Definition of bulky disease in early stage Hodgkin lymphoma in computed tomography era: prognostic significance of measurements in the coronal and transverse planes.

Disease bulk is an important prognostic factor in early stage Hodgkin lymphoma, but its definition is unclear in the computed tomography era. This retrospective analysis investigated the prognostic significance of bulky disease measured in transverse and coronal planes on computed tomography imaging. Early stage Hodgkin lymphoma patients (n=185) treated with chemotherapy with or without radiotherapy from 2000-2010 were included. The longest diameter of the largest lymph node mass was measured in transverse and coronal axes on pre-treatment imaging. The optimal cut off for disease bulk was maximal diameter greater than 7 cm measured in either the transverse or coronal plane. Thirty patients with maximal transverse diameter of 7 cm or under were found to have bulk in coronal axis. The 4-year overall survival was 96.5% (CI: 93.3%, 100%) and 4-year relapse-free survival was 86.8% (CI: 81.9%, 92.1%) for all patients. Relapse-free survival at four years for bulky patients was 80.5% (CI: 73%, 88.9%) compared to 94.4% (CI: 89.1%, 100%) for non-bulky; Cox HR 4.21 (CI: 1.43, 12.38) (P=0.004). In bulky patients, relapse-free survival was not impacted in patients treated with chemoradiotherapy; however, it was significantly lower in patients treated with chemotherapy alone. In an independent validation cohort of 38 patients treated with chemotherapy alone, patients with bulky disease had an inferior relapse-free survival [at 4 years, 71.1% (CI: 52.1%, 97%) vs 94.1% (CI: 83.6%, 100%), Cox HR 5.27 (CI: 0.62, 45.16); P=0.09]. Presence of bulky disease on multidimensional computed tomography imaging is a significant prognostic factor in early stage Hodgkin lymphoma. Coronal reformations may be included for routine Hodgkin lymphoma staging evaluation. In future, our definition of disease bulk may be useful in identifying patients who are most appropriate for chemotherapy alone.

Aggregation of melanoma tumour site within Western Australian families.

BACKGROUND: Evidence is emerging that melanoma has distinct aetiologic pathways and subtypes, characterized by factors like anatomic site of the tumour. To explore genetic influences on anatomic subtypes, we examined the extent to which melanomas in first-degree relatives shared the same body site of occurrence. METHODS: Population-level linked data was used to identify the study population of over 1.5 million individuals born in Western Australia between 1945 and 2014, and their first-degree relatives. There were 1009 pairs of invasive tumours from 677 family pairs, each categorised by anatomic site. Greater than expected representation of site-concordant pairs would suggest the presence of genetic factors that predispose individuals to site-specific melanoma. RESULTS: Comparing observed versus expected totals, we observed a modest increase in site concordance for invasive head/neck and truncal tumours (P=0.02). A corresponding analysis including in situ tumours showed a similar concordance (P=0.05). No further evidence of concordance was observed when stratified by sex. CONCLUSION: In conclusion, modest evidence of aggregation was observed but with inconsistent patterns between sites. Results suggest that further investigation into the familial aggregation of melanoma by tumour site is warranted, with the inclusion of genetic data in order to disentangle the relative contributions of genetic and environmental factors.

Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma.

PURPOSE: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors. EXPERIMENTAL DESIGN: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness. RESULTS: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness. CONCLUSIONS: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.

Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets.

BACKGROUND: Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. OBJECTIVE: To identify genetic alterations with potential clinical implications in NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. RESULTS AND LIMITATIONS: TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p<0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio=3.14, 95% confidence interval: 1.51-6.51, p=0.002). CONCLUSIONS: Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. PATIENT SUMMARY: Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests.

Prognostic factors in myoepithelial carcinoma of salivary glands: a clinicopathologic study of 48 cases.

Myoepithelial carcinoma (MECA) is an underrecognized rare tumor with a diverse clinical behavior. The histologic features of this tumor are not well characterized, much less its grading, which is controversial. The objective of this study is to provide a better characterization of MECA and its prognostic factors. A total of 48 cases were retrieved from the pathology files. The cases were subjected to a detailed histopathologic, immunohistochemical, statistical, and clinical analysis. Tumors were classified as de novo MECA in 22 cases (46%) and carcinoma ex-pleomorphic adenoma (CA ex-PA) in 26 cases (54%). Tumor necrosis, high mitotic count (≥6/10 high-power fields), and severe pleomorphism were identified in 38%, 33%, and 21%, respectively. Perineural invasion, vascular invasion, and positive margins were noted in 10%, 12%, and 47%, respectively. Median follow-up was 38 months. Four patients had lymph node metastasis at presentation, 9 developed local recurrences, and 12 had distant metastases with the lung being the most common site (83%). The presence of CA ex-PA, necrosis, and vascular invasion correlated significantly with disease-free survival (P=0.02, 0.01, 0.03, respectively). No distant recurrence was noted in all 23 patients lacking necrosis in their neoplasms (median follow-up: 44 mo). MECA is a relatively aggressive tumor that is associated with a high rate of distant metastasis (27%). Compared with de novo MECA, CA ex-PA correlates with worse clinical outcome. A grading system based on the presence of tumor necrosis should be used to identify high-grade MECA and predict its clinical behavior.

Tumor Budding Correlates With the Protumor Immune Microenvironment and Is an Independent Prognostic Factor for Recurrence of Stage I Lung Adenocarcinoma.

BACKGROUND: Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma. METHODS: Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and forkhead box P3+ (FoxP3+) lymphocytes, CD68+ macrophages, IL-7 receptor, and IL-12 receptor ß2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using the competing risks method. RESULTS: In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs 12%, P < .001), which was confirmed in the validation cohort (P = .005). Tumor budding stratified the risk of recurrence for acinar-predominant (22% vs 9%, P < .001), papillary-predominant (22% vs 13%, P = .045), and solid-predominant (39% vs 19%, P = .022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7 receptor overexpression (P < .001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (hazard ratio, 1.61; P = .008). CONCLUSIONS: Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with the protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at the invading edge as a biologic driver of tumor aggressiveness.

Finding disease genes: a fast and flexible approach for analyzing high-throughput data.

Linkage disequilibrium (LD) is the non-random distribution of alleles across the genome, and it can create serious problems for modern linkage studies. In particular, computational feasibility is often obtained at the expense of power, precision, and/or accuracy. In our new approach, we combine linkage results over multiple marker subsets to provide fast, efficient, and robust analyses, without compromising power, precision, or accuracy. Allele frequencies and LD in the densely spaced markers are used to construct subsamples that are highly informative for linkage. We have tested our approach extensively, and implemented it in the software package EAGLET (Efficient Analysis of Genetic Linkage: Estimation and Testing). Relative to several commonly used methods we show that EAGLET has increased power to detect disease genes across a range of trait models, LD patterns, and family structures using both simulated and real data. In particular, when the underlying LD pattern is derived from real data, we find that EAGLET outperforms several commonly used linkage methods. In-depth analysis of family data, simulated with linkage and under the real-data derived LD pattern, showed that EAGLET had 78.1% power to detect a dominant disease with incomplete penetrance, whereas the method that uses one marker per cM had 69.7% power, and the cluster-based approach implemented in MERLIN had 76.7% power. In this same setting, EAGLET was three times faster than MERLIN, and it narrowed the MERLIN-based confidence interval for trait location by 29%. Overall, EAGLET gives researchers a fast, accurate, and powerful new tool for analyzing high-throughput linkage data, and large extended families are easily accommodated.