Citations

BackgroundIn patients undergoing transnasal endoscopic sellar surgery, an analysis of risk factors and predictors of intraoperative and postoperative cerebrospinal fluid leak (CSF) would provide important prognostic information.MethodsA retrospective review of patients undergoing endoscopic sellar surgery for pituitary adenomas or craniopharyngiomas between 2002 and 2014 at 7 international centers was performed. Demographic, comorbidity, and tumor characteristics were evaluated to determine the associations between intraoperative and postoperative CSF leaks. Correlations between reconstructive and CSF diversion techniques were associated with postoperative CSF leak rates. Odds ratios (OR) were identified using a multivariate logistic regression model.ResultsData were collected on 1108 pituitary adenomas and 53 craniopharyngiomas. Overall, 30.1% of patients had an intraoperative leak and 5.9% had a postoperative leak. Preoperative factors associated with increased intraoperative leaks were mild liver disease, craniopharyngioma, and extension into the anterior cranial fossa. In patients with intraoperative CSF leaks, postoperative leaks occurred in 10.3%, with a higher postoperative leak rate in craniopharyngiomas (20.8% vs 5.1% in pituitary adenomas). Once an intraoperative leak occurred, craniopharyngioma (OR = 4.255, p = 0.010) and higher body mass index (BMI) predicted postoperative leak (OR = 1.055, p = 0.010). In patients with an intraoperative leak, the use of septal flaps reduced the occurrence of postoperative leak (OR = 0.431, p = 0.027). Rigid reconstruction and CSF diversion techniques did not impact postoperative leak rates.ConclusionIntraoperative CSF leaks can occur during endoscopic sellar surgery, especially in larger tumors or craniopharyngiomas. Once an intraoperative leak occurs, risk factors for postoperative leaks include craniopharyngiomas and higher BMI. Use of septal flaps decreases this risk.

ABSTRACT Calcium supplementation is indicated for the treatment of nutritional rickets. Our aim was to determine the optimal dose of calcium for treatment of children with rickets. Sixty-five Nigerian children with radiographically confirmed rickets were randomized to daily supplemental calcium intake of 500 mg (n = 21), 1000 mg (n = 23), or 2000 mg (n = 21). Venous blood, radiographs, and forearm areal bone density (aBMD) were obtained at baseline and at 8, 16, and 24 weeks after enrollment. The primary outcome was radiographic healing, using a 10-point radiographic severity score. The radiographic severity scores improved in all three groups, but the rate of radiographic healing (points per month) was significantly more rapid in the 1000-mg (–0.29; 95% confidence interval [CI] –0.13 to –0.45) and 2000-mg (–0.36; 95% CI –0.19 to –0.53) supplementation groups relative to the 500-mg group. The 2000-mg group did not heal more rapidly than the 1000-mg group. Of those who completed treatment for 24 weeks, 12 (67%), 20 (87%), and 14 (67%) in the 2000-mg, 1000-mg, and 500-mg groups, respectively, had achieved a radiographic score of 1.5 or less (p = 0.21). Serum alkaline phosphatase decreased and calcium increased similarly in all groups. Forearm diaphyseal aBMD improved significantly more rapidly in the 2000-mg group than in the 500-mg and 1000-mg groups (p < 0.001). Daily calcium intakes of 1000 mg or 2000 mg produced more rapid radiographic healing of rickets than 500 mg, but 2000 mg did not have greater benefit than 1000 mg. Some children require longer than 24 weeks for complete healing of nutritional rickets. © 2016 American Society for Bone and Mineral Research.

Circulating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.

