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AIMS - Well-differentiated small intestinal neuroendocrine tumours (SI-NETs) are often multifocal, and this has been suggested to impart worse disease-free survival. Practice guidelines have not been established for World Health Organisation (WHO) grading of multiple primary lesions.
METHODS AND RESULTS - We identified 68 patients with ileal/jejunal SI-NET for a combined total of 207 primary lesions. Each case was evaluated for patient age and sex; size of all tumours; presence of lymph node metastases, mesenteric tumour deposits or distant metastases; and disease-specific outcome. Ki67 staining was performed on all 207 primary lesions. The relationship between multifocality and clinicopathological factors was compared using Fisher's exact test. Outcome was tested using Cox proportional hazard regression. Forty-two patients had unifocal disease, and 26 had multifocal disease (median five lesions, range = 2-32). Most tumours were WHO grade 1 (201 of 207, 97%). Of the five patients with grades 2/3 tumours, three patients had unifocal disease, one patient had two subcentimetre grade 2 lesions (including the largest) and eight subcentimetre grade 1 lesions, and one patient had one 1.6-cm grade 3 lesion and one subcentimetre grade 1 lesion. There was a positive correlation between tumour size and Ki67 index (coefficient 0.28; 95% confidence interval 0.05-0.52, P = 0.017). There was no significant association between multifocality and nodal metastases, mesenteric tumour deposits, distant metastases or disease-specific survival.
CONCLUSIONS - In patients with multifocal SI-NET, unless a particular lesion has a high mitotic rate, only staining the largest lesion for Ki67 should serve to grade almost all cases accurately. Multifocality does not appear to significantly impact patient survival.
© 2018 John Wiley & Sons Ltd.

BACKGROUND - Curative-intent treatment for localized hilar cholangiocarcinoma (HC) requires surgical resection. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall (OS) and recurrence free survival (RFS) in patients undergoing curative resection.
METHODS - We reviewed patients with resected HC between 2000 and 2015 from the ten institutions participating in the U.S. Extrahepatic Biliary Malignancy Consortium. We analyzed the impact of AT on RFS and OS. The probability of RFS and OS were calculated in the method of Kaplan and Meier and analyzed using multivariate Cox regression analysis.
RESULTS - A total of 249 patients underwent curative resection for HC. Patients who received AT and those who did not had similar demographic and preoperative features. In a multivariate Cox regression analysis, AT conferred a significant protective effect on OS (HR 0.58, P = 0.013), and this was maintained in a propensity matched analysis (HR 0.66, P = 0.033). The protective effect of AT remained significant when node negative patients were excluded (HR 0.28, P = 0.001), while it disappeared (HR 0.76, P = 0.260) when node positive patients were excluded.
CONCLUSIONS - AT should be strongly considered after curative-intent resection for HC, particularly in patients with node positive disease.
© 2017 Wiley Periodicals, Inc.

Differentiating osteoclast-rich lesions of bone (giant cell tumor of bone [GCTB], chondroblastoma [CBA], and aneurysmal bone cyst [ABC]) can be challenging, especially in small biopsies or fine-needle aspirations. Mutations affecting codons 34 and 36 of either H3 Histone Family Member 3A (H3F3A) and/or 3B (H3F3B) are characteristically seen in GCTB and CBAs. We devised a simple assay to identify these mutations and evaluated its applicability for routine clinical diagnosis. One hundred twenty-four tissue specimens from 108 patients (43 GCTBs, 38 CBAs and 27 ABCs) were collected from the archives of the Calgary Laboratory Services/University of Calgary and Vanderbilt University Medical Center. Histology was reviewed by an expert orthopedic pathologist. A single base extension assay (SNaPshot) is used to interrogate each nucleotide in codons 34 and 36 of H3F3A and codon 36 of H3F3B. Final diagnoses were generated after re-reviewing cases and incorporating molecular findings. Of 43 GCTBs, 38 (88%) had an H3F3A G34W mutation; 35 of 38 CBAs (92%) had a K36M mutation in either H3F3B (N = 31; 82%) or H3F3A (N = 4; 11%); none of 27 ABCs had a tested mutation. Molecular findings changed the histomorphologic diagnosis in 5 cases (3 GCTB changed to ABC, and 2 ABC changed to GCTB). These findings support the diagnostic utility of mutational analysis for this differential diagnosis in certain challenging cases when clinicoradiologic and histomorphologic features are not definitive, particularly for distinguishing cellular ABC versus GCTB with secondary ABC.
Copyright © 2017 Elsevier Inc. All rights reserved.

