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Purpose: Both paclitaxel (P) and carboplatin (C) have a significant activity in non-small cell lung cancer (NSCLC). Weekly administration of P is active, is dose intense, and has a favorable toxicity profile. To evaluate the efficacy and toxicity of weekly P and C in advanced-stage NSCLC, we initiated this phase II study in patients with advanced NSCLC (III B with pleural effusion and stage IV). Patients and Methods: Eligible patients were treated with paclitaxel 100 mg/m2 intravenously (iv) over 1 h followed by carboplatin AUC 2 iv over 30 min. This treatment was administered weekly for 3 of every 4 wk until disease progression or intolerable toxicities. Results: Of the 30 patients enrolled in the study, one patient did not meet the eligibility criteria. Of the remaining 29 patients, 6 did not complete at least two cycles of treatment and hence were not assessable for response. The overall response rate was 43.5% (10/23) (all partial responses). An additional 43.5% had stable disease. The median time to progression was 162 d and the median duration of response was 169 d. Overall survival at 1 yr on intent-to-treat analyses was 44% and median survival was 10.8 mo. We observed the following grade 3/4 toxicities: hypersensitivity to paclitaxel (13%), hypersensitivity to carboplatin (3%), neutropenia (31%), thrombocytopenia (7%); 31% experienced grade 1 neuropathy and 17% experienced grade 2 neuropathy. Conclusions: We conclude that weekly paclitaxel and carboplatin is active and very well tolerated in patients with advanced NSCLC.

Purpose: A major clinical problem in the treatment of breast cancer is the inherent and acquired resistance to antiestrogen therapy. In this study, we sought to determine whether antiprogestin treatment, used as a monotherapy or in combination with antiestrogen therapy, induced growth arrest and active cell death in antiestrogen-resistant breast cancer cells. Experimental Design: MCF-7 sublines were established from independent clonal isolations performed in the absence of drug selection and tested for their response to the antiestrogens 4-hydroxytamoxifen (4-OHT) and ICI 182,780 (fulvestrant), and the antiprogestin mifepristone (MIF). The cytostatic (growth arrest) effects of the hormones were assessed with proliferation assays, cell counting, flow cytometry, and a determination of the phosphorylation status of the retinoblastoma protein. The cytotoxic (apoptotic) effects were analyzed by assessing increases in caspase activity and cleavage of poly(ADP-ribose) polymerase. Results: All of the clonally derived MCF-7 sublines expressed estrogen receptor and progesterone receptor but showed a wide range of antiestrogen sensitivity, including resistance to physiological levels of 4-OHT. Importantly, all of the clones were sensitive to the antiprogestin MIF, whether used as a monotherapy or in combination with 4-OHT. MIF induced retinoblastoma activation, G1 arrest, and apoptosis preceded by caspase activation. Conclusions: We demonstrate that: (a) estrogen receptor+progesterone receptor+, 4-OHT-resistant clonal variants can be isolated from an MCF-7 cell line in the absence of antiestrogen selection; and (b) MIF and MIF plus 4-OHT combination therapy induces growth arrest and active cell death of the antiestrogen-resistant breast cancer cells. These preclinical findings show potential for a combined hormonal regimen of an antiestrogen and an antiprogestin to combat the emergence of antiestrogen-resistant breast cancer cells and, ultimately, improve the therapeutic index of antiestrogen therapy.

