggressive behavior (including SETD2, CDKN2A, and members of the NRF pathway) were also identified in 6 of 15 cases tested (40%). Given this molecular and immunophenotypic data, we subsequently reviewed an additional group of 60 consecutive pT2b-pT3 PRCCs to allow for comparisons between cases with and without microcysts, to assess for potential associations with other recently described histologic patterns (ie, "unfavorable architecture": micropapillary, solid, and hobnail), and to assess interobserver reproducibility for diagnosing architectural patterns and grade. Of the total combined 102 PRCCs, 67 (66%) had microcystic architecture within the intrarenal component but were commonly admixed with other patterns (39% had micropapillary, 31% solid, and 31% hobnail). Twenty-seven cases (26%) had metastatic disease, and 24 of these 27 (89%) had microcystic architecture in the intrarenal tumor. Within the pT3 subset, 21 of 22 cases with metastases (95%) had extrarenal invasion as either individual microcysts in renal sinus fat or aggregates of microcysts bulging beyond the confines of the capsule. Backward elimination and stepwise regression methods to detect features significantly associated with adverse outcome identified solid architecture (hazard ratio [HR]: 6.3; confidence interval [CI]: 2.1-18.8; P=0.001), hobnail architecture (HR: 5.3; CI: 1.7-16.7; P=0.004), and microcystic architecture at the tumor-stromal interface (HR: 4.2; CI: 1.1-16.7; P=0.036) as strongest. Of architectural patterns and grade, the microcystic pattern had a substantial interobserver agreement (κ score=0.795) that was highest among the 6 observers. In summary, PRCCs with microcystic architecture represents a subset of historically "type 1" PRCC with a predilection for morphologically distinctive extrarenal involvement and metastatic disease. Microcysts co-vary with other "unfavorable" architectural patterns also associated with higher risk for aggressive disease (ie, micropapillary, hobnail, and solid), but microcysts were more common and have superior interobserver reproducibility. These findings suggest that microcystic PRCC should be recognized as a potentially aggressive histologic pattern of growth in PRCC.

The concept of a "p53 null phenotype" (complete loss of staining) is well-recognized in the gynecologic pathology literature, implicitly reflecting that this staining pattern represents a TP53 mutation. However, in the genitourinary pathology literature, a p53 null phenotype has only been addressed regarding the prognosis of invasive urothelial carcinoma, and not as a diagnostic biomarker for urothelial carcinoma in situ (CIS). Herein, 25 cases of urothelial carcinoma in situ [diagnoses made on hematoxylin and eosin (HE) stained sections] showing null pattern p53 staining were retrieved from 22 different patients (16 males and 6 females, age range 52-85 years; average 69.6 years), most commonly showing large cell pleomorphic pattern morphology. One representative tissue block per case was selected for next-generation DNA sequencing (NGS). All 21 cases (100%) passing quality control for NGS showed at least 1 TP53 mutation (majority nonsense or frameshift mutations), including 3 cases with 2 mutations and 3 cases with 3 mutations. Three patients with multiple available samples harbored 1 or more shared TP53 mutations at 2 different time points, indicating clonality of the temporally distinct lesions. Additionally, 2 patients had an additional unique TP53 mutation at a later time point, suggesting intratumoral heterogeneity and/or temporal clonal evolution. While urothelial CIS remains an HE diagnosis in most cases, a p53 immunostain may be useful in a subset of challenging cases. This study demonstrates that a p53 null phenotype represents an aberrant result in urothelial CIS with supportive molecular analysis showing a previously unknown level of complexity for TP53 mutations among these noninvasive lesions. Adequate recognition of the p53 null phenotype as a "biologically supportive result", similar to strong and diffuse staining with p53, is important and may warrant a formal consensus statement for recommended p53 reporting (i.e., "wild type" versus "aberrant or mutant").

INTRODUCTION AND OBJECTIVE:The prognostic significance of a ‘second’ biochemical recurrence (sBCR) after salvage radiation therapy (sRT) with/without hormonal therapy following primary radical pros...