BACKGROUND AND OBJECTIVES - The incidence of atrial fibrillation is high in ESRD, but limited data are available on the incidence of atrial fibrillation across a broad range of kidney function. Thus, we examined the association of eGFR and urine albumin-to-creatinine ratio with risk of incident atrial fibrillation.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We meta-analyzed three prospective cohorts: the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Cox regression models were performed examining the association of eGFR and urine albumin-to-creatinine ratio with incident atrial fibrillation adjusting for demographics and comorbidity. In additional analyses, we adjusted for measures of subclinical cardiovascular disease (by electrocardiogram and cardiac imaging) and interim heart failure and myocardial infarction events.
RESULTS - In the meta-analyzed study population of 16,769 participants without prevalent atrial fibrillation, across categories of decreasing eGFR (eGFR>90 [reference], 60-89, 45-59, 30-44, and <30 ml/min per 1.73 m), there was a stepwise increase in the adjusted risk of incident atrial fibrillation: hazard ratios (95% confidence intervals) were 1.00, 1.09 (0.97 to 1.24), 1.17 (1.00 to 1.38), 1.59 (1.28 to 1.98), and 2.03 (1.40 to 2.96), respectively. There was a stepwise increase in the adjusted risk of incident atrial fibrillation across categories of increasing urine albumin-to-creatinine ratio (urine albumin-to-creatinine ratio <15 [reference], 15-29, 30-299, and ≥300 mg/g): hazard ratios (95% confidence intervals) were 1.00, 1.04 (0.83 to 1.30), 1.47 (1.20 to 1.79), and 1.76 (1.18 to 2.62), respectively. The associations were consistent after adjustment for subclinical cardiovascular disease measures and interim heart failure and myocardial infarction events.
CONCLUSIONS - In this meta-analysis of three cohorts, reduced eGFR and elevated urine albumin-to-creatinine ratio were significantly associated with greater risk of incident atrial fibrillation, highlighting the need for further studies to understand mechanisms linking kidney disease with atrial fibrillation.
Copyright © 2017 by the American Society of Nephrology.

Triple negative breast cancers (TNBC) are aggressive tumors, with high rates of metastatic spread and targeted therapies are critically needed. We aimed to assess the prognostic and predictive value of a 3q 19-gene signature identified previously from lung cancer in a collection of 4,801 breast tumor gene expression data. The 3q gene signature had a strong association with features of aggressiveness such as high grade, hormone receptor negativity, presence of a basal-like or TNBC phenotype and reduced distant metastasis free survival. The 3q gene signature was strongly associated with lung metastasis only in TNBC (P < 0.0001, Hazard ratio (HR) 1.44, 95% confidence interval (CI), 1.31-1.60), significantly associated with brain but not bone metastasis regardless of TNBC status. The association of one 3q driver gene FXR1 with distant metastasis in TNBC (P = 0.01) was further validated by immunohistochemistry. In addition, the 3q gene signature was associated with better response to neoadjuvant chemotherapy in TNBC (P < 0.0001) but not in non-TNBC patients. Our study suggests that the 3q gene signature is a novel prognostic marker for lung and/or brain metastasis and a predictive marker for the response to neoadjuvant chemotherapy in TNBC, implying a potential role for 3q genes in the mechanism of organ-specific metastasis.

