Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer.

PURPOSE: Preclinical data demonstrate STAT3 as an important regulator in HER2+ tumors, and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+ cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer. METHODS: Patients with metastatic HER2+ breast cancer progressing on at least 2 lines of HER2-directed therapy were eligible. The phase I portion determined the tolerable dose of ruxolitinib in combination with trastuzumab. The primary objective of the phase II was to assess the progression free survival (PFS) of the combination of ruxolitinib plus trastuzumab compared to historical control. RESULTS: Twenty-eight patients were enrolled, with a median number of prior therapies of 4.5. Ruxolitinib 25 mg twice daily was the recommended phase II dose with no dose limiting toxicities (DLTs). Of 26 evaluable patients in phase II, the median PFS was 8.3 weeks (95% CI 7.1, 13.9). Among the 14 patients with measurable disease, 1 patient had a partial response and 4 patients had stable disease. Most of the adverse events were hematologic. CONCLUSION: While well tolerated with a strong preclinical rationale, the combination of ruxolitinib and trastuzumab did not lead to an improvement in PFS compared to historical control in patients with trastuzumab-resistant metastatic HER2+ breast cancer.

Simultaneous administration of mifepristone and misoprostol for early termination of pregnancy: a randomized controlled trial.

AIM: To compare the efficacy of different intervals of misoprostol administration (simultaneously vis-à-vis 24 h), after mifepristone, in women undergoing medical termination of pregnancy up to gestation of 49 days. METHODS: Eighty eligible women with single intrauterine pregnancy of ≤ 7 weeks of gestation requesting abortion were randomized to receive either 200 mg of mifepristone orally and 400 µg of misoprostol vaginally simultaneously (Group 1) or at 24-h interval (Group 2).Women who had no bleeding after the drugs were offered a second dose of misoprostol 24 h after the first dose. All patients were followed up on day 14. Primary outcome measure was the complete abortion rate. Secondary outcome measures were the induction-abortion interval, adverse effects, especially bleeding, and treatment acceptability rate. Treatment was considered a failure if surgical intervention was needed for any indication. RESULTS: Complete abortion was achieved in 38 women [95%; 95% confidence interval (CI) 88%, 100%] in Group 1 and 39 women (97.50%; 95% CI 93%,100%) in Group 2 (p = 0.56). A second dose of misoprostol was needed in two patients in Group 1 and in only one patient in Group 2. The induction-abortion interval was 6.50 ± 1.48 h in Group 1 and 5.95 ± 1.81 h in Group 2 (p = 0.13). The difference in frequency of adverse effects in the two groups was statistically insignificant (p = 0.18). The treatment acceptability rate was 97.50% in Group 1 and 95% in Group 2 (p = 0.56). CONCLUSION: Simultaneous administration of mifepristone and 400 µg vaginal misoprostol is an effective alternative to standard regimens for medical abortion up to 49 days of gestation.

A study of thyroid status in hyperemesis gravidarum.

Study was undertaken to assess thyroid status in hyperemesis gravidarum. 150 women pregnant with <20 weeks of gestation were selected randomly and out of these 100 women presenting with hyperemesis formed study group while 50 normal pregnant women served as controls. 53% of hyperemetic pregnant women were primigravidae and 82% of pregnant women presented with vomiting at less than 12 weeks of gestation. Statistically significant, 22% of hyperemetic women had increased serum T(3) levels while T(4) levels were increased in 67% of women in study group as compared to 8% and 16% respectively in control group. TSH levels were decreased in 18% of hyperemetic women as compared to 8% in control group with decrease in mean TSH level statistically significant. 22% of hyperemetic women had electrolyte disturbances and 7% were ketonuric. In clinically euthyroid women, biochemically altered thyroid function can attribute to vomiting and its prolongation to second trimester.

Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: a New York Cancer Consortium trial.

The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A-500 mg intramuscular (i.m.) day -14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B-1.6 mg/m2 intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (α=0.10, ß=0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, P=0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 α level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P=0.03, 1-sided χ2-test; 95% CI for difference (14.5%)=-0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs.

