Napabucasin plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine in previously untreated metastatic pancreatic adenocarcinoma: an adaptive multicentre, randomised, open-label, phase 3, superiority trial.

Background: Compared with normal cells, tumour cells contain elevated levels of reactive oxygen species (ROS). Increased levels of the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) correlate negatively with the survival of patients with pancreatic cancer. Napabucasin is an investigational, orally administered ROS generator bioactivated by NQO1. Methods: In the open-label, phase 3 CanStem111P study (NCT02993731), adults with previously untreated metastatic pancreatic adenocarcinoma (mPDAC) were randomised (1:1) to napabucasin plus nab-paclitaxel with gemcitabine or nab-paclitaxel with gemcitabine alone. The primary endpoint was overall survival (OS). In exploratory analyses, OS was evaluated in the subgroup of patients with tumours positive for pSTAT3 (biomarker-positive). Findings: Between 30 January 2017 and 20 February 2019, a total of 1779 patients were screened across 165 study sites in Austria, Australia, Belgium, Canada, China, Czech Republic, France, Germany, Italy, Japan, Korea, Netherlands, Poland, Portugal, Russia, Singapore, Spain, Taiwan, Ukraine, and the US. Of the 565 and 569 patients randomised to the napabucasin and control treatment arms, respectively, 206 and 176 were biomarker-positive. Median (95% confidence interval [CI]) OS in the napabucasin and control treatment arms was 11.4 (10.5-12.2) and 11.7 (10.7-12.7) months, respectively (hazard ratio, 1.07; 95% CI, 0.93-1.23). Due to the lack of OS improvement in the napabucasin arm, CanStem111P was terminated due to futility. In the biomarker-positive subgroup, no difference between treatment arms was found for OS. Grade ≥3 adverse events were reported in 85.4% and 83.9% of napabucasin-treated and control-treated patients, respectively. The incidence of gastrointestinal-related grade ≥3 events was higher with napabucasin (diarrhoea: 11.6% vs 4.9%; abdominal pain: 10.0% vs 4.8%). Interpretation: Our findings suggested that although the addition of napabucasin to nab-paclitaxel with gemcitabine did not improve efficacy in patients with previously untreated mPDAC, the safety profile of napabucasin was consistent with previous reports. CanStem111P represents the largest cohort of patients with mPDAC administered nab-paclitaxel with gemcitabine in the clinical trial setting. Our data reinforce the value of nab-paclitaxel plus gemcitabine as a platform for novel therapeutics approaches in mPDAC. Funding: The Sumitomo Pharma Oncology, Inc.

Diced cartilage grafts wrapped in AlloDerm for dorsal nasal augmentation.

Dorsal nasal augmentation is commonly performed for various aesthetic deficiencies and/or reconstructive defects such as the saddle nose deformity. However, the optimal technique for volume augmentation has yet to be identified. The senior author (F.P.) has since developed a new modified technique using wrapped diced cartilage within an AlloDerm. This novel construct provides the plastic surgeon a smooth, convenient, pliable option with similar operative times as compared with other popular techniques. In summary, this technique has been proven to be successful in achieving attractive, safe, and acceptable outcomes in nasal dorsal configuration and overall patient satisfaction.

Breast cancer incidence in adolescent males undergoing subcutaneous mastectomy for gynecomastia: is pathologic examination justified? A retrospective and literature review.

BACKGROUND: Most medical centers routinely perform or require the pathologic examination of breast tissue that is excised for adolescent gynecomastia; however, its utility is questionable, given the benign nature of the condition. METHODS: A retrospective chart review was conducted to examine the incidence of pathologic abnormalities in patients 21 years or younger who had undergone subcutaneous mastectomy for gynecomastia. A literature review was also performed to determine the historical prevalence of cases of atypia or malignancy in cases of adolescent gynecomastia. Finally, an informal survey was performed of major children's hospitals regarding their practice of pathologic examination for adolescent gynecomastia. RESULTS: The chart review demonstrated that over the past 10 years, 81 patients with gynecomastia underwent subcutaneous mastectomy. All cases were negative for malignancy, with only one case of cellular atypia. The literature has historically reported six cases of carcinoma and five cases of atypia. Of 22 survey respondents, all either routinely performed or required pathologic examination of breast tissue excised for gynecomastia. The out-of-pocket cost for self-pay patients to perform pathologic examinations has been quoted at $1268 for bilateral cases. CONCLUSIONS: The incidence of malignancy or abnormal pathology associated with gynecomastia tissue in the adolescent male is extremely low, and given the associated costs, the pathologic examination of breast tissue excised for gynecomastia in individuals 21 years of age or younger should be neither routinely performed nor required but should be performed only when desired by either the patient, the patient's family, or the managing physician.

Pearls of orbital trauma management.

Orbital fractures account for a significant portion of traumatic facial injuries. Although plastic surgery literature is helpful, additional pearls and insights are provided in this article from the experience of an oculoplastic surgeon. The fundamentals remain the same, but the perceptions differ and provide a healthy perspective on a long-standing issue. The most important thing to remember is that the optimal management plan is often variable, and the proper choice regarding which plan to choose rests upon the clinical scenario and the surgeon having an honest perception of his or her level of expertise and comfort level.