BACKGROUND - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with improved survival in some cancers, but evidence for ovarian cancer is limited.
METHODS - Pooling individual-level data from 12 Ovarian Cancer Association Consortium studies, we evaluated the association between self-reported, pre-diagnosis use of common analgesics and overall/progression-free/disease-specific survival among 7694 women with invasive epithelial ovarian cancer (4273 deaths).
RESULTS - Regular analgesic use (at least once per week) was not associated with overall survival (pooled hazard ratios, pHRs (95% confidence intervals): aspirin 0.96 (0.88-1.04); non-aspirin NSAIDs 0.97 (0.89-1.05); acetaminophen 1.01 (0.93-1.10)), nor with progression-free/disease-specific survival. There was however a survival advantage for users of any NSAIDs in studies clearly defining non-use as less than once per week (pHR=0.89 (0.82-0.98)).
CONCLUSIONS - Although this study did not show a clear association between analgesic use and ovarian cancer survival, further investigation with clearer definitions of use and information about post-diagnosis use is warranted.

BACKGROUND - The role of the chemokine CCL2 in breast cancer is controversial. While CCL2 recruits and activates pro-tumor macrophages, it is also reported to enhance neutrophil-mediated anti-tumor activity. Moreover, loss of CCL2 in early development enhances breast cancer progression.
METHODS - To clarify these conflicting findings, we examined the ability of CCL2 to alter naïve and tumor entrained neutrophil production of ROS, release of granzyme-B, and killing of tumor cells in multiple mouse models of breast cancer. CCL2 was delivered intranasally in mice to elevate CCL2 levels in the lung and effects on seeding and growth of breast tumor cells were evaluated. The TCGA data base was queried for relationship between CCL2 expression and relapse free survival of breast cancer patients and compared to subsets of breast cancer patients.
RESULTS - Even though each of the tumor cell lines studied produced approximately equal amounts of CCL2, exogenous delivery of CCL2 to co-cultures of breast tumor cells and neutrophils enhanced the ability of tumor-entrained neutrophils (TEN) to kill the less aggressive 67NR variant of 4T1 breast cancer cells. However, exogenous CCL2 did not enhance naïve or TEN neutrophil killing of more aggressive 4T1 or PyMT breast tumor cells. Moreover, this anti-tumor activity was not observed in vivo. Intranasal delivery of CCL2 to BALB/c mice markedly enhanced seeding and outgrowth of 67NR cells in the lung and increased the recruitment of CD4+ T cells and CD8+ central memory T cells into lungs of tumor bearing mice. There was no significant increase in the recruitment of CD19+ B cells, or F4/80+, Ly6G+ and CD11c + myeloid cells. CCL2 had an equal effect on CD206+ and MHCII+ populations of macrophages, thus balancing the pro- and anti-tumor macrophage cell population. Analysis of the relationship between CCL2 levels and relapse free survival in humans revealed that overall survival is not significantly different between high CCL2 expressing and low CCL2 expressing breast cancer patients grouped together. However, examination of the relationship between high CCL2 expressing basal-like, HER2+ and luminal B breast cancer patients revealed that higher CCL2 expressing tumors in these subgroups have a significantly higher probability of surviving longer than those expressing low CCL2.
CONCLUSIONS - While our in vitro data support a potential anti-tumor role for CCL2 in TEN neutrophil- mediated tumor killing in poorly aggressive tumors, intranasal delivery of CCL2 increased CD4+ T cell recruitment to the pre-metastatic niche of the lung and this correlated with enhanced seeding and growth of tumor cells. These data indicate that effects of CCL2/CCR2 antagonists on the intratumoral leukocyte content should be monitored in ongoing clinical trials using these agents.