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), caused by a germline mutation in the fumarate hydratase (FH) gene, predisposes patients to uterine and cutaneous smooth muscle tumors and an aggressive type of renal cell carcinoma. Almost all women with HLRCC develop symptomatic uterine leiomyomas resulting in surgery at young ages, presenting an ideal opportunity for early detection of these patients and the implementation of surveillance measures for renal cell carcinoma. FH-deficient uterine leiomyomas can show characteristic morphologic features (FH-d morphology) that have been previously described. Immunohistochemistry (IHC) for FH can also be helpful in detecting FH deficiency in leiomyomas, which manifests as complete loss of staining for FH. However, the distribution and topography of FH-d morphology and FH loss by IHC in the context of multiple leiomyomas in patients with HLRCC has not been evaluated. The aim of this study is to describe in detail the clinical and pathologic characteristics of uterine leiomyomas from women with HLRCC. Six patients with proven FH germline mutations were included. All available slides were reviewed and FH IHC staining was performed on multiple blocks when possible. Clinical data were extracted from online medical records. All 6 patients presented with symptomatic uterine fibroids and underwent myomectomy (age 24 to 36 y), followed by hysterectomy in 2 patients (age 31 and 40 y). Specimens showed conventional leiomyomas, cellular leiomyomas and leiomyomas with bizarre nuclei. FH-d morphology was present in leiomyomas from all patients and was typically observed as a diffuse finding in the majority of slides across different leiomyoma types. FH-d morphology was absent in some leiomyoma sections from one patient and the morphologic features were focal and subtle in leiomyomas from 2 patients. Both hysterectomy specimens were also notable for showing scattered irregular tongues and nodules of smooth muscle proliferation (leiomyomatosis-like) in the background myometrium. Immunohistochemical staining of multiple slides per patient for FH showed either retained staining in all sections (2/6 cases), loss of staining in all sections (1 case) or variable staining across different leiomyomas (3 cases). In conclusion, patients with HLRCC undergo surgery at young ages for highly symptomatic uterine leiomyomas. FH-d morphology is usually a diffuse and well developed finding across different leiomyomas but may be absent or focal and subtle. FH IHC can show variable results and presence of retained FH staining should not be used to exclude the possibility of HLRCC. Referral for genetic counselling and testing should be considered in a young patient with uterine leiomyomas showing FH-d morphology even if immunohistochemical staining for FH is retained.

Objective In small (≤2 cm) oral tongue squamous cell carcinoma (OTSCC), we sought to clarify the contribution of pathologic features including perineural invasion (PNI), lymphovascular invasion (LVI), and worst pattern of invasion-5 (WPOI-5) to clinical outcomes relative to tumor depth of invasion (DOI) of > or ≤ 4 mm. Methods Cases of ≤2 cm OTSCC treated surgically between 2000 and 2017 at an academic cancer center were reviewed, with retrospective pathologic slide review of DOI, LVI, PNI, and WPOI-5. Primary outcome measures included occult nodal positivity, 2-year locoregional recurrence (LRR), disease-specific survival (DSS), and overall survival (OS). Results One hundred tumors were included in analyses; 50 had DOI ≤ 4 mm, while 50 had DOI > 4 mm. When DOI was ≤4 mm, the presence of PNI, LVI, or WPOI-5 was not associated with higher rates of occult cervical metastasis, LRR, or OS. When DOI was >4 mm, there was no difference in rates of occult cervical metastasis or LRR with each feature. On multivariate analysis, only the presence of two or more adverse features was associated with higher LRR (OR 5.7, P = .01) and worse DSS (HR 6.5, P = .02). Conclusion The rate of occult cervical metastases in small (≤2 cm) OTSCC when DOI is ≤4 mm is very low even when PNI, LVI, or WPOI-5 is present, and 2-year LRR is no different. When DOI is >4 mm, the strongest predictor of recurrence and survival on multivariate analysis is the presence of two or more features in the tumor. Level of evidence 4 Laryngoscope, 130:1715-1720, 2020.

