Decatur Memorial Hospital

Importance: Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. Objective: To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. Design, Setting, Participants: Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. Interventions: Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. Main Outcomes and Measures: The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). Results: Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks. Conclusions and Relevance: Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option. Trial Registration: clinicaltrials.gov Identifier: NCT00869206.

The hemitongue paralysis that occurs as a result of a classic hypoglossal-facial nerve crossover procedure can result in profound functional deficits in speech, mastication, and swallowing. The procedure is not an option in patients with bilateral facial paralysis or those at risk for combined cranial nerve deficits. To address some of the drawbacks and limitations of this classic procedure, we developed the hypoglossal-facial nerve interpositional jump graft (12-7 jump graft) procedure. This procedure involves interposing a nerve graft between a partially severed but functionally intact twelfth cranial nerve and the degenerated seventh cranial nerve, and is often combined with other reanimation procedures. To date, we have performed 33 12-7 jump graft procedures in 30 patients (three were treated for bilateral facial paralysis); this report describes the procedure and its indications, and details the results of 23 procedures performed in 20 patients for whom 24-month follow-up data are available. Twelfth nerve deficits occurred in only three patients in this report. Recovery of facial function began between 3 and 24 months postoperatively. Facial tone and symmetry were achieved in every patient, no patient had significant mass movement, and 13 patients (two of whom were treated for bilateral facial paralysis) had excellent and three had superb restoration of facial movement. These results show the 12-7 jump graft to be a valuable adjunct for facial reanimation in selected patients.

PURPOSE: Combination of antiprogrammed cell death protein-1 (PD-1) plus anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy. METHODS: Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non-anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR. RESULTS: Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody-based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1-negative, non-T-cell-inflamed, and intermediate tumor phenotypes. CONCLUSION: To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.

PURPOSE: Veliparib, a poly (ADP ribose) polymerase inhibitor, potentiated standard chemotherapy against small-cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of veliparib with cisplatin and etoposide (CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC). MATERIALS AND METHODS: on days 1 through 3) along with veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P). The primary end point was progression-free survival (PFS). Using an overall one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a 37.5% reduction in the PFS hazard rate. RESULTS: A total of 128 eligible patients received treatment on protocol. The median age was 66 years, 52% of patients were men, and Eastern Cooperative Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5 months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR, 0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3 versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17) for the CE+V and CE+P arms, respectively. The overall response rate was 71.9% versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a significant treatment-by-strata interaction in PFS: Male patients with high lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI, 0.22 to 0.51) but there was no evidence of benefit among patients in other strata (PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade ≥ 3 hematology toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia (8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery was comparable. CONCLUSION: The addition of veliparib to frontline chemotherapy showed signal of efficacy in patients with ES-SCLC and the study met its prespecified end point.

PURPOSE: Somatic mutations and copy number variation in the ERBB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ERBB molecular alterations are associated with clinical response. PATIENTS AND METHODS: In this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ERBB3, and ERBB4 was conducted. RESULTS: The first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities were observed; two patients required dose reduction for grade 3 fatigue and rash. Overall, five of 23 patients (21.7%) met PFS3 (two partial response, three stable disease). Notably, among the 21 tumors analyzed, five of six patients (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 6.3, and 5.0 months, respectively) versus none of 15 patients without alterations (P < .001). Three of four patients with HER2 amplification and three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 amplification and ERBB3 mutation never progressed on therapy, but treatment was discontinued after 10.3 months as a result of depressed ejection fraction. The median time to progression/discontinuation was 6.6 months in patients with HER2/ERBB3 alterations versus 1.4 months in patients without alterations (P < .001). CONCLUSION: Afatinib demonstrated significant activity in patients with platinum-refractory UC with HER2 or ERBB3 alterations. The potential contribution of ERBB3 to afatinib sensitivity is novel. Afatinib deserves further investigation in molecularly selected UC.