The purpose of this retrospective study was to evaluate infectious complications in patients receiving mobilization chemotherapy for stem cell collection prior to autologous peripheral blood stem cell transplantation. An additional goal was to evaluate risk factors associated with the development of infectious complications. At the Medical College of Georgia BMT center, 54 patients were administered mobilization chemotherapy for the purpose of collecting stem cells between June, 1997, and May, 2002. All patients received Filgrastim in addition to chemotherapy, and 50 of 54 patients received prophylactic acyclovir, fluconazole, and ciprofloxacin until neutrophil recovery. The median duration to neutrophil recovery was 11 days. Fourteen of 54 (26%) patients developed fever/infections during the mobilization phase. One patient developed both a catheter-related infection and Clostridium difficile colitis, increasing the total number of infectious episodes to 15. Twelve patients had a documented site of infection whereas 2 patients had neutropenic fever with no identifiable source. Eight of the 15 (55%) infections were Gram-positive catheter infections. All the patients were treated successfully with antibiotics. No systemic fungal infections were identified and none of the patients died from complications related to mobilization chemotherapy. Logistic regression was applied for univariate and multivariate analysis and showed that age, sex, diagnosis, neutrophil recovery, disease status, use of salvage chemotherapy, and mobilization regimen used did not affect the infection rate. In our series of 54 patients, 14 patients developed fever/infections during mobilization. Although there is a substantial risk of infectious complications among patients who receive mobilization chemotherapy, it is not clear that prophylactic antibiotics decrease infectious complications. Because the vast majority of infections are Gram-positive catheter infections, it appears reasonable to employ Gram-positive prophylaxis. Controlled studies should be conducted to define the optimum mobilization regimens as well as the optimum combination of prophylactic antibiotics.

The purpose of this study was to determine if therapeutic levels of Rituximab could be achieved in a patient with renal failure being dialyzed and if Rituximab is removed by hemodialysis. A 54-year-old man with low-grade lymphoma and renal failure on hemodialysis received 8 weekly treatments of Rituximab at 375 mg/M(2). Serum Rituximab levels were obtained before and after each treatment, before and after dialysis following each treatment, as well as in the dialysate fluid. The serum levels of Rituximab increased gradually with each treatment and were comparable to levels in patients with normal renal function. The postdialysis levels were higher than the predialysis levels as a consequence of hemo-concentration after dialysis. Rituximab was not detected in the dialysate fluid. The patient developed life-threatening hyperkalemia after the fourth treatment, which we believe occurred secondary to tumor lysis. Therapeutic levels of Rituximab may be maintained in patients undergoing dialysis. Rituximab is not eliminated by hemodialysis.

Our purpose was to determine the risk of ototoxicity in breast cancer patients receiving a myeloablative regimen consisting of cyclophosphamide 6000 mg/m2, thiotepa 500 mg/m2 and carboplatin 800 mg/m2 (CTCb) followed by stem cell transplantation. Fourteen consecutive patients with breast cancer were treated with high dose chemotherapy consisting of the CTCb regimen followed by stem cell transplantation. A pretransplant complete hearing study was obtained which consisted of hearing case history, audiometry and tympanometry. In addition, DPOAE (Distortion Product Otoaccoustic Emissions) was done to evaluate measurable changes in the cochlear (outer hair cell) functioning. Pre-transplant, all patients had no clinical evidence of hearing impairment and hearing studies were normal. Eleven patients had hearing studies and a telephone interview posttransplant. One patient was lost to follow-up and two patients died. One of the 11 patients tested had an abnormal post-transplant hearing study but none of them had clinically detectable hearing impairment. In our prospective study of breast cancer patients treated with the CTCb regimen, we did not observe clinically detectable hearing impairment in any of the patients tested.

Two patients presented with anasarca, fevers and sweats. Subsequent evaluation revealed aggressive lymphoproliferative disease. Both patients were treated with CHOP chemotherapy. One patient responded with spontaneous, vigorous diuresis and complete resolution of the edema. She relapsed two months later with recurrent edema that responded a second time to salvage chemotherapy. The second patient died of gram positive sepsis a week after diagnosis. As anasarca is an unusual presenting symptom of non-Hodgkin's lymphoma, we postulated that the malignant cells were secreting a cytokine that resulted in "vascular leakage" of fluid and development of diffuse edema. Several serum cytokine levels were tested. Both patients had elevated TNF-alpha levels, which could have been the cause of the edema; or there might be yet another unidentified mediator that was responsible for the anasarca. We report these two cases to bring to attention the unusual nature of this presentation.