Purpose: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors. Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, following a modified 3+3+3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint. Results: The safety analysis set included 111 patients who received ≥1 dose of AMG 337. Thirteen patients had ≥1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg once daily; the MTD for twice-daily dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade ≥3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n = 6) and fatigue (n = 5). Maximum plasma concentration occurred at 3.0 hours following 300-mg once-daily dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%–17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%–50.2%) in MET-amplified patients; median (range) duration of response was 202 (51–1,430+) days in all patients and 197 (64–1,430+) days in MET-amplified patients. Conclusions: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation. See related commentary by Ma, p. 2375

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that results in cognitive decline and a number of other neuropsychiatric symptoms. One area that is often affected by neuropsychiatric disease is the response to sudden, loud noises, as measured by the acoustic startle response (ASR), and prepulse inhibition (PPI), which indicates sensory-gating abilities. Evidence suggests AD patients, even early in the disease, show alteration in ASR. Studies have also shown changes in this measure in transgenic mouse models of AD. To assess the homology of 5xFAD mice to AD patients, the current study analyzed several aspects of the startle response in these mice using a protocol with fewer trials than previous studies. It was found that the 5xFAD mice had a delayed startle response, similar to what has been observed in AD sufferers. These results suggest the ASR may be a useful tool in assessing the efficacy of potential therapeutics, and that a simplified protocol may be more sensitive to between-groups differences for this task.

BACKGROUND Patient experiences with health care have been widely used as benchmark indicators of quality for providers, health care practices, and health plans. OBJECTIVE The objective of this study was to summarize the literature regarding the associations between Consumer Assessment of Healthcare Providers and Systems (CAHPS) patient experiences and clinical and quality outcomes. RESEARCH DESIGN A systematic review of the literature was completed using PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature on December 14, 2019. Separate searches were conducted to query terms identifying CAHPS surveys with clinical and quality outcomes of care. Two reviewers completed all components of the search process. STUDY SELECTION Studies investigating associations between CAHPS composite ratings and health care sensitive clinical outcomes or quality measures of care were included in this review. Studies were excluded if they did not investigate patient experiences using CAHPS composite ratings or if CAHPS composites were not treated as the independent variable. RESULTS Nineteen studies met inclusion criteria, 10 investigating associations of CAHPS composite ratings with clinical outcomes and 9 investigating these associations with quality measures. Patient-provider communication was the most studied CAHPS composite rating and was significantly associated with self-reported physical and mental health, frequency of emergency room visits and inpatient hospital stays, hospitalization length, and CAHPS personal physician global ratings. CONCLUSIONS Ratings of patient experience with care may influence clinical and quality outcomes of care. However, key inconsistencies between studies affirm that more research is needed to solidify this conclusion and investigate how patient experiences differentially relate to outcomes for various patient groups.

The discovery of covalent inhibitors binding the switch II (SWII) pocket has enabled therapeutic intervention in KRASG12C driven tumors and represents a milestone in targeting KRAS-driven cancers. However, the transient nature and high energetic barrier required for binding this pocket has been an obstacle in successfully targeting other KRAS mutant oncoproteins. We report the discovery of KRAS Conformation Locking Antibodies for Molecular Probe discovery (CLAMP)s that specifically recognize the unique conformation of KRASG12C induced by covalent inhibitors. KRAS CLAMPs enable single cell resolution of covalent inhibitor-bound KRASG12C in cells and in vivo tumor models, providing a biomarker for direct target engagement of KRASG12C inhibition. KRAS CLAMPs bind multiple KRAS mutants and stabilize an open conformation of the SWII pocket increasing the affinity of weak non-covalent SWII pocket ligands. This work provides new insights into KRASG12C upon treatment with covalent inhibitors and offers a path towards targeting the SWII pocket in other RAS mutants.

BackgroundImmune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI.MethodsWe undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors.ResultsWe identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03).ConclusionsThe presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.

The quantitative MRI metric, T1, has been used to characterise fibroinflammation in the liver; however, the T1 value alone is unable to differentiate between fibrosis and inflammation. We evaluate the potential utility of classical machine learning techniques (K-Nearest Neighbours, Support Vector Machine and Random Forest) to address this problem using information in the T1 map. We also compare to transfer learning, utilising multiple methods to alleviate the effects of class imbalance. Random Forest with Adaptive Synthetic Sampling was superior to mean T1 in categorising fibroinflammation. Despite the relatively small number of samples (n=289) and large class imbalance, our results demonstrate potential in using the whole T1 map with machine learning for this task.