Nodular lymphocyte predominant hodgkin lymphoma: biology, diagnosis and treatment.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an uncommon variant of classical Hodgkin lymphoma. It is characterized histologically by presence of lymphohistiocytic cells which have B-cell phenotype, are positive for CD19, CD20, CD45, CD79a, BOB.1, Oct.2, and negative for CD15 and CD30. Patients often present with early stage of disease and do not have classical B symptoms. The clinical behavior appears to mimic that of an indolent non-Hodgkin lymphoma more than that of classical Hodgkin disease. The purpose of the present report is to define the biology of NLPHL, review its clinical presentation, and summarize the available clinical data regarding treatment.

Is mifepristone 100mg an effective alternative to standard dose for medical abortion.

OBJECTIVE: To study the efficacy of a low dose of mifepristone (100 mg) in combination with misoprostol, in women undergoing medical termination of pregnancy up to gestation of 49 days. MATERIAL AND METHODS: A prospective study was performed in 50 women (mean age 26.54±3.68 years) with single intrauterine pregnancy of up to 49 days of gestation, presenting to our institution between November 2007 and October 2009. 100 mg mifepristone was given orally, followed 24 hours later by 400 micrograms misoprostol vaginally. Misoprostol 400 micrograms was repeated vaginally on the third day if indicated. The primary outcome of complete abortion rate and secondary outcomes of induction-abortion interval and adverse effects, especially bleeding, were assessed. RESULTS: Mean period of gestation was 38.74±3.90 days. None of the women expelled the products of conception before misoprostol insertion. A second dose of misoprostol was needed in four patients. Complete abortion was achieved in 94.00% of patients, incomplete abortion in 4% and missed abortion in 2%. Approximately all the women reported one or more adverse effects but none of them had any serious ones, the most common being pain in 42 (84%) women followed by nausea, vomiting, fever and diarrhoea in 12 (24%), 6 (12%), 4 (8%) and 3 (6%) women respectively. The overall acceptability rate of the dosing regimen in our study was 94%. CONCLUSION: A regimen of low dose mifepristone (100 mg) followed 24 hours later by vaginal misoprostol can be safely and effectively used for early abortion.

Acute promyelocytic leukemia in HIV-infected adults: a case report and review of therapeutic considerations.

The incidence of acute promyelocytic leukemia (APL) in patients with HIV is exceedingly rare, making the establishment of therapeutic approaches challenging and often individualized. We report the case of a 43-year-old female who presented with fatigue and malaise, and was concurrently diagnosed with APL and HIV. Induction and consolidation with all-trans-retinoic acid (ATRA), idarubicin, and mitoxantrone were initiated in conjunction with highly active anti-retroviral therapy (HAART) consisting of tenofovir/emtricitabine, fosamprenavir, and raltegravir. A complete morphologic, cytogenetic, and molecular response was achieved post-induction. Therapeutic strategies should consider overlapping effects of current agents in targeting both pathologies. ATRA has been found to induce apoptosis in HIV-infected leukemic cells, and protease inhibitor therapy has furthermore been reported to be synergistic with ATRA in inducing differentiation of APL cell lines. Pending further investigation, regimens with protease inhibitor backbones may represent a viable first-line strategy for patients elected to receive HAART in addition to ATRA and standard chemotherapy.

Primary central nervous system mucosa-associated lymphoid tissue lymphoma: case report and literature review.