Central nervous system (CNS) involvement in early (Rai Stage 0 and Stage 1) chronic lymphocytic leukemia (CLL) is rare, with only five cases reported. We present the sixth reported case, a 77-year-old male with a 4 year history of Stage 0 CLL who presented with sudden onset of diplopia and headache. Workup revealed a leukemic involvement of his CNS and he responded well to treatment with intrathecal (IT) methotrexate. After his third IT treatment, he developed a change in his mental status, consistent with a chemotherapy induced encephalopathy, which was effectively treated with IT hydrocortisone. In addition to the case presentation, we review the previously reported cases in an effort to determine any characteristics common among the Stage 0/1 CLL patients with reported CNS involvement.

Autoimmune thrombocytopenia after high-dose chemotherapy and autologous bone marrow/peripheral blood stem cell transplantation occurs infrequently and only six cases meeting the criteria have been reported in the literature. All six of these patients had either acute myelogenous leukemia (AML) or lymphoblastic lymphoma (LBL). Immune thrombocytopenia following autologous transplantation in solid tumors has not been reported. We report the first case of autoimmune thrombocytopenia after high-dose chemotherapy and peripheral blood stem cell transplantation in a patient with breast cancer. A review of the literature has been conducted and treatment options are discussed. In two patients the condition resolved with treatment and in a third patient it improved. Immune-mediated thrombocytopenia in the post-transplant period is one of the causes of a low platelet count. It should be recognized promptly and treated.

In this study, human MCF-7 breast cancer cells, which express functional estrogen and progesterone receptors, were used to compare the efficacy of combined antiestrogen plus antiprogestin therapy to antiestrogen monotherapy. Cells were treated with the antiestrogen 4-hydroxytamoxifen (4-OHT) and/or the antiprogestin mifepristone (MIF) and effects on cell proliferation (cytostatic action), cell cycle phase, the phosphorylation state of the tumor suppressor retinoblastoma protein (Rb), and induction of active cell death (cytotoxic action) were determined. Combination hormonal therapy showed both increased cytostatic and cytotoxic activity as compared to either monotherapy. The increased cytostatic action was mediated by Rb activation; whereas, the cytotoxic (pro-apoptotic) action of combined hormonal therapy correlated to a significant reduction in Rb protein levels. To test the apparent role of Rb protein loss in the pro-apoptotic action of combined hormonal therapy, Rb was downregulated in MCF-7 cells using siRNA-targeting. The siRNA-mediated knockdown of Rb combined with 4-OHT therapy resulted in a pro-apoptotic action similar to that resulting from 4-OHT and MIF combination treatment, which included increased cell detachment from the monolayer, high-molecular-weight genomic DNA fragmentation, and cleavage of poly ADP-ribose polymerase (PARP) and lamin A. From these studies, we conclude that Rb protein downregulation is required for 4-OHT-treated, estrogen receptor positive (ER+) breast cancer cells to undergo active cell death. We discuss the potential of using an antiprogestin such as MIF plus antiestrogen treatment to more effectively downregulate Rb in ER+ breast cancer cells to increase the overall cytotoxic action of hormonal therapy.

Introduction: A well-developed quality of life (QoL) instrument is valuable in identifying the burden of illness. We were interested in exploring whether existing QoL instruments were suitable for patients in our medical setting and, if not, whether this could be rectified by adapting an existing valid and reliable instrument to meet the specific needs of our patient population. For the purposes of this study, we chose to evaluate the quality of life of patients with breast cancer. Specifically, we were interested in two aspects of QoL in women with breast cancer. The first was whether existing instruments were pertinent to the women in our venue. The second research interest was dependent upon the first. If current instruments were found wanting, could this be rectified through the creation and validation of new domains of relevance to these patients? Method: First, five patients were interviewed to ascertain QoL issues pertinent to women in our medical setting. Second, to determine regional appropriateness of existing breast cancer QoL instruments, a search was conducted to identify and review existing breast cancer specific QoL instruments. Third, an addendum was created (to be used in conjunction with an existing instrument identified through the search) that contained three QoL domains not typically found: Financial, Spirituality and Satisfaction with Medical Care. The addendum was then tested along with an existing instrument (FACT-B). Results: Internal consistency for the new scales, Satisfaction with Medical Care, Spirituality, and Financial had alpha coefficients of 0.81, 0.80, and 0.63 respectively. The total score for FACT-B plus addendum was 0.69. Pearson’s correlation coefficients were 0.49 for Financial, 0.64 for Satisfaction with Medical Care, and 0.70 for Spirituality. Total test/retest was 0.71.