Abstract The bouba/kiki effect—the association of the nonce word bouba with a round shape and kiki with a spiky shape—is a type of correspondence between speech sounds and visual properties with potentially deep implications for the evolution of spoken language. However, there is debate over the robustness of the effect across cultures and the influence of orthography. We report an online experiment that tested the bouba/kiki effect across speakers of 25 languages representing nine language families and 10 writing systems. Overall, we found strong evidence for the effect across languages, with bouba eliciting more congruent responses than kiki. Participants who spoke languages with Roman scripts were only marginally more likely to show the effect, and analysis of the orthographic shape of the words in different scripts showed that the effect was no stronger for scripts that use rounder forms for bouba and spikier forms for kiki. These results confirm that the bouba/kiki phenomenon is rooted in crossmodal correspondence between aspects of the voice and visual shape, largely independent of orthography. They provide the strongest demonstration to date that the bouba/kiki effect is robust across cultures and writing systems. This article is part of the theme issue ‘Voice modulation: from origin and mechanism to social impact (Part II)’.

PURPOSE: To determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Between June 1998 and February 1999, 41 patients with metastatic RCC were enrolled onto this multi-institutional phase II study of gemcitabine 600 mg/m(2) over 30 minutes on days 1, 8, and 15 and 5-FU 150 mg/m(2)/d via continuous IV infusion through a permanent catheter on days 1 to 21 of a 28-day cycle. Patients had a Cancer and Leukemia Group B performance status of 0 or 1, with a median time since diagnosis of metastatic disease of 10 months (range, 0 to 129 months). Thirty-three patients (80%) had multiple metastatic sites, and 34 patients (83%) had prior chemotherapy or immunotherapy. RESULTS: Of the 39 assessable patients, there were no complete responses but seven partial responses (objective response rate = 17%; 95% confidence interval, 8% to 34%). Five minor responses (25% to 50% decreased tumor size) were also observed. The duration of response for the seven partial responders was 2, 3, 7, 8, 10, 11, and 14 months. Median progression-free survival for the gemcitabine/5-FU group was 28.7 weeks versus 8 weeks for a similar cohort of patients treated on previous phase II studies at the University of Chicago (P =.008). The regimen was well tolerated, with fatigue, mucositis, nausea/vomiting, and grade 2 hematologic toxicities being most common. CONCLUSION: Weekly gemcitabine with continuous infusion 5-FU is an active combination in patients with metastatic RCC. Therapy was well tolerated and produced an improvement in progression-free survival over historical controls.

The purpose of this study was to investigate the effects of the design of the screw, the depth of insertion, the vertebral level, and the quality of the host bone on the pull-out resistance of screws used in the lateral masses. The study included twelve fresh cervical spines from human cadavera. Radiographs were made of each specimen to ensure the absence of defects, and then the cancellous-bone density of the vertebral bodies was measured at each level with quantitative computed tomography scanning. Six commercially available screws of various diameters and thread configurations (2.7, 3.2, 3.5, and 4.5-millimeter cortical-bone screws; a 3.5-millimeter cancellous-bone screw; and a 3.5-millimeter self-tapping screw) that are currently used for fixation of the cervical lateral masses were tested for axial load to failure. A twelve-by-twelve Latin square design was used to randomize the screws with regard to level (second through seventh cervical vertebrae), side (right and left), and depth of insertion (unicortical or bicortical purchase). Each screw was then subjected to uniaxial load to failure. The data were analyzed to determine if the diameter of the screw, the thread configuration, the number of cortices engaged, the cervical level, or the bone density was associated with the load to failure. Three major subgroups (greatest, intermediate, and lowest pull-out resistance) were identified. The subgroup with the greatest pull-out resistance included only screws with bicortical purchase; the 3.2, 3.5, and 4.5-millimeter cortical-bone screws and the 3.5-millimeter cancellous-bone screw were in this subgroup. Regardless of the thread configuration, no screw with unicortical purchase was in the group with the greatest pull-out resistance. Two of the three values in the subgroup with the lowest pull-out resistance were for the 3.5-millimeter self-tapping screw (with unicortical or bicortical purchase). The cancellous-bone density of the vertebral body was not associated with pull-out resistance and it did not vary significantly according to the cervical level, with the numbers available. However, the pull-out resistance of the screws varied significantly (p = 0.004) by level: it was the greatest at the fourth cervical level, decreasing cephalad and caudad to that level.

