The hematopoietic cell transplantation comorbidity index (HCT-CI), a weighted index of 17 pretransplantation comorbidities, has been validated in nonmyeloablative and myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) studies, but it has not been specifically tested in patients with non-Hodgkin lymphoma (NHL) receiving reduced-intensity conditioning (RIC). We performed a retrospective analysis to assess the impact of the HCT-CI on outcomes of NHL patients treated with HSCT relative to treatment-related mortality (TRM), disease-related mortality (DRM), with a specific emphasis on overall survival (OS). Individual pretransplantation and disease-related factors also were analyzed with HCT-CI relative to their impact on OS. All patients were uniformly treated with an identical pretransplantation induction regimen and an identical RIC regimen (cyclophosphamide [Cy]/fludarabine [Flu]), and received T cell–replete allografts from HLA-matched siblings. The analysis included 63 NHL patients with a median HCT-CI score of 2 (range, 0 to 11). The HCT-CI (0 to 2 comorbidities vs 3+ comorbidities) demonstrated a potential association with TRM, but not with DRM, at 100 days (4.5% vs 26.3%) and at 1 year (13.6% vs 36.8%) posttransplantation. The factor most strongly associated with OS was response to pretransplantation chemotherapy (P = .0001), based on a composite measure. In a Cox model, pretransplantation chemotherapy response remained the most important factor (P < .0001) relative to OS, and there was a trend (P = .056) toward HCT-CI adding predictive value for OS. Although HCT-CI may be useful for predicting TRM, our data further underscore the importance of response to chemotherapy before transplantation as a predictor of overall transplantation outcome in NHL patients being considered for RIC allogeneic HSCT.
Comorbidity index; Non-Hodgkin lymphoma; Reduced intensity conditioning; Allogeneic
There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R).
Patients and Methods
One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4+ count < 200/μL) or progressive disease.
Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3+ (P < .001), CD4+ (P < .001), and CD8+ (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001).
DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies.
Thyroid cancer diagnosis in the United States has increased by 2.3-folds in the last three decades. Up to 30% of thyroid fine-needle aspiration biopsy (FNAB) results are inconclusive. Several differentially expressed microRNAs (miRNAs) have been identified as candidate diagnostic markers for thyroid nodules. We hypothesized that these differentially expressed miRNAs may improve the accuracy of FNAB in difficult to diagnose thyroid nodules.
Expression levels of four miRNAs (miR-7, -126, -374a, and let-7g) were analyzed using quantitative real-time reverse transcription-polymerase chain reaction in 95 FNAB samples as the training set. A predictor model was formulated based on the most differentially expressed miRNA (miR-7) ΔCt value and the model was applied on a separate cohort of 59 FNAB samples as the validation set.
miR-7 was the best predictor to distinguish benign from malignant thyroid FNAB samples. The other three miRNAs were co-expressed and did not significantly contribute to the predictor model. miR-7 had a sensitivity of 100%, specificity of 29%, positive predictive value (PPV) of 36%, negative predictive value (NPV) of 100%, and overall accuracy of 76% when applied to the validation set. In subgroup analysis of preoperative nondiagnostic, indeterminate, or suspicious FNAB samples, the predictor model had an overall accuracy of 37% with sensitivity of 100%, specificity of 20%, PPV of 25%, and NPV of 100%.
miR-7 may be a helpful adjunct marker to thyroid FNAB in tumor types which are inconclusive. Given the high NPV of miR-7, a patient with a benign result based on the predictor model may be followed as opposed to performing an immediate diagnostic thyroidectomy. Future prospective clinical trials evaluating its accuracy in a larger cohort are warranted to determine its clinical utility.