Background: Androgen Receptor (AR) signaling is a new target present in and under evaluation in all breast cancer subtypes. AR expression is noted in 70%-90% of primary breast tumors, up to 75% of all breast cancer metastases and is associated with resistance to endocrine therapy. Orteronel, an oral, selective, nonsteroidal inhibitor of androgen synthesis, is being developed as an endocrine therapy for hormone-sensitive cancers. In preclinical studies, orteronel suppresses sex hormone levels in blood and hormone-dependent malignant tissue. This study will evaluate the safety and efficacy of orteronel in the treatment of AR+ MBC. Study Objectives: This phase II trial is designed to determine the response rate and disease control rate (CR+PR+SD at 6 mo) following treatment with orteronel in pts with AR+ MBC. Two groups will be evaluated: Cohort 1 will include pts with AR+, triple negative (TN) (ER-/PR-/HER2-) MBC, and Cohort 2 will include pts with AR+, ER+ and/or PR+ MBC (may be HER2+ or HER2-). Secondary objectives include evaluation of PFS and OS, safety and tolerability, as well as evaluation of changes in serum levels of total and free testosterone, sex hormone binding globulins (SHBG), adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate (DHEA-S), cortisol and estradiol during orteronel treatment. As an exploratory objective, archived tumor tissue will be analyzed for the presence of phosphatidylinositol 3-kinase (PIK3CA) mutations and loss of phosphatase and tensin homolog (PTEN). Eligibility: Pts ≥18 years with AR+ (≥10% staining by immunohistochemistry) MBC, either TN or ER+ and/or PR+, are eligible. TNBC pts must have had 1-3 prior chemotherapy regimens in the advanced setting and ER+ and/or PR+ pts must have had 1-3 prior hormonal therapies and ≥1 chemotherapy regimen in the advanced setting. HER2+ pts must have received ≥2 lines of HER2-directed therapies. Additional eligibility criteria include: ECOG PS 0-2; adequate bone marrow and organ function, including left ventricular ejection fraction of ≥50%. Trial Design: Six pts will be enrolled and treated with orteronel in the lead-in phase to confirm safety and tolerability. In the absence of any safety concerns, subsequent pts will be enrolled to either Cohort 1 or Cohort 2 (described above). Cohort 1 will contain 31 pts with AR+ TNBC and Cohort 2 will contain 55 pts with AR+ ER+ and/or PR+ MBC. All pts will receive 300 mg orteronel PO BID over a 4 week cycle. Pts will be evaluated with CT scans every 2 cycles and treatment will continue until disease progression or unacceptable toxicity. Response rate and disease control rate will be presented as the point estimate along with 95% confidence interals calculated using both asymptotic normal approximation and exact binomial methods. Simon’s two-stage design will be applied using alpha=0.10 and power=0.80 for each cohort. Blood samples will be collected at baseline, on Cycle 2 Day 1, Cycle 4 Day 1, and at the end of treatment to evaluate serum total and free testosterone, SHBG, ACTH, DHEA-S, cortisol, and estradiol levels. Archival tumor samples will be collected for exploratory PTEN and PIK3CA biomarker evaluations. This trial is currently enrolling and has a total accrual goal of 86 pts. Citation Format: Denise A Yardley, Suzanne F Jones, Nancy W Peacock, Mythili Shastry, Robyn R Young, Andre M Kallab, Howard A Burris III. A phase II study with orteronel as monotherapy in patients with androgen receptor (AR) expressing metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-07.

