Marker Of Clinical Response Research Articles

Introduction: challenging established dogma

Introduction: challenging established dogma

Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications

Tumor-infiltrating myeloid cells are involved in crucial processes during tumor development. A subset of monocytes that express the angiopoietin receptor Tie2 play an important role in tumor angiogenesis. Selective depletion of these Tie2-expressing monocytes (TEMs) in tumor-bearing mice inhibits tumor angiogenesis and growth, suggesting that they might regulate angiogenic processes in tumors by providing paracrine support to nascent blood vessels. TEMs have also been identified in human blood and tumors. We discuss here the therapeutic opportunities emanating from the discovery of TEMs, which include the identification of new antitumor targets, monitoring TEMs as surrogate markers for clinical responses in cancer patients, and the possible use of TEMs as cellular vehicles for gene delivery to tumors.

Cyclin degradation for cancer therapy and chemoprevention

Cancer is characterized by uncontrolled cell division resulting from multiple mutagenic events. Cancer chemoprevention strategies aim to inhibit or reverse these events using natural or synthetic pharmacologic agents. Ideally, this restores normal growth control mechanisms. Diverse classes of compounds have been identified with chemopreventive activity. What unites many of them is an ability to inhibit the cell cycle by specifically modulating key components. This delays division long enough for cells to respond to mutagenic damage. In some cases, damage is repaired and in others cellular damage is sufficient to trigger apoptosis. It is now known that pathways responsible for targeting G1 cyclins for proteasomal degradation can be engaged pharmacologically. Emergence of induced cyclin degradation as a target for cancer therapy and chemoprevention in pre-clinical models is discussed in this article. Evidence for cyclin D1 as a molecular pharmacologic target and biological marker for clinical response is based on experience of proof of principle trials.

Preclinical antitumor activity of the oral platinum analog satraplatin

Satraplatin is an orally available platinum analog. The purpose of this study was to better characterize satraplatin's preclinical antitumor efficacy in a variety of sensitive and resistant human tumor cell lines and in a prostate cancer xenograft model and to evaluate the effect of satraplatin on PSA expression and/or secretion in a prostate cancer cell line. Satraplatin and its primary metabolite JM-118 were preclinically tested for their cytotoxic activity in a range of cancer cells including: human prostate, those forming the NCI drug screening panel, and those resistant to anti-cancer drugs. Also, the antiproliferative efficacy of satraplatin was tested in vivo in a human prostate cancer model. The effect of satraplatin and JM-118 on PSA transcription was measured by quantitative real time PCR. Satraplatin and JM-118 inhibited in vitro and in vivo the growth of prostate cancer cells in a dose-dependent fashion. The IC50 cytotoxicity values for satraplatin ranged from 1 to 3 microM for androgen-insensitive cells and was 11 microM for the androgen-sensitive cell line. Interestingly, JM-118 was up to 16-fold more potent than satraplatin. Oral administration of satraplatin to nude mouse PC-3 xenograft models inhibited the growth of these human tumors. Satraplatin had no direct effect on PSA transcription and the observed decrease in secreted PSA correlated with a decrease in cell number. When evaluated in the NCI drug-screening panel, satraplatin was most active in leukemia and small cell lung cancer cell lines. Both satraplatin and JM-118 were tested on cells resistant to chemotherapeutic agents. Satraplatin and JM-118 were equally active in the cisplatin-resistant A129cp80 ovarian carcinoma cell line, with activity comparable to that observed in the parent line. Neither expression of MDR1, BCRP, MRP1, nor altered tubulin or topoisomerase I were found to mediate resistance to satraplatin or JM-118. Although these resistance mechanisms contribute to drug resistance for a number of chemotherapeutics, they do not appear to play a role in satraplatin resistance. These results demonstrate that satraplatin and JM-118 have preclinical antitumor activity in human prostate cancer and other tumor types as well, including several cell lines displaying drug resistance to cisplatin, docetaxel and mitoxantrone. In addition, the results suggest that PSA should be further evaluated as a relevant marker of clinical response in patients with prostate cancer treated with satraplatin.