Nitric oxide synthases (NOSs) have been shown to modulate thermal hyperalgesia and mechanical hypersensitivity in inflammatory and neuropathic pain. However, little is known about the effect of NOSs on baseline function of sensory nerve fibers. Using genetic deficiency and pharmacologic inhibition of NOSs, we examined the impact of the three isoforms NOS1, NOS2, and NOS3 on baseline nocifensive behavior by measuring current vocalization threshold in response to electrical stimulation at 5, 250, 2000 Hz that preferentially stimulate C, Aδ, and Aβ fibers. In response to 5, 250 and 2000 Hz, NOS1-deficient animals had significantly higher current vocalization thresholds compared with wild-type. Genetic deficiency of NOS2 was associated with higher current vocalization thresholds in response to 5 Hz (C-fiber) stimulation. In contrast, NOS3-deficient animals had an overall weak trend toward lower current vocalization thresholds at 5 Hz and significantly lower current vocalization threshold compared with wild-type animals at 250 and 2000 Hz. Therefore, NOSs distinctively affect baseline mouse current vocalization threshold and appear to play a role on nocifensive response to electrical stimulation of sensory nerve fibers.
Nociception; Pain; Vocalization; Nitric oxide; Mouse
Pancreatic cancer is the 4th-leading cause of cancer-related death, and studies on the clinical relevance of its genomic imbalances are warranted.
Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens. Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent validation cohort of 61 resected pancreatic cancers. The functions of gene identified were evaluated by proliferation, cell cycle and migration assays in pancreatic cancer cells.
We demonstrated recurrent copy number gains and losses in the first cohort. Loss of 18q22.3 was significantly associated with short-term overall survival in the first cohort (p=0.019). This cytoband includes the Carboxypeptidase of glutamate-like (CPGL) gene. CPGL gene deletion was associated with shorter overall survival in the validation cohort (p=0.003). CPGL deletion and mutations of TP53 or Kras appear to be independent events. A Cox model analysis of the two cohorts combined showed that loss of 18q22.3/deletion of the CPGL gene was an independent poor prognostic factor for overall survival (hazard ratio=2.72, p=0.0007). Reconstitution of CPGL or its splicing-variant CPGL-B into CPGL-negative pancreatic cancer cells attenuated cell growth, migration, and induced G1-accumulation.
Loss of 18q22.3/deletion of the CPGL gene is a poor prognostic marker in resected pancreatic cancer, and functional studies suggest the CPGL gene as growth suppressor gene in pancreatic cancer.
Pancreatic cancer; Comparative genomics; CPGL protein; human; Prognosis; Growth suppressor
Brain metastases are a significant cause of cancer patient morbidity and mortality, yet preventative and therapeutic options remain an unmet need. The cytokine PEDF is downregulated in resected human brain metastases of breast cancer compared to primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a pro-survival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish that PEDF as both a metastatic suppressor and a neuroprotectant in the the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences.
PEDF; breast cancer; brain metastasis; neurons; neuronal injury
Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence® herbal tonic is a complex mixture of eight herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. In this study four experimental groups of female MMTV-Neu mice were left untreated or treated with 3% Flor-Essence® in utero, from birth until 5 weeks of age, or throughout their lifetime. Palpable mammary tumor incidence and body weight was determined weekly for each group. The mice were sacrificed at 28 weeks of age and mammary tumors were enumerated to determine average tumor incidence and multiplicity for each group. Female mice exposed to Flor-Essence® herbal tonic in utero weighed significantly more than the control group (p < 0.001). The average tumor incidence and tumor multiplicity in the experimental mice treated with Flor-Essence® herbal tonic did not differ from the control animals. Flor-Essence® does not inhibit mammary tumor incidence or mammary tumor multiplicity in MMTV-Neu transgenic mice. Flor-Essence® exposure in utero causes increased body weight in experimental animals. This conclusion challenges widely available anecdotal information as well as the hopes of the consumer that this product will inhibit or suppress tumor development.
Flor-Essence® herbal tonic is a complex mixture of eight herbal extracts often used by women with breast cancer in hopes that it will help cure disease or prevent recurrence. There is currently very little scientific data to support or refute its self-administration. We tested whether Flor-Essence® would influence tumor development in the mammary glands of a mouse model of Her2/neu breast cancer. The tonic was given at different life stages to determine if timing of the exposure influenced the response to treatment. This report shows that Flor-Essence® did not inhibit mammary tumor development in the treated mice challenging anecdotal information, as well as the hopes of the consumer, that this product will inhibit or suppress tumor development. This report also shows that Flor-Essence® exposure in utero causes increased body weight in experimental animals.
complementary and alternative medicine; MMTV-Neu; herbal tonic; mammary tumors; transgenic; mouse; dietary supplement; essiac
PANVAC is a recombinant poxviral vaccine that contains transgenes for MUC-1, CEA and 3 T-cell costimulatory molecules. This study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients.
