Citations

Objectives/HypothesisTo highlight the phenomenon of cholesteatoma arising from the vascular strip following tympanoplasty and tympanomastoidectomy.Study DesignMulti‐institutional retrospective chart review.MethodsConsecutive adult and pediatric patients evaluated between 2000 and 2015 with acquired cholesteatoma arising from the skin of a prior vascular strip were identified. Patients with evidence of residual or recurrent cholesteatoma elsewhere in the middle ear, mastoid, or ear canal were excluded.ResultsSeventeen cases (71% female, 53% right‐sided) were identified, and the mean age at presentation was 39.2 years. Patients presented on average 12.9 years following prior otologic surgery, which was most commonly tympanoplasty without mastoidectomy (59%). However, younger patients presented with symptoms sooner following prior surgery (r = 0.61, r2 = 0.37, P = 0.0095). The most common presenting symptom was otorrhea (76%). All patients were found to have mastoid cholesteatoma with bony erosion, and three patients exhibited additional tegmen or posterior fossa bone defects. The middle ear was not involved with cholesteatoma in any case. A canal wall down procedure was performed due to extensive bony canal erosion in 29% of cases.ConclusionThe vascular strip is an uncommon source of iatrogenic cholesteatoma that can present years following an otherwise uncomplicated otologic surgery. The findings presented herein highlight the importance of careful vascular strip orientation at the conclusion of otologic surgery.Level of Evidence4. Laryngoscope, 127:698–701, 2017

AbstractBackground and AimTumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population‐based CRC utilizing a combination of tumor and germline testing approaches.MethodsColorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR‐deficient tumors and a subset of MMR‐proficient CRCs.ResultsOf the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR‐deficient CRC without MLH1 methylation and a gene mutation were considered Lynch‐like and comprised 41.1% and 25.2% of the MMR‐deficient CRCs for the ACCFR and MCCS, respectively.ConclusionsIdentification of MMR gene mutation carriers in Australian CRC‐affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR‐deficient CRCs will have unknown etiology (Lynch‐like) proving problematic for clinical management.

Abstract Background: The identification of organ-specific targetable signatures may help design more effective treatment for patients with metastatic breast cancer (MBC). We took a multi-OMIC approach to assess whether the AKT-mTOR pathway is globally activated during metastatic progression or whether it represents an organ-specific target. Methods: Snap frozen biopsies from 25 MBC patients enrolled in a prospective phase II trial were used. Sites of metastasis were classified as liver (n=8) and others (n=17), the latter including cutaneous, lung, lymph nodes, and intra-abdominal lesions. Signaling analysis of the 25 cases was performed using Reverse Phase Protein Microarray (RPPA) coupled with Laser Capture Microdissection. Activation of the AKT-mTOR pathway was quantified as phosphorylation of AKT (S473) and the mTOR target p70S6 (T389). Matched exome (WES) and RNASeq data were available for 17 of 25 patients, five with liver metastases. Sequencing data was processed using an in-house developed pipeline to identify somatic events including coding mutations, copy number alterations, gene fusions, and differential expression. Activation of the AKT-mTOR pathway and sequencing data were compared between hepatic and non-hepatic lesions using an integrated RPPA and genomic approach. Results: Among liver metastases, AKT was activated in 4 of the 8 (50.0%) patients, while 6 of the 8 cases (75.0%) showed activation of p70S6. Sequencing data revealed mutation of PIK3CA in 4 of the 5 liver metastases (80.0%). Three of the PIK3CA mutated specimens with catalytic domain mutations (codons 1023 and 147) demonstrated co-activation of AKT and p70S6, while the fourth case, containing a helical domain mutation (E542K), had activation of p70S6 only. The PIK3CA wild-type liver metastasis demonstrated low activation of AKT and p70S6. For non-hepatic metastases AKT was activated in 2 of the 17 cases (11.8%) and p70S6 in 5 of the 17 patients (29.4%). Discussion: Although these results need further validation, activation of the AKT-mTOR pathway appears to be a hepatic specific signature in MBC and could be used for the selection of targeted agents for hepatic lesions. Citation Format: Pierobon M, Wong S, Reeder A, Anthony SP, Robert NJ, Northfelt DW, Jahanzeb M, Vocila L, Wulfkuhle J, Dunetz B, Aldrich J, Byron S, Craig D, Liotta L, Petricoin EF, Carpten J. The AKT-mTOR pathway as a potential organ-specific drug target signature of hepatic metastases from breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-21.