Obsessive-compulsive disorder (OCD) generally responds to first-line treatment but patients often relapse. The United Kingdom National OCD Inpatient Service treats patients who have failed to respond to at least two trials of SRI, augmented with a dopamine blocker and two trials of ERP. Despite this, they have profound treatment-refractory OCD and require 24-h nursing care due to severe OCD. We examined patients' Y-BOCS score on admission, discharge and at each follow-up from all patients discharged over 5 years (02/01/2014-31/12/18). Data were analysed using SPSS. Paired student t-tests were used to assess improvement from admission to discharge and each follow-up. Over 5 years, 130 adult patients were treated: 79 male and 51 female with an average age of 42.3 years (20-82; sd14.4). Their ethnic backgrounds were; 115 Caucasian, 11 South Asian, 1 Chinese, and 3 Unspecified. On admission, the average Y-BOCS total score was 36.9 (30-40; sd2.6). At discharge, patients had improved on average by 36% (Y-BOCS reduction to 23.4 = moderate OCD). Similar reduction in Y-BOCS continued throughout the year with an average Y-BOCS of 22.9 at 1 month (n = 69); 23 at 3 months (n = 70); 21.3 at 6 months (n = 78) and 21.9 at 1 year (n = 77). Twenty-seven patients did not attend any follow-up appointment whilst others attended at least one appointment with the majority attending more than 3. Using student t-test, improvements at discharge, 1, 3, 6, and 12 months post-treatment showed a highly significant improvement (p < 0.001). Gains made following inpatient treatment for treatment-refractory OCD were generally maintained until 1 year post-treatment.

Conservative care, a comprehensive treatment path for advanced kidney disease most suitable for individuals unlikely to benefit from dialysis, is underutilized in the United States. One reason is an absence of robust education about this approach and how to discuss it with potential candidates. To address this need, we developed a multimodal conservative care curriculum for nephrology fellows. This curriculum consists of four online modules that address essential concepts and communication skills related to conservative care. It is followed by an in-person, interactive, "flipped classroom" session facilitated by designated nephrology educators at participating Accreditation Council for Graduate Medical Education nephrology training programs. Curriculum effect was assessed using surveys completed by participating fellows immediately before and following the curriculum and for participating nephrology educators following flipped classroom teaching; 148 nephrology trainees from 19 programs participated, with 108 completing both pre- and postcurriculum surveys. Mean self-reported preparedness (measured on a five-point Likert scale) increased significantly for all ten concepts taught in the curriculum. The mean correct score on eight knowledge questions increased from 69% to 82% following the curriculum (P

A simple and fast stability-indicating liquid chromatographic method with diode array detection (DAD) was developed and validated for the determination of dapagliflozin (DAPA) in bulk and tablets, in the presence of its major degradation products (DP). The drug was subjected to hydrolytic, oxidative, photolytic, thermal and humidity/thermal stress conditions, showing significant degradation under humidity/thermal with the formation of two DP, which were preliminarily identified by liquid chromatography with diode array detector coupled with electrospray ionization–tandem mass spectrometry (HPLC-DAD-ESI-MS/MS). Chromatographic separation of dapagliflozin and its DP was achieved with a core-shell RP-18 column, using acetonitrile and water as mobile phase in isocratic elution mode. The described method was linear over a range of 50–150 μg/mL. For precision, the relative standard deviation (RSD) was