Twenty-six patients were enrolled and given monthly vaccinations. Clinical and immune outcomes were evaluated.
These patients were heavily pretreated, with 21 of 26 patients having ≥ 3 prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. Breast cancer: For the 12 patients enrolled, median time to progression was 2.5 months (1 – 37+) and median overall survival was 13.7 months. Four patients had stable disease. One patient had a complete response by RECIST and remains on study ≥ 37 months, with a significant drop in serum IL-6 and IL-8 by day 71. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. Ovarian cancer:Median time to progression for patients (n=14) was 2 months (1 – 6) and median overall survival was 15.0 months. Updated data are presented here for one patient treated with this vaccine in a previous trial, with a time to progression of 38 months.
Some patients who had limited tumor burden with minimal prior chemotherapy appeared to benefit from the vaccine. Further studies to confirm these results are warranted.
Therapeutic Vaccine; Immune Response; Immuno-Oncology
Metastatic breast cancer (MBC) response to allogeneic lymphocytes requires donor T-cell engraftment and is limited by graft-versus-host disease (GVHD). In mice, Type-II-polarized T cells promote engraftment and modulate GVHD whereas Type-I-polarized T cells mediate more potent graft-versus-tumor (GVT) effects. This Phase-I translational study evaluated adoptive transfer of ex-vivo-costimulated Type-I/Type-II (T1/T2) donor T cells with T-cell-depleted (TCD) allogeneic stem-cell transplantation (AlloSCT) for MBC.
Patients had received anthracycline, taxane and antibody therapies, been treated for metastatic disease and an HLA-identical-sibling donor. Donor lymphocytes were costimulated ex vivo with anti-CD3/anti-CD28 antibody-coated magnetic beads in IL-2/IL-4-supplemented media. Patients received reduced-intensity conditioning, donor stem cells and T1/T2 cells, and monitoring for toxicity, engraftment, GVHD and tumor response; results were compared with historical controls, identically treated except for T1/T2-product infusions.
Mixed Type-I/Type-II CD4+-T cells predominated in T1/T2 products. Nine patients received T1/T2 cells at Dose-Level 1 (5×106 cells/kg). T-cell donor chimerism reached 100% by a median of 28 days. Seven (78%) developed acute GVHD. At Day +28, five patients had partial responses (56%) and none had MBC progression; thereafter, two patients had continued responses. Donor-T-cell engraftment and tumor responses appeared faster than in historical controls, but GVHD rates were similar and responders progressed early, often following treatment of acute GVHD.
Allogeneic T1/T2 cells were safely infused with TCD-AlloSCT, appeared to promote donor engraftment, and may have contributed to transient early tumor responses.
The treatment of metastatic renal cell carcinoma (RCC) with high-dose interleukin-2 (HD IL-2) has resulted in durable tumor regression in a minority of patients. The current study presents the authors’ 20-year experience administering this immunotherapeutic agent.
Patients with metastatic RCC (n = 259) were treated with HD IL-2 alone from January 13, 1986 through December 31, 2006 at the Surgery Branch of the National Cancer Institute. Potential predictive factors for response and survival, both pretreatment and treatment-related, were first subjected to univariate analysis and then to multivariate logistic regression or a Cox proportional hazards model. Finally, the authors investigated Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic factors for survival to assess their predictive value in the patient population in the current study.
A total of 23 patients experienced a complete response and 30 patients achieved a partial response, for an overall objective response rate of 20%. All partial responders had developed disease recurrence at the time of last follow-up, but only 4 complete responders had experienced disease recurrence by that time. Despite toxicities, only 2 patients developed treatment-related mortalities over this same time period. A higher baseline weight (P =.05) and MSKCC prognostic factors (P = .02) were found to be the variables most associated with response. For survival >4 years and overall survival, several pretreatment and treatment-related factors maintained significance, but none more so than response (P <.0001).