Many sarcomas are of intermediate nature, with aggressive local behavior and low-to-moderate tendency to metastasize. A low-grade fibromyxoid sarcoma had abnormal glucose uptake in the principal tumor and contralateral lung metastases with pleural involvement demonstrated with F-18 FDG positron emission tomography (PET). A high-grade malignant hemangiopericytoma had abnormal glucose uptake in the principal tumor and a metastasis in an ipsilateral paratracheal lymph node, but was falsely negative in a small adjacent intraparenchymal lung metastasis. F-18 FDG PET could be useful in rare soft tissue sarcomas to demonstrate sites of possible metastasis and direct biopsy, but is of uncertain negative predictive value with small tumor deposits.

Mifepristone (MIF) is an antiprogestin with potent anti-glucocorticoid and anti-androgen activity. MIF also appears to have anti-tumor activity independent of its ability to bind to nuclear receptors. In this study, we tested the ability of MIF to inhibit the growth of ER and PR negative breast cancer cells. In addition, because high-dose anti-estrogen treatment has been shown to inhibit ER and PR negative breast cancer cells, we compared the anti-proliferative activity of MIF to that of the anti-estrogen 4-hydroxytamoxifen (TAM) or combination hormonal therapy (MIF + TAM). MIF and TAM therapy induced a significant time- and dose-dependent growth inhibition and, ultimately, induced cell death in MDA-231 cells as evidenced by increased DNA fragmentation, cytochrome c release from the mitochondria, and the activation of caspase-3. The anti-proliferative activity of TAM plus MIF combination treatment was at least additive as compared to either monotherapy. The earliest indicator of TAM and MIF cytostatic and cytotoxic action on MDA-231 cells was a significant (p

The outcome of patients with aggressive refractory diffuse large B-cell lymphoma (DLCL) is generally poor. A 43-year-old female with DLCL, who relapsed after first line chemotherapy (CHOP--cyclophosphamide, doxorubicin, vincristine, and prednisone) and progressed despite salvage chemotherapy (EPOCH-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), was treated effectively with 8 cycles of Rituximab. She is without evidence of disease with a follow-up of 32 months. We report this case to bring to attention the possibility of sustained durable remission with single agent Rituximab in refractory DLCL.

Adult T-cell leukemia/lymphoma (ATLL), in its acute stage, is a uniformly fatal disease. ATLL is caused by the human T-cell lymphotropic virus I (HTLV-1), a retrovirus endemic in numerous areas throughout the world including Japan, the Caribbean, Central and South America and certain areas of the United States. Although the progression from HTLV-1 carrier status to ATLL occurs only rarely, ATLL is incurable and thus prevention of HTLV-1 transmission should be a primary goal. With the development of new anti-retroviral and monoclonal therapies, there exist potential cures or at least prolonged remissions for patients diagnosed with ATLL. We present a case of ATLL that, to our knowledge, is only the third reported case in Georgia. In addition, we present a brief review of the literature, including potential new treatment regimens that appear to have promise in the treatment of ATLL.

Tumor lysis syndrome, resulting from the abrupt release of intracellular ions into the blood stream due to sudden tumor cell death, is a serious complication of chemotherapy treatment. This syndrome occurs more frequently in hematologic malignancies and lymphomas. Its incidence in solid tumors is rare, but has a high mortality rate owing to the lack of prophylactic therapy to prevent this complication. We report a case of tumor lysis syndrome accompanied by death in a patient with extensive stage small cell lung cancer who was treated with cisplatin and etoposide, and review the risk factors associated with the syndrome in solid tumor patients who are likely to respond to chemotherapy.

Cryptococcal meningitis following autologous stem cell transplantation in a patient with multiple myeloma