The non-receptor protein tyrosine phosphatase SHP2 (PTPN11) plays an important role in the regulation of RAS/MAPK signal transduction downstream of growth factor receptor activation. Loss of SHP2 activity suppresses tumor cell growth, making SHP2 a potential target for cancer therapy. Here we report the discovery of GDC-1971 (formerly RLY-1971), a highly potent, selective, and orally bioavailable small-molecule SHP2 inhibitor that stabilizes SHP2 in a closed, auto-inhibited conformation. GDC-1971 potently inhibits both wild-type SHP2 (IC50 1 uM), indicating a link between KRAS GTP hydrolysis and SHP2 dependency. Despite this trend, some non-KRAS G12C or G12A cell lines harboring other KRAS mutations responded to GDC-1971 in vitro, suggesting some heterogeneity in RTK/SHP2 signaling dependence in subsets of other KRAS mutants. In vivo, GDC-1971 demonstrates dose-dependent RAS/MAPK pathway inhibition and induces significant tumor-growth inhibition in human xenograft models harboring EGFR and KRAS alterations at continuous daily doses that are well tolerated. Given the reported role of SHP2 as a critical mediator of resistance to targeted therapies, we assessed the activity of GDC-1971 combinations in multiple contexts. We observed increased suppression of the MAPK signaling cascade and anti-proliferation synergy when combining GDC-1971 with EGFR, ALK, and KRAS G12C inhibitors in vitro. The observed in vitro synergy translated to dramatic anti-tumor growth effects in vivo. GDC-1971 in combination with the KRAS G12C covalent inhibitor GDC-6036 resulted in significant regressions at doses well below those required for single agent activity in a KRAS G12C-mutant NSCLC xenograft model. In rodent and dog toxicology studies, GDC-1971 is well tolerated at exposures above those required to induce regression in xenograft models. The biochemical and cellular potency and favorable pharmaceutical properties of GDC-1971 support the further clinical development in RTK/MAPK pathway altered tumors using continuous daily dosing alone and in combination with other targeted agents, including the KRAS-G12C inhibitor GDC-6036 (clinical trial NCT04449874). Citation Format: Bret Williams, Alexander Taylor, Olivia Orozco, Christopher Owen, Elizabeth Kelley, Andre Lescarbeau, Kelley Shortsleeves, Randy Kipp, Vy Nguyen, Erin Brophy, Jeremy Wilbur, Yong Tang, David Lanzetta, Nigel Waters, Sherri Smith, Fabrizio Giordanetto, Paul Maragakis, Jack Greismann, Lindsay Willmore, Eric Therrien, Yang Xiao, Marie Evangelista, Luca Gerosa, Eva Lin, Mark Merchant, Alfonso Arrazate, Emily Chan, Pablo Sáenz-López Larrocha, Stefan Chun, Thomas Hunsaker, Gauri Deshmukh, Christine M. Bowman, David E. Shaw, Mark Murcko, Mahesh Padval, W Patrick Walters, James Watters, Donald A. Bergstrom. Discovery and characterization of the potent, allosteric SHP2 inhibitor GDC-1971 for the treatment of RTK/RAS driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3327.

This paper presents the results of a study undertaken by Victoria University of Wellington in association with the Ministry of Business, Innovation and Employment over the period December 2018 to August 2019, to assess whether businesses that are offering goods or services to consumers in New Zealand on standard form terms are including potentially unfair contract terms in those contracts. The study compared the 2015 and 2018 versions of the same standard form contracts in relation to 119 businesses to assess if those businesses had reduced the number and nature of potentially unfair terms appearing in their contracts since 2015. The study also considered the number and nature of potentially unfair terms appearing in contracts of a total of 134 businesses offering goods and services in 2018. The study found that all the contracts examined in 2018 contained potentially unfair terms and that the number of potentially unfair contract terms in standard form contracts had increased between 2015 and 2018.

Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses5 mg are often not tolerated when combined with other TKIs

Skeletal muscle and adipose tissue express the vitamin D receptor and may be a mechanism through which vitamin D supplementation slows cancer progression and reduces cancer death. In this exploratory analysis of a double-blind, multicenter, randomized phase II clinical trial, 105 patients with advanced or metastatic colorectal cancer who were receiving chemotherapy were randomized to either high-dose vitamin D3 (4000 IU) or standard-dose (400 IU) vitamin D3. Body composition was measured with abdominal computed tomography at enrollment (baseline) and after cycle 8 of chemotherapy (16 weeks). As compared with standard-dose vitamin D3, high-dose vitamin D3 did not significantly change body weight [&minus, 0.7 kg, (95% CI: &minus, 3.5, 2.0)], body mass index [&minus, 0.2 kg/m2, 1.2, 0.7)], muscle area [&minus, 1.7 cm2, 9.6, 6.3)], muscle attenuation [&minus, 0.4 HU, 4.2, 3.2)], visceral adipose tissue area [&minus, 7.5 cm2, 24.5, 9.6)], or subcutaneous adipose tissue area [&minus, 8.3 cm2, 35.5, 18.9)] over the first 8 cycles of chemotherapy. Among patients with advanced or metastatic colorectal cancer, the addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy did not result in any changes in body composition.