HD IL-2 can induce complete tumor regression in a small number of patients, and many patients have experienced extended disease-free intervals. Given its relative safety, HD IL-2 should still be considered a first-line therapy in patients with metastatic RCC who have an overall good performance status.
renal cell carcinoma; interleukin-2; immunotherapy; metastatic
High-dose ketoconazole and docetaxel have shown activity as single agents against castration-resistant prostate cancer (CRPC). The goal of this phase I study was to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of coadministered docetaxel and ketoconazole.
Patients with metastatic CRPC received weekly docetaxel for 3 of every 4 weeks, plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole).
The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly for three weeks out of four escalating from 5 to 43 mg/m2, with starting doses of ketoconazole of 600, 800, or 1200 mg/day. Declines in prostate-specific antigen of ≥ 50% were seen in 62% of patients. Of 25 patients with soft tissue disease, 7 (28%) had partial response. Median overall survival was 22.8 months, and was significantly greater in docetaxel-naïve patients than in patients pretreated with docetaxel (36.8 vs. 10.3 months; P = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy, and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (P < 0.01). Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1200 mg/day, 1.6-fold with 800 mg/day, and 1.3- to 1.5-fold with 600 mg/day.
Results suggest that the combination of weekly docetaxel and ketoconazole has significant antitumor activity in CRPC with manageable toxicities. The extremely long survival in the docetaxel-naïve cohort (36.8 months) warrants additional larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.
castration-resistant prostate cancer; docetaxel; ketoconazole; drug-drug interaction; CYP3A4
We reviewed reoperations for persistent or recurrent sporadic parathyroid adenoma to evaluate and compare our current results and outcomes to our previous experience.
From 1996 to 2008, 237 patients with persistent or recurrent hyperparathyroidism after failed operation underwent reoperation. Patients were re-explored with the assistance of non-invasive and sometimes invasive imaging.
A missed adenoma was suspected pre-operatively in 163 patients. Reoperation resulted in long-term resolution of hypercalcemia in 92%. Adenomas were in entopic locations in 32%; the most frequent ectopic location was the thymus (20%). Sestamibi scanning and ultrasonography were the most successful non-invasive imaging studies (96% positive predictive value (PPV) and 84% PPV respectively). Forty-four percent of patients had a reoperation based solely on non-invasive imaging. Of the invasive procedures performed, arteriography resulted in the best localization (92% PPV). Permanent recurrent laryngeal nerve injury occurred in 1.8%.
Compared to our prior experience (1982–1995), outcomes remained similar (92% resolution of hypercalcemia and 1.8% recurrent nerve injury currently versus 96% and 1.3% previously). Fewer patients received invasive studies for pre-operative localization (56% vs 73%, respectively). The decreased use of invasive imaging is due to technical improvements and greater confidence in the combination of ultrasonography and sestamibi scanning.
Chronic graft versus host disease (cGVHD) remains a major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. 189 adults with cGVHD (33% moderate and 66% severe according to NIH global scoring) were consecutively enrolled onto a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of 4 prior systemic therapies (PST) for their cGVHD. Lower albumin (p<0.0001), higher CRP (C-reactive protein; p=0.043), higher platelets (p=0.030) and higher number of PST (p<0.0001) were associated with active disease defined as clinician's intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (p=0.021) and higher number of PST (p<0.0001) were associated with more severe diseased defined by NIH global score. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity.
chronic graft versus host disease; inflammation; activity; CRP; platelets
Spiritual well-being (Sp-WB) is a resource that supports adaptation and resilience, strengthening quality of life (QOL) in patients with cancer or other chronic illnesses. However, the relationship between Sp-WB and QOL in patients with chronic GVHD (cGVHD) remains unexamined.
52 participants completed the Functional Assessment of Chronic Illness Therapy – Spiritual Well-Being (FACIT-Sp) questionnaire as part of a multidisciplinary study of cGVHD.