Primary presentation of intradural non-Hodgkin lymphoma is rare. Recently, B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) have been recognized as an important pathologic subtype. When MALT lymphomas present in the central nervous system (CNS), they are distinguishable from primary high-grade CNS lymphomas. We present the clinicopathologic features of 5 patients with primary CNS MALT lymphoma treated at our institution from 1999 to 2006. Four out of 5 patients were women, and all patients presented with headaches, focal motor deficits, or cranial nerve palsy. Radiologic studies demonstrated ill-defined dural masses in 3 and well-defined masses in 2 patients. Pathology revealed small to medium-sized cells with a moderate amount of cytoplasm and irregular nuclear borders, expressing pan B-cell markers (CD19, CD20, and CD79a) but lacking CD10, CD23, and cyclin D1, confirming low-grade MALT lymphoma. Plasma cells were encountered in all the biopsies with variable reactive T-cell infiltration. wedge chain restriction was seen in 3 patients. Therapy consisted of either surgical resection, whole-brain radiation, or systemic or intrathecal chemotherapy. There was no evidence of recurrence or systemic relapse in 4 patients at 4 years of follow-up. One patient died in 2 months, unrelated to CNS lymphoma. This case series illustrates the rare occurrence of low-grade dural B-cell lymphoma and the need to consider this entity in the differential diagnosis of CNS lesions.

Pooled efficacy analysis from a phase I-II study of biweekly irinotecan in combination with gemcitabine, 5-fluorouracil, leucovorin and cisplatin in patients with metastatic pancreatic cancer.

Development of treatments to improve the outcomes achieved with single-agent gemcitabine therapy for metastatic pancreatic cancer remains a research priority. G-FLIP (gemcitabine, 5-fluorouracil, leucovorin and cisplatin) is a four-drug regimen designed to maximize sequence-dependent synergy, while attempting to minimize toxicity among the four drugs. The dose-limiting toxicities and maximum tolerated dose of irinotecan as part of the G-FLIP regimen have been published. For phase II testing, G-FLIP consisted of sequential gemcitabine 500 mg/m2 at a fixed rate of 10 mg/m2/min, irinotecan 120 mg/m2, bolus 5-fluorouracil 400 mg/m2 and leucovorin 300 mg, followed by a 24-h 5-fluorouracil infusion of 1500 mg/m2 on day 1 and cisplatin 35 mg/m2 on day 2. Cycles were repeated every 14 days. Thirty-three patients with metastatic pancreatic cancer (22 men and 11 women) were treated and 31 were evaluable. Median patient age was 63 years (range 44-78 years) and median Karnofsky performance status score was 70-80. Estimated median time to disease progression was 171 days (6.1 months) and Kaplan-Meir-estimated median overall survival was 229 days (8.1 months). Twelve- and 18-month survivals were 33 and 21%, respectively. As per Response Evaluation Criteria in Solid Tumors criteria, 13 patients had stable disease, seven (22%) attained a partial response, and 10 (32%) had disease progression. One patient attained a complete response and two were not evaluable (one withdrew consent and one died suddenly, each after cycle 1). Treatment generally was well tolerated. Grade 3-4 toxicities/patient were thrombocytopenia (3.1%), leukopenia (15%), neutropenia (21%), neutropenic fever (3%), fatigue (18%) and thrombosis (12.5%). Common grade 1-2 toxicities per patient included nausea/vomiting (69%), diarrhea (45%), constipation (21%) and fatigue (39%). In conclusion, G-FLIP is a feasible outpatient regimen with acceptable toxicity for metastatic pancreatic cancer patients. Disease control rate (stable disease rate plus partial or complete responses) and 1-year survival outcomes are encouraging.

The role of perioperative chemotherapy in the treatment of urothelial cancer.

Cancer of the urothelium is the fourth most common malignancy in men in the U.S. and the ninth most common in women. More than 63,000 Americans will be diagnosed with bladder cancer this year (47,010 men and 16,200 women), and more than 13,000 (8,970 men and 4,210 women) can expect to die of their disease. The approximate 5:1 ratio of incidence to mortality roughly parallels the frequency of superficial to invasive disease. Efforts to improve this ratio have generated a potential paradigm shift in the treatment of urothelial cancer, incorporating increasingly active chemotherapy into treatment regimens for high-risk tumors in both the pre-and postoperative settings. This review summarizes the evolution of chemotherapeutic treatment of urothelial cancer and the rationale for its perioperative administration and addresses the future directions of clinical research in this field.