BACKGROUND: Novel, effective therapies are warranted in the management of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Perifosine is an oral alkylphospholipid that inhibits AKT phosphorylation and has shown preclinical antitumor activity in head and neck cancer cell lines and xenografts. PATIENTS AND METHODS: We conducted a phase II trial of perifosine in patients with incurable, recurrent or metastatic SCCHN. Previous therapy for recurrent or metastatic disease was limited to no more than one prior chemotherapy and one prior targeted/biologic agent regimen. Patients had to have measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate laboratory parameters. Perifosine was given as a loading dose of 150 mg every 6 hours x 6 doses orally in the first two days, with antiemetic prophylaxis, followed by 100 mg/day orally without interruption. Administration via gastrostomy tube was allowed. Tumor response was assessed every two cycles (eight weeks). Biomarkers in pathways potentially affected by perifosine, including AKT, P-AKT, P38, p53 and p21 were measured on tumor tissue by immunohistochemistry by manual and automated methods. RESULTS: Nineteen patients were enrolled. No objective responses were observed. One patient had stable disease as best response and 18 patients progressed at first evaluation. The median overall survival time was 5.5 months and the median progression-free survival time was 1.7 months. The most frequent toxicities were gastrointestinal (constipation, nausea, vomiting) and fatigue. One patient developed grade 4 anorexia. Although the sample size was small, a significant correlation was detected between high expression of P38 and AKT in baseline tumor tissue and better survival. CONCLUSIONS: Perifosine in the doses and schedule used lacks single-agent activity in SCCHN. Our data do not justify further investigation of perifosine as a single agent in SCCHN.

PURPOSE: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown. EXPERIMENTAL DESIGN: Selumetinib is an oral small-molecule inhibitor of MAP-ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal-regulated kinase (ERK) and mTOR phosphorylation. RESULTS: Common drug-related toxicities were grade 1-2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027). CONCLUSIONS: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials.

Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m(2) once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3-64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2-5.4 months). Median OS was 8.2 months (95% CI, 5.1-9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.

Heredofamilial paragangliomas account for less than 10% of those arising in the head and neck. Multiplicity, multicentricity, and bilaterality is roughly three times more common than in the spontaneous variety. Not unlike other hereditary neuroendocrine tumor syndromes, familial paragangliomas appear to follow an autosomal dominant transmission, with variable penetrance and expressivity. This article describes a surgical experience with nine bilateral, multicentric cervical paragangliomas (7 carotid body, 1 vagal, and 1 sympathetic) occurring in four siblings less than 35 years of age. The literature on familial paragangliomas of the head and neck is reviewed. The postulated genetic mechanisms accounting for these and other hereditary tumors are discussed. The clinical and surgical aspects of spontaneous and familial paragangliomas are compared.

BACKGROUND AE-941 is a standardized aqueous shark cartilage extract with antiangiogenic properties that has previously been evaluated in phase I and II clinical trials. Our objective was to determine the effect of adding AE-941 to chemoradiotherapy on overall survival of patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS A randomized, double-blinded, placebo-controlled, phase III clinical trial was designed to test the efficacy of AE-941 in unresectable stage III NSCLC patients who were treated with chemoradiotherapy. Between June 5, 2000, and February 6, 2006, 379 eligible patients were enrolled in community and academic oncology centers across the United States and Canada. In February 2006, the trial was closed to new patient entry before meeting the target sample size because of insufficient accrual. All subjects received induction chemotherapy followed by concurrent chemotherapy with chest radiotherapy. Each participating center administered one of the two chemotherapy regimens, either carboplatin and paclitaxel, or cisplatin and vinorelbine. The primary endpoint was overall survival, and secondary endpoints were time to progression, progression-free survival, tumor response rate, and toxic effects. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS There was no statistically significant difference in overall survival between the chemoradiotherapy plus AE-941 group (n = 188; median survival = 14.4 months, 95% confidence interval = 12.6 to 17.9 months) and the chemoradiotherapy plus placebo group (n = 191; median survival = 15.6 months, 95% confidence interval = 13.8 to 18.1 months) (P = .73). Time to progression, progression-free survival, and tumor response rates were not statistically significantly different between the AE-941 and the placebo groups. No differences between the two groups were observed in common grade 3 or higher toxic effects attributable to chemoradiotherapy. CONCLUSIONS The addition of AE-941 to chemoradiotherapy did not improve overall survival in patients with unresectable stage III NSCLC. This study does not support the use of shark cartilage-derived products as therapy for lung cancer.