Background Website content and accessibility has the potential to influence the applicant's decision whether to interview for the program or not. The objective of our study is to determine the content and accessibility of the American Academy of Family Physicians (AAFP) Directory and accredited geriatric (family medicine) fellowship program websites. Methods A list of geriatric (family medicine) fellowship programs was retrieved using the AAFP Directory and verified for accreditation. Contact information was compared between the directory and the fellowship websites. The programs' website links from the directory were evaluated and compared with Google search. The websites' accessibility and content were assessed for program, education, and application overview. Results Fifty programs were identified, but 43 programs were chosen for analysis. There was an incongruence of over 50% of contact information between the AAFP Directory and the website page. Regarding content, most websites were lacking in fellows' profile information, previous research studies, and application ID. Conclusion AAFP Directory and fellowship websites can improve geriatric (family medicine) fellowship recruitment by updating their information and providing more accessible and accurate content.

The genetic basis of flowering time changes across environments, and pleiotropy may limit adaptive evolution of populations in response to local conditions. However, little information is known about how genetic architecture changes among environments. We used genome-wide association studies (GWAS) in Boechera stricta (Graham) Al-Shehbaz, a relative of Arabidopsis, to examine flowering variation among environments and associations with climate conditions in home environments. Also, we used molecular population genetics to search for evidence of historical natural selection. GWAS found 47 significant quantitative trait loci (QTLs) that influence flowering time in one or more environments, control plastic changes in phenology between experiments, or show associations with climate in sites of origin. Genetic architecture of flowering varied substantially among environments. We found that some pairs of QTLs showed similar patterns of pleiotropy across environments. A large-effect QTL showed molecular signatures of adaptive evolution and is associated with climate in home environments. The derived allele at this locus causes later flowering and predominates in sites with greater water availability. This work shows that GWAS of climate associations and ecologically important traits across diverse environments can be combined with molecular signatures of natural selection to elucidate ecological genetics of adaptive evolution.

Context Medication nonadherence is an important barrier to achieving optimal clinical outcomes. Currently, there are limited data on methods used to train medical students about medication adherence. Objective To evaluate the knowledge, confidence, and attitudes of first-year osteopathic medical students before and after a 30-minute peer-to-peer medication adherence education program led by a third-year pharmacy student. Methods All first-year medical students from Touro University California College of Osteopathic Medicine were invited to participate in 1 of 3 medication adherence educational sessions held in May 2019. A third-year pharmacy student who received training from Touro University California College of Pharmacy faculty served as the peer educator. Each session took approximately 1 hour to complete. The session included a preprogram survey, a 30-minute program, and a postprogram survey. Survey items included demographics; medication adherence knowledge, confidence, and attitudes; and attitudes toward the peer-to-peer educational format. Statistical comparisons of preprogram and postprogram knowledge, confidence, and attitudes were made using a paired t test, the McNemar test, and the Wilcoxon signed-rank test. P Results Twenty-three students participated in the study. Medication adherence knowledge scores improved after the program (17.4 [77.4%] vs 9.98 [92.2%]; PP Conclusion A 30-minute peer-to-peer program led by a pharmacy student improved first-year medical students’ knowledge, confidence, and attitudes with regard to medication adherence and provided an effective format to enhance interprofessional learning and collaboration.

531 Background: EV is an antibody-drug conjugate which recently received full FDA approval for treatment-refractory aUC. Molecular biomarkers and characteristics of patients (pts) most likely to respond to EV therapy have not been well defined. Methods: We retrospectively identified all aUC pts treated with EV at our institution. Clinicopathologic, treatment and response data were abstracted from pt charts. Pts were considered responders to EV if they had a complete response on initial scans after 2-3 months of treatment, or were treated with EV for ≥ 6 months. Responders and non-responders were compared in terms of their molecular and clinical characteristics using Chi-squared test. Most common somatic alterations present in ≥10 pts ( TERTp, TP53, CDKN2A, CDKN2B) were also used to divide pts with available next-generation sequencing (NGS) results into groups with and without these alterations. Log rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among these groups. Results: Between 1/2020 and 8/2021 a total of 32 pts received EV and 28 had NGS data available with either FoundationOne (14 pts), UCSF500 (13 pts) or Strata (1). Median age was 69.5 years, 24 (75%) were male, 22 (69%) Caucasian, 22 (69%) had pure urothelial histology and 22 (69%) primary tumor location in the bladder. At EV start, 24 (75%) had visceral metastases (mets), 8 (25%) had liver mets, and 13 (41%) had bone mets. Median follow-up from EV start was 12.5 months (range 0.5-36); 20 (63%) pts received EV monotherapy, and 12 (37%) received EV as part of a combination regimen. Non-responders were more likely to have bone metastases (69% vs 21%, p

