Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma.

Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911-17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

A pure brain metastasis of choriocarcinoma from a mixed germ cell tumor of the ovary.

We report a pure brain metastasis of choriocarcinoma from a mixed germ cell tumor of the ovary in a 19-year-old patient. This condition is extremely rare. Following abdominal operative procedures, multiple courses of combination chemotherapy, and resection of chemotherapy-resistant pulmonary metastases, a brain metastasis developed during chemotherapy. Craniotomy with resection of the neoplasm, brain radiation, and further chemotherapy was followed by disappearance of a pulmonary metastasis and long-term survival of the patient.

Intraperitoneal contrast material improves the CT detection of peritoneal metastases.

The preoperative detection of peritoneal metastases from gynecologic malignancies is difficult; in particular, CT often fails to detect peritoneal implants. This study was designed to determine if the administration of intraperitoneal iodinated contrast media would increase the CT detection of such peritoneal metastases. Prospectively, both standard and intraperitoneal contrast-enhanced CT studies of the abdomen and pelvis were performed in 16 patients with suspected gynecologic tumors. All patients then underwent operative staging, with the location and number of metastases documented. The intraperitoneal enhanced CT studies were more sensitive in the detection of peritoneal metastases than standard CT examinations. Whereas routine CT detected peritoneal metastases in seven (64%) of 11 patients with surgically proved implants, the intraperitoneal enhanced CT studies detected peritoneal metastases in all 11 patients. Depending on the specific intraperitoneal compartments involved, the sensitivity of intraperitoneal enhanced CT in the detection of peritoneal metastases was two- to fourfold greater than that of standard CT examinations. Our results suggest that intraperitoneal enhanced CT is superior to standard CT in the detection of peritoneal metastases.

Symptomatic central venous thrombosis and long-term right atrial catheters.

The use of long-term right atrial access catheters is increasing due to their value as aids in the administration of chemotherapy and hyperalimentation. A rare complication of catheter use is subclavian vein thrombosis. Suspicion of subclavian venous thrombosis based on clinical findings should be confirmed by venography. Therapy should be individualized, but may include antibiotics, catheter removal, thrombolytics, and anticoagulants. Resolution of symptoms is the usual outcome, but this may be influenced by other compounding factors.

Resection of the pubic bone as an adjunct to management of primary, recurrent, and metastatic pelvic malignancies.

Patients with locally advanced vulvovaginal carcinomas with pubic bone encroachment or fixation pose a treatment dilemma. The purpose of this study was to evaluate the outcome in 12 patients who have undergone pubic bone resection at the University of Minnesota as part of treatment of locally extensive primary, recurrent, or metastatic vulvovaginal carcinomas. Six patients with primary vulvar carcinomas and six patients with recurrent or metastatic vulvovaginal carcinomas underwent bone resection as part of their surgical therapy. Survival in the primary treatment group was 50%, with no local recurrences. Survival in the recurrent/metastatic disease group was 83%, with a follow-up time of 9 months to 15 years. One vulvar and one groin recurrence have occurred in the recurrent/metastatic group. Pubic bone resection added little to surgical morbidity and gave good functional results. Pubic bone resection, in combination with radical extirpative procedures, is an option for treatment of patients with locally extensive vulvovaginal carcinomas, particularly those with previous radiation therapy.

Association of Ki-ras with amplified DNA sequences, detected in human ovarian carcinomas by a modified in-gel renaturation assay.

A modified in-gel DNA renaturation technique, which detects DNA sequences amplified greater than 7-fold in human DNA, was used to analyze gene amplification in surgical specimens of primary and metastatic ovarian carcinomas. Amplified DNA sequences were detected in two of eight tumors. Hybridization of these samples with different oncogene probes revealed that both tumors contained an amplified Ki-ras gene, which in one case was coamplified with c-myc. In one of the tumors, Ki-ras was found to be amplified in both the primary tumor and three different metastatic nodules. No mutations at codons 12 or 61 of Ki-ras were detected in these tumors. No additional cases of Ki-ras or c-myc amplification were detected by Southern hybridization in the tumors that were found to be amplification negative by modified in-gel renaturation assays. These results indicate that gene amplification in ovarian carcinomas is likely to involve the Ki-ras oncogene.