A Phase I, Dose-finding Study in Patients With Advanced Solid Malignancies of the Oral Gamma-Secretase Inhibitor PF-03084014.

Purpose: To estimate the maximum tolerated dose (MTD) for continuous oral administration of the gamma-secretase inhibitor PF-03084014, determine the recommended phase 2 dose (RP2D), and evaluate safety and preliminary activity in patients with advanced solid tumors. A total of 64 patients received treatment. The MTD was estimated to be 220 mg BID. The RP2D was determined to be 150 mg BID, based on the better safety profile versus the 220-mg BID dose, given comparable NOTCH-related target inhibition. The most common treatment-related AEs were diarrhea, nausea, fatigue, hypophosphatemia, vomiting, rash, and decreased appetite, which were generally mild to moderate in severity. One patient with advanced thyroid cancer had a complete response and five of seven response-evaluable patients with desmoid tumor achieved a partial response (71.4% objective response rate). Tumor responses were mostly durable, ranging from 1.74+ to 24+ months. PF-03084014 demonstrated a generally dose-dependent pharmacokinetic profile at doses ranging from 20 to 330 mg BID. Consistent down-modulation of NOTCH-related HES4 gene expression was observed in peripheral blood from all evaluable patients. Conclusions: Further development of PF-03084014 for the treatment of patients with advanced solid tumors is warranted and currently under evaluation.

Desmoid type fibromatosis is an uncommon benign disease entity of which its etiology is currently unknown. It constitutes 0.3% of all solid neoplasms, but it is rarely seen in the breast and even more scarcely reported to develop in association with breast implant. We present ultrasonography and magnetic resonance imaging findings of a 29-year-old female patient with fibromatosis after breast implant surgery. Knowledge of imaging findings of breast fibromatosis associated with implant will be helpful for accurate diagnosis and appropriate management.

The medical records of 16 patients (9 female and 7 male; age range, 5-66 years) with 24 lesions that had a histologic diagnosis of desmoid tumors were reviewed at our institution. Six cases were extra-abdominal, 4 intra-abdominal, and 6 in the abdominal wall. Sonography can show a desmoid tumor’s site, size, contour, margin, echogenicity, homogeneity, vascularity, and resistive index value in detail.

We conducted a systematic review to determine the optimal treatment options in patients with desmoid tumours who have declined observational management. Significant toxicities were reported for all treatment modalities, including surgical morbidity, and rt- and chemotherapy-related toxicities. In patients who have declined observational management, the local control rate was higher with surgery plus rt than with surgery alone. However, the additional rt-related complications should be considered in treatment decision-making. Surgery, rt, and systemic therapy are all reasonable treatment options for patients with desmoid tumours.

We set out to determine the optimal treatment options-surgery, radiation therapy (rt), systemic therapy, or any combinations thereof-for patients with desmoid tumours once the decision to undergo active treatment has been made (that is, monitoring and observation have been determined to be inadequate).provide clinical-expert consensus opinions on follow-up strategies in patients with desmoid tumours after primary interventional management. Surgery with or without rt can be a reasonable treatment option for patients with desmoid tumours whose surgical morbidity is deemed to be low.The decision about whether rt should be offered in conjunction with surgery should be made by clinicians and patients after weighing the potential benefit of improved local control against the potential harms and toxicity associated with rt. Depending on individual patient preferences, systemic therapy alone or rt alone might also be reasonable treatment options, regardless of whether the desmoid tumours are deemed to be resectable.

Patients referred to the soft tissue tumour group at Helsinki University Central Hospital (HUCH) for a desmoid tumour (primary or recurred) during 1987-2007 and receiving surgical treatment with or without adjuvant treatment were included in this retrospective review. All locations and also patients with a F.A.P.-associated tumour were included. Extra-abdominal location showed lower local control despite the fact that 27% of patients also received radiation therapy. In this review, the occurrence (14%) of concurrent neoplasms was higher than expected with unusual tumour types noted including two GISTs. In those patients in whom surgical treatment is chosen, adjuvant radiation therapy should also be considered in order to decrease morbidity from aggressive surgery aiming at R0 resection. Further studies are suggested to illuminate the biological association between the desmoid tumour and other neoplasms.