Abstract Purpose: Somatic mosaic mutation in the PPM1D gene have been associated with risk of breast and ovarian cancer. Somatic mosaic mutations in blood cells may be associated with older age and chemotherapy exposure. We wanted to determine if somatic mosaic mutations in PPM1D and in other genes are associated with older age and repeated exposure to chemotherapy, rather than a contributor to risk of disease. Experimental design: We used targeted capture and massively parallel genomic sequencing to sequence DNA from PBMCs from affected patients for PPM1D as well as 60 other DNA repair genes. For a number of samples with PPM1D mutations, we re-sequenced at greater depth on patients where PBMCs that were collected at diagnosis and recurrence. Results: We identified somatic mosaic mutations in exon 6 of PPM1D in 4 out of 474 (0.8%) individuals that were newly diagnosed and had no previous chemotherapy, in 3 out of 29 (10%) individuals newly diagnosed but receiving chemotherapy and in 58 of 274 (21%) individuals with relapsed platinum resistant ovarian cancer (p&lt;0.0001). The presence of PPM1D mutations in exon 6 was strongly associated with more advanced age (p=0.011, Wilcoxon test) and more than one chemotherapy regimen (p=0.026, Fisher's exact test). In paired blood samples from 13 patients, PPM1D mutations present at relapse were either not detected or detected at a lower percentage compared to blood obtained soon after diagnosis. Somatic mosaic mutations were also identified in TP53 in 7 of 274 (2.5%) women with relapsed platinum resistant cancer. In one of these cases, we had an earlier blood sample from diagnosis in which the mutation was not present at time near diagnosis. Conclusion: We found that somatic mosaic PPM1D mutations in PMBCs are associated with advanced age and repeated exposure to chemotherapy. Mosaic mutations in other genes were not confirmed with the exception of TP53, for which mutations are also detectable after extensive treatment. It seems likely that mosaic PPM1D mutations in blood from cancer patients may be a result of selection by chemotherapy of age-induced somatic mutations during exposure to chemotherapy. Further studies are needed to determine the clinical significance of these mutations. Citation Format: Maria I. Harrell, Barbara M. Norquist, Tom Walsh, Mark F. Brady, Ming K. Lee, Robert Hershberg, Kimberly R. Kalli, Heather Lankes, Eric Q. Konnick, Colin C. Pritchard, Bradley J. Monk, John K. Chan, Robert Burger, Scott H. Kaufmann, Michael J. Birrer, Elizabeth M. Swisher. Old age and chemotherapy contribute to the selection of PPM1D somatic mosaic mutations in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B71.

Abstract Background: Defects in homologous recombination (HR) DNA repair are common in high grade serous ovarian, peritoneal and fallopian tube carcinoma (HGSOC). Other than mutations in BRCA1 and BRCA2 (BRCA1/2), the molecular causes of HR deficiency have not been well delineated. The frequency of HR deficiency in non-serous ovarian carcinoma is not known. We previously identified that germline and somatic HR mutations in 13 genes in OC was associated with improved survival. We sought to replicate these data in an independent tumor set, while sequencing a larger number of DNA repair genes. Methods: We used BROCA-HR to sequence 65 DNA repair genes in germline (blood) and tumor DNA from 363 women with ovarian (262), peritoneal (91), or fallopian tube (10) carcinoma from an institutional tissue bank. Cox proportional hazards models, adjusted for stage and residual tumor after cytoreduction, were used to assess associations between mutations in DNA repair genes in HR or related pathways and overall survival from diagnosis. Results: In total, 96/363 (25%) patients had 59 germline and 45 somatic deleterious mutations in HR genes, including 34 germline and 22 somatic BRCA1/2 mutations. Damaging mutations found in other HR genes included 25 germline and 23 somatic in the following genes: 5 ATM, 6 ATR, 1 BAP1, 2 BARD1, 6 BLM, 2 BRIP1, 2 BRE, 1 BRCC3, 2 CHEK2, 1 ERCC1, 1 FANCG, 1 FANCI, 2 FANCL, 8 FANCM, 1 NBN, 2 PALB2, 1 RAD51D, 1 RBBP8, 1 SLX4, 1 UIMC1 and 1 XRCC2. Of 322 HGSOC, HR mutations occurred in 86 patients (26.7%) including 54 (16.8%) germline and 32 somatic (9.9%). HR mutation rates were similar across the different non-serous histologies. Of 13 clear cell OC, 2 (15.3%) had germline mutations in non-BRCA1/2 HR genes and 3 (23.1%) had PTEN/PIK3CA mutations. Of 27 endometrioid OC, 3 (11.1%) had HR mutations (1 germline BRCA1, and 2 non-BRCA1/2 somatic HR mutations). PTEN/PIK3CA mutations were identified in 9 (2.8%) HGSOC, 3 (23.1%) clear cell and 2 (7.5%) endometrioid. HR mutations demonstrated a trend towards improved long-term overall survival (hazard ratio = 0.78, 96% CI 0.57-1.05) after accounting for stage and debulking status. Conclusions: These data not only indicate that damaging HR mutations, both germline and somatic, are found in endometrioid and clear cell as well as HGSOC, but also confirm our previous results showing an association between HR mutations and improved overall survival in OC. We are now sequencing 163 additional non-serous OC to augment the current analysis and these data will be available at presentation. Citation Format: Maria I. Harrell, Matthew J. Maurer, Ethan P. Heinzen, Ming K. Lee, Kimberly R. Kalli, Kathy J. Agnew, Ann L. Oberg, Tom Walsh, Barbara M. Norquist, Lynn C. Hartmann, Scott H. Kaufmann, Elizabeth M. Swisher. Homologous recombination mutations and overall survival in high-grade serous, endometrioid, and clear cell ovarian carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A07.

