Phase I study of lapatinib plus trametinib in patients with KRAS -mutant colorectal,non-small cell lung,and pancreatic cancer

KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.     

Investigation of aneuploidy induction in mouse oocytes following exposure to vinblastine-sulfate,pyrimethamine, diethylstilbestrol diphosphate,or chloral hydrate

The various causative and mechanistic phenomena associated with aneuploidy induction require considerable investigation to better understand the etiology of chromosome missegregation. We investigated the potential of vinblastine sulfate, pyrimethamine, diethylstilbestrol diphosphate, and chloral hydrate to induce numerical and structural chromosome changes in female mouse germ cells. Superovulated ICR mice were administered the compounds either by intraperitoneal injection or oral gavage, and oocytes were collected and processed for cytogenetic analysis 17 hr later. Vinblastine sulfate, administered i.p., induced a significant increase in the frequency of ovulated Ml oocytes and of hyperploid Mll oocytes compared to controls, but did not increase the frequency of structural aberrations. Pyrimethamine, diethylstilbestrol diphosphate, and chloral hydrate did not increase the frequency of numerical or structural chromosome changes in female mouse germ cells. © 1993 Wiley-Liss, Inc.     

The Istituto Rizzoli-Beretta experience with osteosarcoma of the jaw

Twenty-eight osteosarcomas (OS) of the jaw were reported. There were 15 male and 13 female patients (age range, 9 to 68 years; mean, 36.9 years); 57.1% of the patients were older than 30 years of age. Swelling was the most frequent symptom; it was reported on an average of 6 months before diagnosis. Most of the tumors of the maxilla (eight patients) occurred in the alveolar ridge (six of eight). In the mandible (20 patients), the body was the preferred site (11 of 20). Radiographically most of the lesions were either lytic and sclerotic or only lytic. Histologically, 12 cases (42.9%) were osteoblastic osteosarcoma, ten (35.8%) were chondroblastic, four (14.3%) were fibroblastic, and two (7%) were round cell OS. Of the 28 cases, three (10.7%) were low grade, and 25 (89.3%) were high grade. Thirteen patients had intralesional surgery, and 13 had marginal surgery as their initial treatment. Recurrence was the rule in the first group, and it was 69% in the second group. Twenty patients (71%) died, and eight are alive. Of these, two are alive with disease. In the six patients who are alive and disease-free, all but one had marginal to wide surgical margins at the time of the first procedure or wide margins at the time of the recurrences along with chemotherapy or radiation therapy. In the patient in which the surgical margins were marginal, the lesion was small 2.5 X 2 cm. This patient was alive without evidence of disease after 9 years of follow-up.     

CO2 laser therapy of the Bartholin's gland cyst: surgical data and functional short- and long-term results

The Bartholin's gland cyst is a condition that occurs in approximately 2% of women, most of whom are of reproductive age. Although benign, it is associated with significant patient discomfort. Definitive treatment involves the surgical removal of the entire cyst. The objective of this study was to describe an alternative conservative surgical technique with CO(2) laser adopted in our institution and to evaluate the feasibility, complication rate, and results obtained with this technique in an office setting. Our study showed that CO(2) laser treatment of the Bartholin's gland cyst can be carried out safely in an outpatient setting, with minimum patient discomfort and high long-term cure rates.     

Nasal septal perforations: our surgical technique.

OBJECTIVE: The aim of this paper was to describe our surgical technique for the treatment of nasal septal perforations. STUDY AND DESIGN: We studied 31 patients with nasal septal perforation treated with an endoscope-assisted technique, based on a bilateral dissection of monopedicled mucosal flaps from the nasal fossa floor, sutured at the edge of the perforation previously unstuck, without any graft interposed between the two mucosal layers. RESULTS: In our experience with 31 patients, the use of this technique led to the persistent closing (with follow-up for at least one year) of 96.3% of the perforations smaller than 3 cm. CONCLUSIONS: Our technique has the advantage of an endonasal approach, without any external incision, and the use of monopedicled flaps from the nasal fossa floor without any graft interposition, avoiding any other surgical procedure and morbidity in the donor site of the graft. The use of nasal endoscopy permits superior precision in all surgical steps. SIGNIFICANCE: The high success rate in perforations smaller than 3 cm seems to confirm the effectiveness of this technique.