Individuals diagnosed with colorectal cancer (CRC) are at risk of developing a metachronous CRC. We examined the associations between personal, tumour‐related and lifestyle risk factors, and risk of metachronous CRC. A total of 7,863 participants with incident colon or rectal cancer who were recruited in the USA, Canada and Australia to the Colon Cancer Family Registry during 1997‐2012, except those identified as high‐risk, for example, Lynch syndrome, were followed up approximately every 5 years. We estimated the risk of metachronous CRC, defined as the first new primary CRC following an interval of at least one year after the initial CRC diagnosis. Observation time started at the age at diagnosis of the initial CRC and ended at the age at diagnosis of the metachronous CRC, last contact or death whichever occurred earliest, or were censored at the age at diagnosis of any metachronous colorectal adenoma. Cox regression was used to derive hazard ratios (HRs) and 95% confidence intervals (CIs). During a mean follow‐up of 6.6 years, 142 (1.81%) metachronous CRCs were diagnosed (mean age at diagnosis 59.8; incidence 2.7/1,000 person‐years). An increased risk of metachronous CRC was associated with the presence of a synchronous CRC (HR = 2.73; 95% CI: 1.30–5.72) and the location of cancer in the proximal colon at initial diagnosis (compared with distal colon or rectum, HR = 4.16; 95% CI: 2.80–6.18). The presence of a synchronous CRC and the location of the initial CRC might be useful for deciding the intensity of surveillance colonoscopy for individuals diagnosed with CRC.

ObjectiveTo describe the clinical presentation and management of patients with cholesterol granulomas (CGs) that develop following temporal bone surgery.Study DesignCase series with chart review.SettingTwo independent tertiary academic referral centers.Subjects and MethodsA multicenter retrospective review was performed to identify all patients between 2001 and 2014 who were diagnosed with a CG that developed following temporal bone surgery. Patients with a history of idiopathic petrous apex CGs were excluded, as were those with <6 months of follow‐up after diagnosis. Demographic and clinical data were recorded at presentation, and the main outcome measure was symptom evolution over time.ResultsA total of 20 patients met inclusion criteria (median age, 55.0 years; 70.0% female), and their cases were analyzed. Diagnosis was made, on average, 149.5 months (median, 94.5; range, 13.0‐480.0) following a temporal bone operation, which was for chronic ear disease in 75.0% of cases. The most common presenting symptoms were otalgia (55.0%) and otorrhea (40.0%). In patients initially managed with observation, 71.4% required no surgical intervention through a mean of 56.8 months (median, 30; range, 12.0‐178.0) of follow‐up. For those who initially underwent surgical excision, durable symptom relief was achieved in 66.7% of cases.ConclusionPostoperative CG formation in the temporal bone is a rare occurrence that can be encountered years following surgery. The present study suggests that conservative management can be appropriate for many cases in which patients are relatively asymptomatic.