265 Background: A recent study ( Fossati et al, 2018) found that higher lymph node count at radical prostatectomy was associated with improved outcomes in patients treated with salvage radiation for elevated prostate-specific antigen (PSA) after surgery. We sought to validate these results in NRG/RTOG 9601, a randomized controlled trial of men with pT2/T3 disease who underwent either radiation (RT) alone or RT+antiandrogen (bicalutamide) therapy for PSA elevation following radical prostatectomy from 1998-2003. Methods: We reviewed available pathology reports for all patients in NRG/RTOG 9601 to determine the nodal count at radical prostatectomy. Clinical data was as of 11/5/2015, same as the primary endpoint for the trial. Cox proportional hazards models were used to assess the effect of number of positive lymph nodes, treatment arm (RT alone or RT+bicalutamide), Gleason score, positive margins, and seminal vesicle invasion on the following endpoints: times to local and distant failure and overall and disease specific survival. Results: Out of the 760 patients originally eligible in the trial, 552 (73%, 276 in each arm) had complete data available. Median node count in the entire cohort was 6 (range 0-33, Q1-Q3 3-9). There were no significant differences between treatment arms in terms of patient demographic or clinical characteristics, including total lymph nodes removed in either arm (RT alone vs RT+bicalutamide median 5 vs 6, p = 0.11). There was no significant association between total lymph nodes and overall survival with both arms combined (HR = 1.00, 95% CI:0.97-1.03, p = 0.87) or in the individual arms alone (RT+Casodex: HR = 1.01, 95% CI:0.97-1.05, p = 0.65; RT+Placebo: HR = 0.98, 95% CI: 0.94-1.03, p = 0.45). There was also no significant association between total lymph nodes and disease-specific survival with both arms combined (HR = 1.00, 95% CI:0.95-1.04, p = 0.84) and in the arms alone (RT+Casodex: HR = 1.00, 95% CI:0.95-1.05, p = 0.92; RT+Placebo: HR = 0.99, 95% CI: 0.92-1.07, p = 0.86). In multivariable analysis performed on the two arms, Gleason score was the only feature associated with worse overall and disease-specific survival, seen only in the RT alone arm. Similar findings were seen when evaluating times to local and distant failure. Conclusions: Lymph node yield in NRG/RTOG 9601 did not show any association with adverse outcomes in the entire cohort, or in either treatment arm alone. The therapeutic benefit of an extensive lymph node dissection in this population remains uncertain. Clinical trial information: NCT00002874.

