Citations

653 Background: Next-generation sequencing often reveals potentially actionable molecular alterations; however, data on approved targeted therapies in non-indicated tumors are limited. MyPathway (NCT02091141) evaluates agents targeting the HER2, EGFR, BRAF, or Hedgehog (Hh) pathways in tumors for which these therapies are not currently indicated. Here, we present early response data for patients with GI tumors. Methods: Eligible patients had metastatic tumors with potentially actionable genomic alterations, identified by a CLIA-certified lab, and progression on standard therapy. Based on the identified alteration, patients received standard doses of trastuzumab + pertuzumab (HER2), erlotinib (EGFR), vemurafenib (BRAF), or vismodegib (Hh). Response was evaluated by the investigator using RECIST v1.1. Results: As of Aug 21, 2015, 96 patients had enrolled, 36 of whom (38%) had GI tumors with the following alterations: HER2 (n=28 [22 amplifications, 5 activating mutations, 1 both]), BRAF (n=4), Hh (n=2 [2 PTCH-1 mutations]), and EGFR (n=2). Patients had a median of 4 (range, 1–8) prior lines of therapy. Tumor types and interim best response data are shown below. Among all evaluable patients with GI tumors (n=26), 5 have had a PR to targeted therapy (duration 3–10+ months). Conclusions: Targetable molecular alterations were found in a variety of GI tumors, resulting in clinical benefit from targeted treatments that would not have otherwise been realized. These early results support this molecular testing strategy. Accrual to the trial continues; based on activity observed, the HER2-positive colorectal cancer cohort will be expanded to ≥30 patients. Additional data will be presented at the meeting. Clinical trial information: NCT02091141. [Table: see text]

Objectives: To describe the clinical presentation, radiological features, and outcome of patients with plasmacytoma of the temporal bone. Methods: Multicenter retrospective case series of all patients diagnosed with plasmacytoma of the temporal bone between 1990 and 2015. Comprehensive literature review of all previously published cases. Results: A total of seven patients (average age, 57.3 yr; 57% women) met inclusion criteria. Three (43%) had a known history of multiple myeloma (MM). The most common symptoms at presentation included otalgia, headache, and dizziness (43%, each). Five (71%) presented with a vascular appearing middle ear mass visible on otoscopy. Four of these patients did not have an established history of MM and were referred with presumptive diagnoses of paraganglioma or endolymphatic sac tumor (ELST). The average maximum tumor diameter was 3.7 cm (median, 3.5 cm; range, 0.9–6.6 cm) and the most commonly involved temporal bone subsites were the middle ear and mastoid (71% each). MM was ultimately diagnosed in six cases (86%). In addition to the new cases presented herein, 18 previously published reports were analyzed. In the 25 aggregate cases, 44% of cases were associated with MM, and the mastoid (72%) and middle ear (53%) were the most commonly involved temporal bone subsites. Conclusion: Plasmacytoma of the temporal bone is rare, and the clinical presentation can closely mimic that of other primary temporal bone tumors. In patients with an established history of MM, it is imperative to have a high index of suspicion for temporal bone plasmacytoma, even when radiological features suggest an alternate diagnosis.

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

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.

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.

Abstract To establish a useful laboratory protocol to investigate possible cases of fatal anaphylaxis, we measured mast-cell-derived tryptase levels and allergen-specific immunoglobulin E (IgE) antibody levels in sera obtained prior to or within 24 h after death from 19 anaphylaxis victims. Elevated serum tryptase levels (range = 12 ng/mL to 150 μg/mL) were found in nine of nine Hymenoptera sting fatalities, six of eight food-induced fatalities, and two of two reactions to diagnostic/therapeutic agents. Tryptase levels were normal (&lt;10 ng/mL) in 57 sequential sera obtained postmortem from six control patients. Tryptase could not be measured by pleural or pericardial fluids for technical reasons. Serum IgE antibodies were elevated in five of the nine Hymenoptera sting fatalities and in eight of the eight fatal food reactions; assays were unavailable for the two diagnostic/therapeutic agents. If elevated, the victim's serum IgE antibodies to food could be used to identify allergens in uneaten portions of foods consumed shortly before the anaphylactic event. IgE antibodies were moderately stable during storage in a variety of anticoagulants at room temperature for up to 11 weeks. Elevated mast-cell-derived tryptase levels in postmortem sera reflect antemortem mast cell activation and may be used as a marker for fatal anaphylaxis. If assays are available for IgE antibodies to relevant allergens, such assays provide evidence for antemortem sensitization; these assays may be modified to identify allergens in foods consumed by victims of food-induced anaphylaxis.

Objectives/HypothesisInverting papillomas (IPs) are benign locally invasive tumors that most commonly present within the sinonasal cavity. Temporal bone involvement is exceedingly rare, with fewer than 30 cases reported within the English literature to date.Study DesignCase series and systematic review of the literature.MethodsFour consecutive subjects with temporal bone inverting papilloma (TBIP) were treated, and an additional 28 previously published cases were identified in the literature. Main outcome measures were disease presentation, diagnostic evaluation, management strategy, and outcome.ResultsA total of 32 cases were analyzed. The median age at diagnosis was 54 years (mean 54.1; range 19–81 years). Nineteen (59%) patients had synchronous or metachronous sinonasal IP, whereas 13 (41%) had isolated temporal bone disease without sinus involvement. Over half of the patients undergoing microsurgical resection experienced at least one recurrence. Compared to patients with a history of sinus IP, subjects with primary TBIP were younger at time of presentation (44 vs. 58 years; P = 0.012); were more commonly female (62% vs. 32%; P = 0.15); and were less likely to have intracranial spread (8% vs. 26%; P = 0.36), cranial neuropathy (8% vs. 26%; P = 0.36), human papillomavirus positivity (11% vs. 57%; P = 0.11), or associated carcinoma (0% vs. 47%; P = 0.004).ConclusionsInverting papilloma of the lateral skull base is rare and can pose a significant therapeutic challenge. Primary lesions of the temporal bone appear to follow a less aggressive clinical course when compared to those arising in association with sinonasal disease. Gross total resection is the preferred method of treatment, when feasible, given the high rate of recurrence with subtotal resection and risk of associated malignancy.Level of Evidence4. Laryngoscope, 125:2576–2583, 2015

Abstract Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.