ObjectivesTo analyze factors that influence hearing preservation over time in cochlear implant recipients with conventional‐length electrode arrays located entirely within the scala tympani.Study DesignCase series with planned chart review.SettingSingle tertiary academic referral center.Subjects and MethodsA retrospective review was performed to analyze a subgroup of cochlear implant recipients with residual acoustic hearing. Patients were included in the study only if their electrode arrays remained fully in the scala tympani after insertion and serviceable acoustic hearing (≤80 dB at 250 Hz) was preserved. Electrode array location was verified through a validated radiographic assessment tool. Patients with <6 months of audiologic follow‐up were excluded. The main outcome measure was change in acoustic hearing thresholds from implant activation to the last available follow‐up.ResultsA total of 16 cases met inclusion criteria (median age, 70.6 years; range, 29.4‐82.2; 50% female). The average follow‐up was 18.0 months (median, 16.1; range, 6.2‐36.4). Patients with a lateral wall electrode array were more likely to have stable acoustic thresholds over time (P <. 05). Positive correlations were seen between continued hearing loss following activation and larger initial postoperative acoustic threshold shifts, though statistical significance was not achieved. Age, sex, and noise exposure had no significant influence on continued hearing preservation over time.ConclusionsTo control for hearing loss associated with interscalar excursion during cochlear implantation, the present study evaluated patients only with conventional electrode arrays located entirely within the scala tympani. In this group, the style of electrode array may influence residual hearing preservation over time.

Consensus diagnostic recommendations to distinguish GORD from eosinophilic oesophagitis (EoE) by response to a trial of proton pump inhibitors (PPIs) unexpectedly uncovered an entity called ‘PPI-responsive oesophageal eosinophilia’ (PPI-REE). PPI-REE refers to patients with clinical and histological features of EoE that remit with PPI treatment. Recent and evolving evidence, mostly from adults, shows that patients with PPI-REE and patients with EoE at baseline are clinically, endoscopically and histologically indistinguishable and have a significant overlap in terms of features of Th2 immune-mediated inflammation and gene expression. Furthermore, PPI therapy restores oesophageal mucosal integrity, reduces Th2 inflammation and reverses the abnormal gene expression signature in patients with PPI-REE, similar to the effects of topical steroids in patients with EoE. Additionally, recent series have reported that patients with EoE responsive to diet/topical steroids may also achieve remission on PPI therapy. This mounting evidence supports the concept that PPI-REE represents a continuum of the same immunological mechanisms that underlie EoE. Accordingly, it seems counterintuitive to differentiate PPI-REE from EoE based on a differential response to PPI therapy when their phenotypic, molecular, mechanistic and therapeutic features cannot be reliably distinguished. For patients with symptoms and histological features of EoE, it is reasonable to consider PPI therapy not as a diagnostic test, but as a therapeutic agent. Due to its safety profile, ease of administration and high response rates (up to 50%), PPI can be considered a first-line treatment before diet and topical steroids. The reasons why some patients with EoE respond to PPI, while others do not, remain to be elucidated.

ObjectiveTo describe surgical outcomes and perioperative complications in patients taking antiplatelet and anticoagulation medications while undergoing cochlear implantation.Study DesignCase series with chart review.SettingTwo tertiary otologic referral center.Subjects and MethodsForty‐six adult patients (2005‐2014) who underwent cochlear implantation while on perioperative antiplatelet and/or anticoagulation therapy without interruption. Outcomes included estimated intraoperative blood loss, perception of increased difficulty secondary to bleeding, and postoperative complications attributable to continuing anticoagulation or antiplatelet therapy.ResultsThe cases of 46 patients (mean age, 69.5 years; 30.2% female) were analyzed. Of these, 39 patients were taking aspirin, 10 warfarin, and 7 clopidogrel. Aside from 3 (6.5%) patients with postoperative bruising without hematoma and 1 patient (2.2%) who reported self‐resolving oral cavity blood, no intraoperative or postoperative complications occurred in any patient that could be ascribed to antiplatelet or anticoagulant use.ConclusionThese data demonstrate that the risk of perioperative complications from continued antiplatelet or anticoagulation therapy is low. For subjects who are at risk of major complications (eg, deep venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident) from temporary medication cessation, continuing antiplatelet or anticoagulation therapy through the perioperative period is an appropriate strategy.