Multiple different schemes are used to assess surgical resection margins in orthopedic pathology, but which is optimal for reporting resection margin status of osteosarcoma is uncertain. Moreover, the minimum tumor clearance (metric width of resection margin) necessary for local control is not well defined. In this investigation, the American Joint Committee on Cancer (AJCC) R system, Musculoskeletal Tumor Society (MSTS) system, and margin distance method for reporting resection margin status were compared in a series of 186 high-grade osteosarcomas. Hazard ratios for local recurrence for each resection margin category were compared with other categories within each margin assessment scheme to assess discriminatory ability. Cross-model comparisons of regression coefficients from parametric survival and logistic regression models were also performed. Predictive accuracy of each margin assessment scheme for determining 2-year local recurrence-free survival was evaluated by comparing the areas under receiver-operating characteristic curves generated from logistic regression analyses. Concordance with clinical outcomes was also calculated. Both the MSTS and margin distance schemes showed significantly greater predictive accuracy and concordance with observed outcomes than the AJCC R system. A margin distance of ≥2 mm significantly decreased the risk of local recurrence. Results were similar after adjustment for confounding prognostic factors (anatomic site, macroscopic lymphovascular invasion, and chemotherapy status). Therefore, surgical resection margins for osteosarcoma should be reported using either the MSTS or margin distance method instead of the AJCC R system.

BACKGROUND - Renal cell cancer (RCC) is a prevalent and lethal disease. At time of diagnosis, most patients present with localized disease. For these patients, the standard of care includes nephrectomy with close monitoring thereafter. While many patients will be cured, 5-year recurrence rates range from 30% to 60%. Furthermore, nearly one-third of patients present with metastatic disease at time of diagnosis. Metastatic disease is rarely curable and typically lethal. Cytotoxic chemotherapy and radiation alone are incapable of controlling the disease. Extensive effort was expended in the development of cytokine therapies but response rates remain low. Newer agents targeting angiogenesis and mTOR signaling emerged in the 2000s and revolutionized patient care. While these agents improve progression free survival, the development of resistance is nearly universal. A new era of immunotherapy is now emerging, led by the checkpoint inhibitors. However, therapeutic resistance remains a complex issue that is likely to persist.
METHODS AND PURPOSE - In this review, we systematically evaluate preclinical research and clinical trials that address resistance to the primary RCC therapies, including anti-angiogenesis agents, mTOR inhibitors, and immunotherapies. As clear cell RCC is the most common adult kidney cancer and has been the focus of most studies, it will be the focus of this review.
Copyright © 2017 Elsevier Inc. All rights reserved.

BACKGROUND - Planning and delivery of IMRT for locally advanced head and neck cancer (LAHNC) can be performed using sequential boost or simultaneous integrated boost (SIB). Whether these techniques differ in treatment-related outcomes including survival and acute and late toxicities remain largely unexplored.
METHODS - We performed a single institutional retrospective matched cohort analysis on patients with LAHNC treated with definitive chemoradiotherapy to 69.3 Gy in 33 fractions. Treatment was delivered via sequential boost (n = 68) or SIB (n = 141). Contours, plan evaluation, and toxicity assessment were performed by a single experienced physician. Toxicities were graded weekly during treatment and at 3-month follow up intervals. Recurrence-free survival, disease-free survival, and overall survival were estimated via Kaplan-Meier statistical method.
RESULTS - At 4 years, the estimated overall survival was 69.3% in the sequential boost cohort and 76.8% in the SIB cohort (p = 0.13). Disease-free survival was 63 and 69% respectively (p = 0.27). There were no significant differences in local, regional or distant recurrence-free survival. There were no significant differences in weight loss (p = 0.291), gastrostomy tube placement (p = 0.494), or duration of gastrostomy tube dependence (p = 0.465). Rates of acute grade 3 or 4 dysphagia (82% vs 55%) and dermatitis (78% vs 58%) were significantly higher in the SIB group (p < 0.001 and p = 0.012 respectively). Moreover, a greater percentage of the SIB cohort did not receive the prescribed dose due to acute toxicity (7% versus 0, p = 0.028).
CONCLUSIONS - There were no differences in disease related outcomes between the two treatment delivery approaches. A higher rate of grade 3 and 4 radiation dermatitis and dysphagia were observed in the SIB group, however this did not translate into differences in late toxicity. Additional investigation is necessary to further evaluate the acute toxicity differences.