TPS214 Background: Approximately 3% of patients (pts) with CRC have the oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation. Sotorasib, a small molecule that specifically and irreversibly inhibits the KRAS G12C mutant protein, has demonstrated modest clinical activity and no dose-limiting toxicities as a single agent in heavily pretreated pts with KRAS p.G12C-mutated CRC. The combination of sotorasib with other anticancer therapies, such as EGFR or MEK inhibitors, may enhance antitumor efficacy and counteract potential escape mechanisms. Other attractive partners for sotorasib in CRC include biologics and chemotherapy combinations. The CodeBreaK 101 master protocol is designed to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple sotorasib-based combinations in pts with KRAS p.G12C mutated solid tumors. Key subprotocols with CRC combination treatment arms are highlighted here. Methods: This is a phase 1b, open-label study evaluating sotorasib alone and in combination regimens in pts with advanced KRAS p.G12C mutated CRC, NSCLC, and other solid tumors. Key regimens being explored in CRC include (1) Subprotocol A: Sotorasib + trametinib (MEK inhibitor) +/- panitumumab (EGFR inhibitor), (2) Subprotocol H: Sotorasib + panitumumab and sotorasib + panitumumab + FOLFIRI, and (3) Subprotocol M: Sotorasib + bevacizumab-awwb + FOLFIRI or FOLFOX. Key eligibility criteria include advanced or metastatic solid tumor with KRAS p.G12C mutation identified through molecular testing in treatment-naïve and pretreated patients depending on cohort. Primary endpoints include dose-limiting toxicities and treatment-emergent or treatment-related adverse events. Secondary endpoints include PK profile of combination regimens and efficacy (objective response, disease control, duration of response, time to response, and progression-free survival assessed per RECIST 1.1, and overall survival). Enrollment is ongoing. Contact Amgen Medical Information for more information: medinfo@amgen.com (NCT04185883). Abbreviations: EGFR = epidermal growth factor receptor; FOLFIRI = 5-fluorouracil + leucovorin + irinotecan; FOLFOX = 5-fluorouracil + leucovorin + oxaliplatin; MEK = mitogen-activated protein kinase. Clinical trial information: NCT04185883.

Cancer stem cells (CSCs) are a sub-population of tumour cells, which are responsible to drive tumour growth, metastasis and therapy resistance. It has recently been proposed that enhanced glucose metabolism and immune evasion by tumour cells are linked, and are modulated by the changing tumour microenvironment (TME) that creates a competition for nutrient consumption between tumour and different sub-types of cells attracted to the TME. To facilitate efficient nutrient distribution, oncogene-induced inflammatory milieu in the tumours facilitate adaptive metabolic changes in the surrounding non-malignant cells to secrete metabolites that are used as alternative nutrient sources by the tumours to sustain its increasing energy needs for growth and anabolic functions. This scenario also affects CSCs residing at the primary or metastatic niches. This review summarises recent advances in our understanding of the metabolic phenotypes of cancer cells and CSCs and how these processes are affected by the TME. We also discuss how the evolving TME modulates tumour cells and CSCs in cancer progression. Using previously described proteomic and genomic platforms, ovarian cancer cell lines and a mouse xenograft model we highlight the existence of metabolic and immune regulatory signatures in chemoresistant ovarian CSCs, and discuss how these processes may affect recurrence in ovarian tumours. We propose that progress in cancer control and eradication may depend not only on the elimination of highly chemoresistant CSCs, but also in designing novel strategies which would intervene with the tumour-promoting TME factors.

BACKGROUND The Paris System for Reporting Urinary Cytology (TPS) published in 2016 provides a standardized approach to evaluating urine cytology. In the authors' practice, a TPS-like approach was adopted in 2012 using similarly defined cytologic criteria and correlating cystoscopic findings, and they also began incorporating the use of cell block (CB) material. The objective of the current study was to assess whether this TPS-like approach with the use of CB, as well as direct implementation of TPS, improved the diagnostic value of urine cytology. METHODS In total, 188 consecutive urine cytology specimens from 2010 through 2016 that had concurrent or subsequent histologic specimens available were retrospectively analyzed for diagnostic correlation. Urine cytology performance was compared between the periods 2010 to 2012 (pre-TPS-like), 2013 to 2016 (TPS-like), and after TPS reclassification, including blind review by a cytopathologist. The contribution of available CB material to final diagnoses also was assessed. RESULTS Both the TPS-like approach and TPS reclassification resulted in significantly lowering the rate of atypical urothelial cells (AUC) diagnosis from 48%, to 21%, to 9% (from pre-TPS, to TPS-like, to after TPS reclassification, respectively; P < 0.01) while increasing the positive predictive value of an AUC diagnosis for high-grade urothelial carcinoma from 21%, to 43%, to 83%, respectively. The use of CBs contributed to a definitive final diagnosis in 24 of 36 cases (66.7%). CONCLUSIONS In support of the new TPS recommendations, the application of stringent "TPS-like" and TPS criteria improves the value of an AUC diagnosis for clinicians and patients by lowering the AUC rate and increasing the positive predictive value of AUC for high-grade urothelial carcinoma. CBs can be used to help resolve problematic cases for more definitive diagnostic categorization.