Salvage Therapy for Advanced Non-Small Cell Lung Cancer: Factors Influencing Treatment Selection

Novel chemotherapies and molecularly targeted agents have improved outcomes for patients with advanced non-small cell lung cancer (NSCLC). Several efficacious regimens are available, which allows for selection of therapy based on factors such as schedule, toxicity profile, patient-specific needs, and individual preferences of the patient. Treatment guidelines recommend platinum-based chemotherapy first line for patients with a good performance status. These regimens offer a modest survival advantage over best supportive care. The role of targeted biologic agents in this setting is being assessed in phase II trials. Results to date show promising activity and tolerability. Erlotinib, docetaxel, and pemetrexed are all approved for patients who progress following one prior regimen for advanced NSCLC. These agents have different tolerability profiles and routes of administration but appear to have similar effects on tumor response and survival, though comparative trials are required to confirm this. Based on the results of a phase III trial, erlotinib is also recommended for third-line use in patients with NSCLC. Identifying predictive markers of clinical response to therapy may provide an opportunity to better select patient subsets appropriate for specific treatment. Recent data have linked various clinical characteristics and biologic markers with outcome to HER-1/EGFR-targeted agents. However, many of these studies are retrospective and based on small patient numbers, and there is evidence of broad benefit across diverse patient subgroups with erlotinib. Prospective, randomized trials are required to validate potential predictive markers fully before they are applied to clinical practice.

GREB1 is a critical regulator of hormone dependent breast cancer growth

Estrogen plays a central role in breast cancer pathogenesis and many potent risk factors for the development of the disease can be explained in terms of increased lifetime exposure to estrogen. Although estrogen regulated genes have been identified, those critically involved in growth regulation remain elusive.METHODS. To identify candidate genes involved in estrogen stimulated breast cancer growth, DNA microarray based gene expression profiles were generated from three estrogen receptor alpha (ER alpha) positive breast cancer cell lines grown under multiple stimulatory and inhibitory conditions. Only three genes were significantly induced by 17beta-estradiol (E2) relative to control in all three cell lines: GREB 1, stromal cell-derived factor 1 (SDF-1) and trefoil factor 1 (pS2). Quantitative real-time PCR assays confirmed that in all three cell lines, GREB 1 was induced by E2, but not by the antiestrogens tamoxifen (TAM) or ICI 182,780. GREB 1 expression level was strongly correlated with ER alpha positivity in 39 breast cancer cell lines of known ER alpha expression status. GREB 1 induction by E2 was rapid (7.3 fold by 2 h for MCF-7) and mirrored the fraction of cells entering S-phase when released from an estrogen deprivation induced cell arrest. Suppression of GREB 1 using siRNA blocked estrogen induced growth in MCF-7 cells and caused a paradoxical E2 induced growth inhibition. These data suggest that GREB 1 is critically involved in the estrogen induced growth of breast cancer cells and has the potential of being a clinical marker for response to endocrine therapy as well as a potential therapeutic target.

Clinical Pharmacogenomics and Transcriptional Profiling in Early Phase Oncology Clinical Trials

Microarray-based expression profiling studies in the field of oncology have demonstrated encouraging correlations between tumor transcriptional profiles and eventual patient outcomes. These findings have fueled great interest in the application of transcriptional profiling to samples available from real-time clinical trials, and clinical pharmacogenomic objectives utilizing transcriptional profiling strategies are becoming increasingly incorporated into clinical trial study designs. Over the last few years several retrospective studies based on the profiling of archival tumor tissues suggest that transcriptional analysis of oncology samples may provide general prognosis measures, and in some cases may even predict response to specific therapies. Recently the FDA released a voluntary genomic data guidance meant to assist both regulatory agencies and pharmaceutical companies alike in evaluating the potential benefit of implementing expression profiling studies during the preclinical and clinical phases of drug development. Despite the great promise afforded by this technology, the ultimate benefit of applying transcriptional profiling in prospective clinical trials has yet to be realized because a number of practical impediments to this process exist. The multi-fold purpose of the current review is to highlight the increasing evidence from studies that have identified transcriptional signatures in archived tumors prognostic of patient outcome, to describe some of the drivers for the implementation of transcriptional profiling strategies in real-time drug development, to discuss the use of transcriptional profiling in the context of increasingly complex translational medicine strategies, and to highlight the practical issues and potential approaches involved in the successful application of clinical pharmacogenomic objectives during real-time clinical trials. Strategic implementation of transcriptional profiling in early oncology clinical trials can provide an opportunity to identify predictive markers of clinical response and eventually provide a substantial step forward towards the era of personalized medicine.

