Choriocarcinoma Syndrome: A Rare Complication's Impact on Metastatic Germ Cell Tumor Outcomes.

Choriocarcinoma syndrome is a rare form of tumor lysis syndrome that predominantly occurs in patients with metastatic germ cell tumors, particularly those presenting with extensive lung metastases. We report a case of a previously healthy 37-year-old male who presented with a painless left-sided neck lump and nipples with an increased sensitivity to light touch. Workup revealed a significantly elevated beta-human chorionic gonadotropin, a testicular mass, and innumerable pulmonary metastases, suggesting metastatic non-seminomatous germ cell tumor. Following the initiation of chemotherapy with etoposide, ifosfamide, and cisplatin (VIP), the patient experienced a rapid decline in respiratory function, culminating in acute respiratory distress syndrome and subsequent death from respiratory failure six weeks after starting treatment. This case emphasizes the importance of early detection and intervention in managing non-seminomatous germ cell tumors and highlights the critical need for awareness of choriocarcinoma syndrome's risks, the challenges of treatment delays for fertility preservation, and the exploration of alternative therapeutic strategies to improve outcomes in this high-risk patient population.

Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study.

PURPOSE: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation-positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. PATIENTS AND METHODS: Patients ages 1 to <18 years who had BRAF V600-mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2. RESULTS: Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26-62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64-94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). CONCLUSIONS: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600-mutant pLGG.

A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors.

PURPOSE: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600-mutated cancers. PATIENTS AND METHODS: This phase I dose-finding part treated patients ages 1 to <18 years with BRAF V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target. RESULTS: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with BRAF V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC0-12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily. CONCLUSIONS: In this first clinical trial in pediatric patients with pretreated BRAF V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.

In vivo optical coherence tomography detection of differences in regional large airway smoke inhalation induced injury in a rabbit model.

Smoke inhalation injury causes acute airway injury that may result in airway compromise with significant morbidity and mortality. We investigate the ability of high resolution endobronchial optical coherence tomography (OCT) to obtain real-time images for quantitatively assessing regional differences between upper tracheal versus lower tracheal and bronchial airway injury responses to smoke inhalation in vivo using a prototype spectral domain (SLD)-OCT system we constructed, and flexible fiber optic probes. 33 New Zealand White rabbits are intubated and mechanically ventilated. The treatment groups are exposed to inhaled smoke. The OCT probe is introduced through the endotracheal tube and maintained in place for 5 to 6 h. Images of airway mucosa and submucosa are obtained at baseline and at specified intervals postexposure. Starting within less than 15 min after smoke inhalation, there is significant airway thickening in the smoke-exposed animals. This is maintained over 5 h of imaging studies. The lower tracheal airway changes, correlating closely with carboxyhemoglobin levels, are much greater than upper tracheal changes. Significant differences are seen in lower trachea and bronchi after acute smoke inhalation compared to upper trachea as measured in vivo by minimally invasive OCT. OCT is capable of quantitatively detecting regional changes in airway swelling following inhalation injury.

Development of a rabbit pleural cancer model by using VX2 tumors.

Primary and secondary pleural cancer remains an important clinical problem, with research progress limited by the lack of a suitable moderate- to large-sized (3 to 4 kg) animal model of pleural cancer. Many potential pleura-based imaging and treatment modalities cannot be investigated sufficiently by using currently available small murine animal models because their pleural space is not comparable to that of humans and therefore does not allow for the use of standard thoracoscopic techniques. Here we describe the development of a reproducible model of pleural malignancy in moderate-sized immunocompetent rabbits. Under thoracoscopic guidance, 9-15 x 10(6) VX2 carcinoma cells were inoculated into the plural space of 3 to 4 kg New Zealand white rabbits that had undergone gentle pleural abrasion. Malignant tumor involvement developed on the visceral and parietal pleural surfaces in an average of 2 to 4 wk. This novel pleural tumor model induction method likely will facilitate a broad range of investigations of pleural cancer diagnostics and therapeutics.

Detection of acute smoke-induced airway injury in a New Zealand white rabbit model using optical coherence tomography.