BACKGROUND: Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer. METHODS: Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline. RESULTS: One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006). CONCLUSIONS: There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. © 2016 American Cancer Society.

The investigators assessed quality of life for 19,747 participants in a double-blind, randomized trial comparing tamoxifen (20 mg daily) and raloxifene (60 mg daily), both given for 5 years, for their ability to lower the risk of invasive breast cancer in postmenopausal women. Patients were followed at nearly 200 centers throughout North America for a median potential time of 4.6 years. Participants completed a 36-item symptom checklist. Quality of life was estimated using the Medical Outcomes Study Short-Form Health Survey and the Medical Outcomes Study Sexual Activity Questionnaire. Depressive symptoms were measured using the Center for Epidemiologic Studies–Depression scale, a 20-item self-report scale. The questionnaires were administered before treatment and every 6 months for 5 years. Quality-of-life scores worsened modestly over 5 years of follow up but did not differ significantly between the 2 treatment groups. Sexual function was slightly better for women assigned to tamoxifen therapy. Raloxifene-treated women reported more severe symptoms over the 5-year study period for musculoskeletal problems, dyspareunia, and weight gain. Women taking tamoxifen reported more severe symptoms from gynecologic problems and more marked vasomotor symptoms, leg cramps, and symptoms of bladder control disorders. There were no significant group differences in mental health problems, including depression. In general, differences in symptom severity between the 2 treatment groups were small.

Postural orthostatic tachycardia syndrome (POTS) is an impaction of the autonomic nervous system initiating orthostatic tachycardia. There are numerous triggers for POTS including viruses, vaccines, and an autoimmune basis. This case report is clinically relevant to better understand the pathophysiology behind the messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccine and the mechanism that triggers autonomic nervous system dysfunction. Furthermore, the overall goal of this case study is to report a unique side effect associated with the novel mRNA COVID-19 vaccine. A 42-year-old male, with no prior symptoms of sinus tachycardia and presyncope episodes, is diagnosed with POTS secondary to the first dose of the mRNA COVID-19 vaccine. Symptoms to this date include sinus tachycardia, dizziness, headaches, and fatigue that are often triggered after a large meal or standing for a longer duration. Numerous diagnostic tests and images failed to confirm any other diagnosis other than POTS. There was a sequential connection between the onset of symptoms approximately one week after taking the first dose of the mRNA COVID-19 vaccine. Currently, POTS in this patient is controlled by lifestyle modification. This case report has broader implications as it can help us understand how the mRNA vaccine works on the body relative to the immune system. Our theory is that the development of antibodies activates an autoimmune reaction that triggers POTS disease. The prevalence of the POTS dysautonomia post-vaccination will be clearer as more data and research are conducted on the side effects from the innovative mRNA vaccines created to combat severe acute respiratory syndrome coronavirus 2.

BACKGROUND: Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS: IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS: The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS: The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION: "Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.