Stimulation of natural killer (NK) cell and macrophage infiltration in pancreatic cancer with virulizin (V), an immunotherapeutic agent

4257 Purpose: V is stimulates macrophages and monocytes in vitro and in vivo. Pancreatic cancer patients treated with V in phase I/II studies showed increased 6 and 12 months survival vs historical controls. V administration was associated with increased NK cell activity in patients showing the best response to V. Hence, NK cell function may be a mediator of V anti-tumor activity. Methods: To determine if V induces NK cell infiltration into tumors, CD-1 nude mice with Capan-1 pancreatic tumor xenografts were treated with V; tumor samples were analyzed by flow cytometry using NK cell-specific antibodies. Anti-tumor activity and NK cell infiltration were also evaluated in human tumor xenografts in CD-1 nude mice depleted of macrophages. Immunohistochemical staining of tumor xenografts was performed to further assess NK cell and macrophage activity. Results: V increased NK cell infiltration of tumors (59.4 – 116.0%). Macrophage depletion reduced both NK cell infiltration of tumors, and anti-tumor activity of V (P=0.1632). V-treated mice showed a significant increase in infiltration of F4/80+ (macrophages) and NK1.1+ (NK) cells, vs saline treated controls. Increased NK1.1+ cell infiltration occurred early in V treatment, and correlated with an early marker for tumor apoptosis. V treatment also resulted in a significant increase in the NK cell number in the spleen. Conclusion: Macrophage-mediated NK cell activation/recruitment is implicated in the mechanism of action of V.. These results suggest that V mediates a sustained infiltration of NK cells and macrophages into tumors. Low NK cell activity may be a risk factor for malignancy and metastases, and a negative prognostic indicator in pancreatic cancer. NK cell function and other immune activities are being assessed as biologic markers of clinical response in a Phase III trial in pancreatic cancer as a first line combination therapy with gemcitabine. NK cell function will be correlated with clinical response parameters. No significant financial relationships to disclose.

Modulation of CD3-zeta as a marker of clinical response to IL-2 therapy in ovarian cancer patients

Objective. In women with advanced ovarian cancer, levels of CD3-zeta on peripheral blood lymphocytes have previously been demonstrated to correlate with responsiveness to interleukin (IL)-2 therapy. The aims of this study were to identify the circulating component that modulated zeta expression and to define whether this suppressive activity could serve as a marker of biotherapy responsiveness. Methods. Sera were obtained from 17 patients with advanced ovarian cancer treated with intraperitoneal IL-2 in a phase I trial between 1987 and 1990. Nine of these patients exhibited a clinical response, while eight did not respond. Six additional sera from age-matched, noncancer-bearing women were used as controls. Jurkat E6-1 cells were used to assay modulation of CD3-zeta by sera and serum-derived components. Jurkat cells were exposed to serum or chromatographically fractionated serum components for 4 days and zeta expression was analyzed by Western immunoblots and quantitated by densitometry. Results. The effect of sera on zeta expression was compared between responders and nonresponders. Incubation of Jurkat cells with sera from responders suppressed CD3-zeta expression by 36.7% (vs. control treated), while treatment with sera from nonresponders produced an 83.7% reduction in zeta expression (difference between groups, P < 0.001). When sera from nonresponders were chromatographically fractionated, a <20 kDa component was identified that correlated with decreased zeta chain expression. This component was diminished in the sera of responders and absence in controls. Conclusions. Thus, in patients with advanced ovarian cancer, a circulating component, which decreases zeta expression, can be identified as a marker for responsiveness to IL-2 therapy.