Sp-WB was generally high (Mean 37.06, SD 9.5). Those with the lowest Sp-WB had significantly longer time since diagnosis of cGVHD (p=0.05) than those with higher Sp-WB. There were no associations between Sp-WB and demographics, cGVHD severity, or intensity of immunosuppression. Participants with the lowest Sp-WB (N=11) reported inferior physical (p = .0009), emotional (p = .003), social (p = .027), and functional well-being (p = < 0.0001) as well as lower overall QOL (p = <0.0001) compared to those with higher Sp-WB. They also had inferior QOL (M 54.88, S.E. 4.19) relative to population norms (M=80.1, S.E. 0.55). Differences between those with the lowest and those with better Sp-WB consistently exceeded the minimal clinically significant difference for all subscales and for overall QOL. Controlling for physical, emotional and social well-being, Sp-WB was a significant independent predictor of contentment with QOL.
Our results suggest that Sp-WB is an important factor contributing to the QOL of patients with cGVHD. Research is needed to identify factors that diminish Sp-WB and to test interventions designed to strengthen this coping resource in patients experiencing the late-effects of treatment.
Hypoxia-inducible factor 1 (HIF-1) α is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1α expression in preclinical models. We designed a pilot trial to measure HIF-1α inhibition in tumor biopsies from patients with advanced solid tumors over-expressing HIF-1α, after treatment with oral topotecan.
Topotecan was administered orally at 1.6 mg/m2 once daily for 5 days/week for 2 weeks, in 28-day cycles. Objectives were to determine inhibition of expression of HIF-1α and HIF-1 target genes in tumor; to assess tumor blood flow by dynamic contrast–enhanced magnetic resonance imaging (DCE-MRI); and to measure pharmacokinetics. Tumor biopsies were collected at baseline and during the second cycle of treatment.
Sixteen patients were enrolled. The dose of topotecan was reduced to 1.2 mg/m2/day due to myelosuppression. Seven patients had paired tumor biopsies. In four patients, HIF-1α nuclear staining became undetectable after treatment (7.5%–50% staining at baseline). Decreased levels of VEGF and GLUT-1 mRNA were measured in four patients; the changes were concordant with reduction in HIF-1α in three patients. Decreased tumor blood flow and permeability were observed by DCE-MRI in seven of ten patients after one cycle. One patient had a partial response accompanied by inhibition of HIF-1α in tumor and reduction in tumor blood flow on DCE-MRI.
This multihistology, target assessment trial of a small molecule inhibitor of HIF-1α demonstrated that topotecan could decrease HIF-1α expression in advanced solid tumors.
Topoisomerase inhibitor; HIF-1; topotecan; pharmacodynamics; VEGF
Most treatments for patients with metastatic melanoma have a low rate of complete regression and thus overall survival in these patients is poor. We have investigated the ability of adoptive cell transfer utilizing autologous, tumor infiltrating lymphocytes to mediate durable complete regressions in heavily pre-treated patients with metastatic melanoma.
Ninety-three patients with measurable metastatic melanoma were treated with the adoptive transfer of autologous tumor-infiltrating lymphocytes administered in conjunction with interleukin-2 following a lymphodepleting preparative regimen on three sequential clinical trials. Ninety-five percent of these patients had progressive disease following a prior systemic treatment. Median potential followup was 62 months.
Objective response rates by RECIST criteria in the three trials using lymphodepleting preparative regimens (chemotherapy alone or with 2Gy or 12Gy irradiation) were 49%, 52% and 72%. Twenty of the 93 patients (22%) achieved a complete tumor regression and 19 have ongoing complete regressions beyond three years The actuarial three and five year survivals for the entire group were 36% and 29% respectively but for the 20 complete responders were 100% and 93%. The likelihood of achieving a complete response was similar regardless of prior therapy. Factors associated with objective response included longer telomeres of the infused cells, the number of CD8+ CD27+ cells infused and the persistence of the infused cells in the circulation at one month (all p2<0.001).
Cell transfer therapy with autologous tumor infiltrating can mediate durable complete responses in patients with metastatic melanoma and has similar efficacy irrespective of prior treatment.
Measurement of tumor response by standard response criteria is challenging in thymic malignancies especially when the pleura is involved, as it often is in stage IV disease. In this study we aimed to determine the effectiveness of volumetric response evaluation criteria in solid tumors (volumetrics) for evaluating response in patients with thymic malignancies treated on a phase II study of belinostat.