Treatment of polycystic liver disease (PLD) focuses on symptom improvement. Generic questionnaires lack sensitivity to capture PLD‐related symptoms, a prerequisite to determine effectiveness of therapy. We developed and validated a disease‐specific questionnaire that assesses symptoms in PLD (PLD‐Q). We identified 16 PLD‐related symptoms (total score 0‐100 points) by literature review and interviews with patients and clinicians. The developed PLD‐Q was validated in Dutch (n = 200) and United States (US; n = 203) PLD patients. We assessed the correlation of PLD‐Q total score with European Organization for Research and Treatment of Cancer (EORTC) symptom scale, global health visual analogue scale (VAS) of EQ‐5D, and liver volume. To test discriminative validity, we compared PLD‐Q total scores of patients with different PLD severity stages (Gigot classification) and PLD‐Q total scores of PLD patients with general controls and polycystic kidney disease patients without PLD. Reproducibility was tested by comparing original test scores with 2‐week retest scores. In total, 167 Dutch and 124 US patients returned the questionnaire. Correlation between PLD‐Q total score and EORTC symptom scale (The Netherlands [NL], r = 0.788; US, r = 0.811) and global health VAS (NL, r = −0.517; US, r = −0.593) was good. There was no correlation of PLD‐Q total score with liver volume (NL, r = 0.138; P = 0.236; US, r = 0.254; P = 0.052). Gigot type III individuals scored numerically higher than type II patients (NL, 46 vs. 40; P = 0.089; US, 48 vs. 36; P = 0.055). PLD patients scored higher on the PLD‐Q total score than general controls (NL, 42 vs. 17; US, 40 vs. 13 points) and polycystic kidney disease patients without PLD (22 points). Reproducibility of PLD‐Q was excellent (NL, r = 0.94; US, 0.96). Conclusion: PLD‐Q is a valid, reproducible, and sensitive disease‐specific questionnaire that can be used to assess PLD‐related symptoms in clinical care and future research. (Hepatology 2016;64:151–160)

Injection of autologous adipose tissue removed via liposuction has been used clinically for facial contouring, the aging face, furrows, facial atrophy, acne scars, nasolabial folds, chin, and various other surgical defects. Survival rates for autografts of fat have been quoted anywhere from 30% to 80%. Our study uses a reproducible rabbit animal model for autotransplantation of adipose tissue and examines the histopathologic changes that occur to the graft over time. Autogenous subcutaneous fat was removed from a dorsal scapular donor site, treated to stimulate cannula damage as in liposuction, then reinjected at the base of the ear. Histologic examination of the grafts were made at 5, 10, 15, 20, 40, and 100 days after transplantation. Hematoxylin‐eosin sections were graded on degree of fibrosis present (0 to 4+), viable fat (1 to 10), degree of inflammation (0 to 4+), and neovascularization (+ or ‐). Viability of fat decreased from 8.5 to 10 at 5 days to 2 viability at 40 days. Acute inflammation peaked at 10 days, followed by the chronic inflammatory response with macrophages and multinucleated giant cells scavenging the dying fat graft. Neovascularization began at 5 days, peaked at 10 days, and remained constant thereafter only at the edge of the graft. Microcysts appeared at 15 days and increased in number in proportion to the decrease in viable fat. In summary, the temporal histologic events are progressive fibrosis; decreased amount of viable fat; inflammation beginning with a neutrophilic response, later a macrophage and giant cell response; and neovascularization at the periphery of the graft insufficient to maintain graft viability. In our animal model, autografts of fat appear to have limited long‐term viability and are replaced by fibrous tissue. This may have clinical implications in autografting of fat in facial plastic and reconstructive surgery.

AbstractBackground & AimsSomatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during somatostatin analogue therapy.MethodsWe pooled the individual patient data of four trials that evaluated long‐acting somatostatin analogues (120 mg lanreotide or 40 mg octreotide) for 6–12 months in polycystic liver disease patients. We performed uni‐ and multivariate linear regression analysis with preselected patient, disease and drug variables to identify independent predictors of response, defined as per cent change in liver or kidney volume (in ADPKD subgroup). All analyses were adjusted for baseline liver volume and centre.ResultsWe included 153 polycystic liver disease patients (86% female, median liver volume 4974 ml) from three international centres, all treated with octreotide (n = 70) or lanreotide (n = 83). Mean reduction in liver volume was 4.4% (range −31.6 to +9.4%). Multivariate linear regression revealed that elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy (−2.7%, 95% CI −5.1 to −0.2%, P = 0.04), independently of baseline liver volume. Somatostatin analogue type, underlying diagnosis and eGFR did not affect response. In our ADPKD subpopulation (n = 100), elevated alkaline phosphatase predicted liver volume reduction (−3.2%, P = 0.03) but did not predict kidney volume reduction (+0.1%, P = 0.97). Total gastro‐intestinal symptom severity decreased with therapy in a subgroup analysis (n = 95; P < 0.001).ConclusionAlkaline phosphatase is a liver‐specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy.

Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end‐stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. Conclusion: At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials. (Hepatology 2016;63:1357–1367)