STUDY DESIGN: A rabbit model for lumbar intertransverse process spine arthrodesis was utilized, with blind evaluation of the control and experimental animals. OBJECTIVES: To establish an animal model for motion-induced nonunion of lumbar intertransverse process spine arthrodesis and to determine if there was an early time period during which excessive motion at the arthrodesis site was deleterious to fusion. SUMMARY OF BACKGROUND DATA: Most previously reported animal models for nonunion of lumbar spine arthrodesis do not use intertransverse process fusion and do not allow variable control of the nonunion-inducing factor. METHODS: Forty-two adult New Zealand white rabbits underwent posterolateral intertransverse process spine arthrodesis with autogenous iliac crest graft. Rabbits in the experimental group (n = 23) underwent a lifting protocol to produce motion at the arthrodesis site; those in the control group (n = 12) remained undisturbed in their cages. Arthrodeses were assessed radiographically and manually to determine if fusion had occurred. RESULTS: Lifted rabbits exhibited a 13% fusion rate compared to a 50% fusion rate in controls. Rabbits lifted during only the first 2 postoperative weeks exhibited a fusion rate that was significantly less (P = 0.03) than that of controls. CONCLUSIONS: A small animal model for motion-induced nonunion of lumbar intertransverse process spine arthrodesis has been established. With respect to excessive motion as a promoter of nonunion in spine arthrodeses, the early postoperative time period appears critical.

Critical limb ischemia (CLI) is typified by rest pain and/or tissue necrosis secondary to advanced peripheral arterial disease (PAD) and is characterized by diminution in limb perfusion at rest. We tested the safety of an angiogenic strategy with CI-1023 (Ad(GV)VEGF121.10), a replication-deficient adenovirus encoding human vascular endothelial growth factor isoform 121 in patients with CLI as part of a phase I trial. Fifteen subjects >35 years of age with CLI and angiographic disease involving the infra-inguinal vessels underwent intramuscular injection of CI-1023 (4 x 10(8) to 4 x 10(10) particle units, n = 13) or placebo (n = 2). All of the patients tolerated the injection well and there were no serious complications related to the procedure. Transient edema was noted in one patient. A total of 79 adverse events were reported over the course of one year. One death (day 136) and one malignancy (day 332) occurred in the CI-1023 group. CI-1023 appears to be well tolerated and safe for single-dose administration in patients with critical limb ischemia due to PAD. Further studies are needed to determine the efficacy of this form of therapeutic angiogenesis.

Although the treatment of anterior cruciate ligament (ACL) tears in skeletally immature patients is still controversial, several studies have advocated ACL reconstruction in selected patients to prevent secondary injury. The proximal tibial physis is a structure at risk during ACL reconstruction in young patients, and physeal growth complications have been reported after surgery in this area. The relationship between the ACL and the proximal tibial physeal/apophyseal regions is poorly understood. This study examined the MRI anatomy of the ACL and the proximal tibia apophysis and epiphysis. MRIs of 59 skeletally immature knees were reviewed (Average age = 12.75 years, range 6-15) to define the anatomy of the epiphyseal and apophyseal regions. Measurements were recorded in three parasagittal planes: (1) at the lateral border of the patellar tendon, (2) the lateral edge of the ACL insertion, and (3) the medial edge of the ACL insertion. A single three-dimensional (3D) computed tomography (CT) scan was used to evaluate the position of standard drill holes used in ACL reconstruction to assess for potential degree of injury to the epiphyseal and apophyseal growth plates. In the parasagittal planes, the average height of the epiphysis was 19.6, 20.7, and 21.5 mm at the lateral border of the patellar tendon, the lateral border of the ACL, and the medial border of the ACL, respectively. At the level of the same landmarks, the apophysis extended below the physis at an average of 20.2, 16.8, and 7.0 mm, respectively. Expressed as a percentage of epiphysis height this was an average of 104, 82, and 33%, respectively. Examination of 3D CT images revealed that variations in drill hole placement had effects on the volume of injury to the proximal tibial physis and apophysis. Drill holes that started more medial, distal, and with a steeper angle of inclination reduced the amount of physis and apophysis violated when compared with holes placed more lateral, proximal, and with a shallow angle of inclination. The proximal tibial physis and apophysis is vulnerable to injury by drill hole placement during ACL reconstruction in skeletally immature patients. This paper defines the anatomic relationship of the apophyseal and epiphyseal regions of the physis in the proximal tibia. The volume of injury to the physis can be reduced by avoiding tunnel placement that is too lateral or too proximal on the tibia. A better understanding of these relationships may guide the placement of tibial drill holes, which have a lower risk of producing significant physeal damage.