We evaluated 25 thymic cancer patients' tumor responses using computed tomography (CT) based response evaluation criteria in solid tumors (RECIST), World Health Organization (WHO), modified RECIST, and volumetrics. As a control we assessed 37 NSCLC patients with RECIST and volumetrics.
Agreement analyses in 23 thymic cancer patients at the time of RECIST-determined progressive disease (PD) compared volumetrics to RECIST, modified RECIST, and WHO criteria. Use of volumetrics was associated with 22% discordance compared to RECIST, 15% vs. modified RECIST, and 22% vs. WHO criteria. Volumetrics revealed PD 72 days earlier than RECIST (p=0.016). In another cohort of 35 NSCLC patients there was 9% discordance between volumetrics and RECIST at the time of PD. Volumetrics demonstrated PD 32 days earlier than RECIST in NSCLC (p=0.0078).
Our study suggests that volumetrics might improve detection of progressive disease. Prospective evaluation of this technique in a larger series of patients with thymic malignancies will be required.
Adrenocortical carcinoma (ACC) is a rare disease without effective chemotherapy treated most appropriately with resection. The aim of this study was to evaluate our experience with liver resection for metastatic ACC.
This study is a retrospective review of patients who underwent liver resection or radiofrequency ablation (RFA) for ACC from 1979 to 2009.
A total of 27 patients were identified. Of the 27, 19 underwent liver resection. Of the 19, 10 had a single liver lesion, and 18 of 19 were rendered free of disease in the liver, although only 11 of 19 were rendered completely free of disease because of extrahepatic disease (EHD). Of the 19, 13 had synchronous EHD. Also, 6 of 17 remained disease free in the liver at a median follow-up of 6.2 years (status of 2 of 19 was unknown). Of the 27 patients, 8 underwent RFA, 7 of 8 became free of disease in the liver, and 5 of 7 had EHD. No patients responded to prior chemotherapy. Median overall survival and survival of patients who underwent liver resection or RFA were both 1.9 years (0.2–12 + years); 5-year actuarial survivals were 29% and 29%, respectively. Disease-free interval (DFI) greater than 9 months from primary resection was associated with longer survival (median 4.1 vs 0.9 years; P = .013).
This study is a tertiary institution series of liver resection and RFA for ACC. Given the lack of effective systemic treatment options and the safety of resection and ablation, liver resection or RFA may be considered in selected patients with ACC metastatic to the liver especially with a long DFI.
The purpose of this pilot study was to evaluate the feasibility and tolerability of weekly intratumoral TNFerade™ injections combined with concurrent capecitabine and radiotherapy in the treatment of patients with locally advanced rectal cancer.
Patients with T3, T4, or N+ rectal cancer received radiotherapy to a total dose of 50.4–54 Gy in combination with capecitabine 937.5 mg/m2 p.o. b.i.d. TNFerade™ at a dose of 4 × 1010 particle units was injected into the rectal tumor on the first day of radiotherapy and weekly for a total of 5 injections. Surgery was performed 5–10 weeks after the completion of chemoradiation.
Nine patients were enrolled in this pilot trial. The stage was cT2 in 2 patients, cT3 in 6 patients, cT4 in 1 patient, N– in 7 patients and N+ in 2 patients. Eight patients completed all treatments. Grade 3 hematologic toxicity was observed in 2 patients. There was no toxicity directly attributable to the injection procedure. A complete pathologic response was observed in 2 of 9 patients.
This study demonstrates the feasibility of weekly intratumoral TNFerade™ injections during chemoradiotherapy for locally advanced rectal cancer. Pathologic responses with this combination compare favorably to published rates.
Rectal carcinoma; Radiation; Neoadjuvant; TNFerade™
Sorafenib, a multikinase inhibitor targeting Raf and VEGFR has shown activity in unselected patients with NSCLC. At present there are no validated biomarkers indicative of sorafenib activity.
Patients received sorafenib 400mg bid daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N=34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI to determine early changes in tumor vascular characteristics were evaluated. Three parameters Ktrans, Kep and ve, were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was performed on days 0, 14, 28 and 54.