Optical coherence tomography (OCT) is a micron scale high-resolution optical technology that can provide real-time in vivo images noninvasively. The ability to detect airway mucosal and submucosal injury rapidly will be valuable for a range of pulmonary applications including assessment of acute inhalation smoke and burn injury. OCT has the potential ability to monitor the progression of airway injury changes including edema, hyperemia, and swelling, which are critical clinical components of smoke-inhalation injury. New Zealand white male rabbits exposed to cold smoke from standardized unbleached burned cotton administered during ventilation were monitored for 6 h using a 1.8-mm diameter flexible fiberoptic longitudinal probe that was inserted through the endotracheal tube. The thickness of the epithelial, mucosal, and submucosal layers of the rabbit trachea to the tracheal cartilage was measured using a prototype superluminescent diode OCT system we constructed. OCT was able to detect significant smoke-injury-induced increases in the thickness of the tracheal walls of the rabbit beginning very shortly after smoke administration. Airway wall thickness increased to an average of 120% (+/-33%) of baseline values by 5 h following exposure. OCT is capable of providing real-time, noninvasive images of airway injury changes following smoke exposure. These studies suggest that OCT may have the ability to provide information on potential early indicators of impending smoke-inhalation-induced airway compromise.

A 13-week, multicenter, randomized, double-blind study of lumiracoxib in hip osteoarthritis.

The aim of this 13-week, multicenter, randomized, double-blind, double-dummy, placebo- and positive-internal (celecoxib)-controlled, parallel-group study was to demonstrate the efficacy, safety, and tolerability of lumiracoxib in primary hip osteoarthritis (OA) patients. Eligible patients (n = 1,262; ACR criteria) were randomized (1:1:1) to receive lumiracoxib 100 mg once daily (o.d.) (n = 427), celecoxib 200 mg o.d. (n = 419), or matching placebo o.d. (n = 416) administered orally. The primary objective was to compare lumiracoxib 100 mg o.d. and placebo with respect to three co-primary efficacy variables: the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index Likert version 3.1 (WOMAC™ LK 3.1) questionnaire, the function subscale of the WOMAC™ LK 3.1 questionnaire, and patient's global assessment of disease activity (100-mm visual analog scale (VAS)) after 13 weeks of treatment. Of the 1,262 randomized patients, 951 completed the study. All randomized patients were included in the intention-to-treat and safety populations. Lumiracoxib was superior to the placebo (p < 0.001) after 13 weeks for all three co-primary endpoints. By week 13, the patient's global assessment of disease activity (100-mm VAS) improved by 23.3 mm (±SD, 27.83 mm) with lumiracoxib and 13.3 mm (±26.71 mm) with placebo. The WOMAC™ function score decreased by 10.4 (±13.56) with lumiracoxib and 6.8 (±12.55) with placebo. The WOMAC™ pain scores decreased by 3.4 (±4.16) with lumiracoxib and 2.2 (±3.94) with placebo at week 13. Similar results were observed for secondary endpoints: OA pain intensity and WOMAC™ total score. Lumiracoxib was similar to celecoxib for all three co-primary endpoints. All treatments were well tolerated. In conclusion, lumiracoxib is effective in reducing pain and improving function in hip OA patients.

Lumiracoxib is effective in the treatment of episodic tension-type headache.

OBJECTIVE: To evaluate the efficacy of single doses of lumiracoxib, the most selective cyclo-oxygenase (COX)-2 inhibitor, in the treatment of episodic tension-type headache (ETTH), with particular emphasis on time to onset of analgesia. BACKGROUND: ETTH is the most frequently occurring type of headache with an annual prevalence rate of up to 40%. Some patients with ETTH do not respond to currently available therapies, thus an effective analgesic is needed that provides a rapid onset of analgesia alongside significant pain relief. Lumiracoxib is the most selective COX-2 inhibitor developed for the treatment of acute and chronic pain. METHODS: In this single-center, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study, patients with ETTH were randomly assigned to receive single-dose lumiracoxib (200 or 400 mg, n = 60 in each group) or placebo (n = 30) within 1 hour of an ETTH. Efficacy was assessed over a 3-hour period, the primary efficacy variable being the time to onset of analgesia. Other efficacy variables included summed pain intensity difference from 0 to 3 hours after dosing, time-specific pain intensity difference, time-specific pain relief, time-specific pain relief intensity difference, total pain relief over 0 to 3 hours, patient's global evaluation of treatment effect, the proportion of patients who achieved onset of analgesia by 1 hour and time to rescue medication intake. Safety was assessed by monitoring and recording of all adverse events (AEs). RESULTS: The median time to onset of analgesia was significantly faster for lumiracoxib 200 mg (47 minutes; 95% confidence interval [CI]: 41, 52) and lumiracoxib 400 mg (41 minutes; 95% CI: 36, 48) than for placebo (>3 hours; both P < .001). Both doses of lumiracoxib were significantly superior to placebo for all secondary efficacy variables. There were no AEs recorded in any treatment group. CONCLUSIONS: Single 200 or 400 mg doses of lumiracoxib provided rapid and effective relief from the acute pain associated with ETTH.