First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations.

PURPOSE: Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms. PATIENTS AND METHODS: Chemotherapy-naïve patients with advanced NSCLC with >or= 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate. RESULTS: Ninety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification. CONCLUSION: First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.

Retinoic acid and the histone deacetylase inhibitor trichostatin a inhibit the proliferation of human renal cell carcinoma in a xenograft tumor model.

PURPOSE: Therapy for advanced renal cell carcinoma (RCC) is ineffective in the majority of patients. We have previously reported that retinoid-induced up-regulation of retinoic acid receptor beta (RARbeta) correlated with antitumor effects in RCCs. Recent studies show that there is a reduction in the level of RARbeta2 expression in cancer cells due in part to histone hypoacetylation. Therefore, we tested whether combining histone deacetylase inhibitors with retinoic acid (RA) would restore RARbeta2 receptor expression, leading to increased growth inhibition in RCC cells. EXPERIMENTAL DESIGN: Cell proliferation, Western blot, and reverse transcription-PCR analyses of two RA-resistant RCC cell lines, SK-RC-39 and SK-RC-45, were assessed in the presence of all-trans retinoic acid (ATRA), trichostatin A (TSA), or the combination of ATRA and TSA. Analysis of apoptosis was also done on SK-RC-39 cells treated with these combinations. Additionally, a xenograft tumor model (SK-RC-39) was used in this study to investigate the efficacy of a liposome-encapsulated, i.v. form of ATRA (ATRA-IV) plus TSA combination therapy. RESULTS: Enhanced inhibition of the proliferation of RCC cell lines and of tumor growth in a xenograft model was observed with the combination of ATRA plus TSA. Reactivation of RARbeta2 mRNA expression was observed in SK-RC-39 and SK-RC-45 cells treated with TSA alone or TSA in combination with ATRA. A partial G0-G1 arrest and increased apoptosis were observed with SK-RC-39 cells on treatment with ATRA and TSA. CONCLUSIONS: The combination of ATRA and the histone deacetylase inhibitor TSA elicits an additive inhibition of cell proliferation in RCC cell lines. These results indicate that ATRA and histone deacetylase inhibitor therapies should be explored for the treatment of advanced RCC.

Phase I trial of interferon alpha2b and liposome-encapsulated all-trans retinoic acid in the treatment of patients with advanced renal cell carcinoma.

BACKGROUND: Studies suggest that retinoic acid (RA) can augment the antitumor effects of interferon-based therapy in patients with advanced renal cell carcinoma (RC); however, this benefit has not been achieved convincingly using oral formulations of 13-cis RA and all-trans RA. Liposome-encapsulated all-trans RA (ATRA-IV) has improved pharmacokinetics with increased and prolonged ATRA serum levels compared with oral retinoids. METHODS: Cohorts of 3-6 patients with progressive metastatic RC received a dose of 3 MU interferon alpha2b per day subcutaneously, which was escalated weekly to 5 MU and then to 10 MU, plus ATRA-IV beginning at a dose of 90 mg/m(2) intravenously three times per week (Monday, Wednesday, and Friday), with a planned escalation to a maximum of 140 mg/m(2). RESULTS: Two of the initial five patients experienced Grade 3 leukopenia while receiving 3 MU interferon and 90 mg/m(2) ATRA-IV. Therefore, the trial was amended to begin ATRA-IV at a dose of 15 mg/m(2) three times per week with a planned escalation by 15 mg/m(2) per cohort plus interferon-alpha at a dose of 3 MU subcutaneously 5 days per week (Monday through Friday), which was escalated weekly to 5 MU and then to 10 MU. Twelve patients were treated on the revised schedule. Toxicity was mild and included Grade 2 anemia (n = 7 patients), leukopenia (n = 2 patients), nausea (n = 2 patients), fatigue (n = 2 patients), fever (n = 2 patients), hepatic toxicity (n = 1 patient), edema (n = 1 patient), neurocortical toxicity (n = 1 patient), headache (n = 1 patient), and infection (n = 1 patient). One patient developed hyperthyroidism, and one patient required admission for bacteremia from a line infection. Dose limiting toxicity was Grade 3 hepatic toxicity, which was observed at a dose of 30 mg/m(2) ATRA-IV in 2 of 6 patients. Only 2 of 12 patients agreed to a dose escalation up to 10 MU interferon-alpha. Of 12 patients who were evaluable for response, 2 patients (17%) had a partial response in bone and lung, including 1 partial response of > 91 weeks' duration, at a dose of 15 mg/m(2) ATRA-IV three times per week and 5 MU interferon-alpha. Five additional patients experienced stable disease, two of whom had disease progression in bone only. CONCLUSIONS: The acceptable toxicity profile and preliminary efficacy results suggest that this regimen warrants further evaluation. ATRA-IV (15 mg/m(2) TIW) and interferon-alpha (3 MU Monday through Friday escalated weekly to 5 MU and to 7 MU) are recommended for further study in patients with advanced RC.