37 pts with previously treated stage IV NSCLC were enrolled in this single center phase II trial. In 34 evaluable patients, 2 had partial responses, and 20 had stable disease for 3-17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%), showed no correlation with response, PFS or OS. Kep, was significant in predicting an improvement in OS (p=0.035) and PFS (p=0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 <6 vs >6 pg/ml (p=0.042) whereas a PFS benefit was seen with bFGF at day 28 <6 vs >6 (p=0.028).
KRAS and EGFR mutational status showed no correlation with response, PFS or OS. Radiological and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.
While the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e. blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT-prolongation and cardiotoxicity.
ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (−/−) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced QTc prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype.
Here, we demonstrate that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT-prolongation from baseline (ΔQTc) over time. Consistent with this observation, we also demonstrate that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower ΔQTc following a single dose of romidepsin.
To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT-prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT-prolongation following the administration of ABCB1-substrate drugs.
Depsipeptide; FK228; polymorphisms; ABCB1; QTc
P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to demonstrate meaningful results. Here we report the results of a pharmacokinetic and pharmacodynamic trial using a third generation, potent, non-competitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel.
In the first treatment cycle, the pharmacokinetics of docetaxel (40 mg/m2) were evaluated after day 1 and day 8 doses, which were administered with or without tariquidar (150 mg). 99mTc-sestamibi scanning and CD56+ mononuclear cell rhodamine efflux assays were performed to assess Pgp inhibition. In subsequent cycles, 75 mg/m2 docetaxel was administered with 150 mg tariquidar every three weeks.
Forty-eight patients were enrolled onto the trial. Non-hematologic grade 3/4 toxicities in 235 cycles were minimal. Tariquidar inhibited Pgp-mediated rhodamine efflux from CD56+ cells and reduced 99mTc-sestamibi clearance from the liver. A 12 to 24% increase in sestamibi uptake in visible lesions was noted in 8 of 10 patients with lung cancer. No significant difference in docetaxel disposition was observed in pairwise comparison with and without tariquidar. Four PRs were seen (4/48); three in the non-small cell lung cancer (NSCLC) cohort, measuring 40%, 57% and 67% by RECIST and one PR in a patient with ovarian cancer.
Tariquidar is well-tolerated with less observed systemic pharmacokinetic interaction than previous Pgp antagonists. Variable effects of tariquidar on retention of sestamibi in imageable lung cancers suggest that follow-up studies assessing tumor drug uptake in this patient population would be worthwhile.
P-glycoprotein; ABC transporter; drug resistance; sestamibi imaging; lung cancer
There are few validated relapse prediction biomarkers for epithelial ovarian cancer (EOC). We have shown progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI) are up regulated, overexpressed survival factors in EOC. We hypothesized they would predict presence of occult EOC.
PGRN, SLPI, and the known biomarker HE4 were measured in EOC patient plasma samples, prospectively collected every 3 months from initial remission until relapse. Clinical data and CA125 results were incorporated into statistical analyses. Exploratory Kaplan-Meier estimates, dividing markers at median values, evaluated association with progression-free survival (PFS) and overall survival (OS). Area-under-the-curve (AUC) statistics were computed from receiver operating characteristic (ROC) curves to evaluate discrimination ability. A Cox proportional hazards model assessed the association between PFS, OS, and biomarkers, adjusting for clinical prognostic factors.
Samples from 23 advanced stage EOC patients were evaluated. PGRN at 3 months was the only biomarker independently associated with PFS (P<0.0001) and OS (P<0.003). When used to predict progression by 18 months, sensitivity and specificity were 93% and 100%, respectively, with AUC = 0.944. The Cox model hazard ratio for PFS, divided at 59 ng/ml by ROC analysis and adjusted for clinical factors, was 23.5 (95% CI: 2.49–220). Combinations with SLPI, HE4, and/or CA125 did not improve the model.
We report pilot data indicating a potential independent association of PGRN on EOC patient PFS and OS. A validation study will be required to confirm this finding and to inform whether PGRN warrants evaluation as a potential screening biomarker.
Progranulin (PGRN); biomarkers; progression free survival; overall survival; epithelial ovarian cancer