Laser Doppler Perfusion Imaging (LDPI) and Transepidermal Water Loss (TEWL) Values in Psoriatic Lesions Treated with Narrow Band UVB Phototherapy. Dermal Vascularity may be useful Indicator of Psoriatic Activity

Objective: This study attempts to objectively measure physiological changes in transepidermal water loss (TEWL), an indicator of skin barrier function and laser Doppler perfusion index (LDPI) an indicator of skin vascularity, of psoriatic skin lesions following treatment to narrowband ultraviolet B (UVB) phototherapy using the psoriasis severity (PS) score as a measurement of clinical phototherapy response. Materials and Methods: Fourteen patients with established diagnosis of plaque type psoriasis were studied. The patients received narrow band UVB phototherapy 3 times a week until clearance of their psoriasis and the frequencies are reduced as clearance is observed. Two psoriasis plaques (“lesional skin”) were used to measure treatment response and another 2 areas of uninvolved (“non-lesional skin”) on the corresponding opposite limbs were identified for comparison. PS score, TEWL and LDPI were carried out at baseline (0 week), 2 weeks and 8 weeks during treatment. Measurements were carried out just before each phototherapy session and repeated 1 hour after phototherapy treatment. Results: The mean PS score decreased by almost 40% after 2 months phototherapy (t = 2.44, P = 0.028). There was no significant difference in PS score between week 0 and week 2, or between week 2 and week 8. After phototherapy, there was no significant difference in LDPI values on the psoriatic lesional skin between week 0 and week 8 or between week 2 and week 8. It appears that phototherapy does not induce inflammation on non-lesional skin to provoke measurable LDPI changes. The mean TEWL values of psoriatic lesional skin were significantly higher than normal skin throughout the study period before and during phototherapy (week 0, t = 5.71, P = 0.000, week 2, t = 9.29, P = 0.00, week 8, t = 6.93, P = 0.000). It appears that the skin barrier function of psoriatic skin improves only minimally as psoriatic lesions improve clinically (as evidenced by the reduction in PS scores) with narrow-band UVB phototherapy, but the dermal vascularity and blood flow and barrier function of the psoriatic skin remained abnormal. Conclusion: It appears that LDPI and TEWL measurement may not be a good surrogate marker of clinical response to narrow-band UVB phototherapy.

Effect ofin vitrointerferon-beta administration on hepatitis C virus in peripheral blood mononuclear cells as a predictive marker of clinical response to interferon treatment for chronic hepatitis C

To test whether in vitro incubation of peripheral blood mononuclear cells (PBMC) with interferon (IFN) could efficiently decrease hepatitis C virus-RNA (HCV-RNA) amount and to analyze whether this effect was associated with clinical response to IFN. Twenty-seven patients with histologically proven chronic hepatitis C were given intravenous administration of 6 million units (MU) IFN-beta daily for 6 weeks followed by three times weekly for 20 weeks. PBMC collected before IFN therapy were incubated with IFN-beta and HCV-RNA in PMBC was semi-quantitatively determined. Twenty-five patients completed IFN therapy. Eight patients (32%) had sustained loss of serum HCV-RNA with normal serum ALT levels after IFN therapy (complete responders). HCV-RNA in PBMC was detected in all patients, whereas it was not detected in PBMC from healthy subjects. In vitro administration of IFN-beta decreased the amount of HCV-RNA in PMBC in 18 patients (72%). Eight of these patients obtained complete response. On the other hand, none of the patients whose HCV-RNA in PBMC did not decrease by IFN-beta was complete responders. Multiple logistic regression analysis revealed that the decrease of HCV-RNA amount in PBMC by IFN-beta was the only independent predictor for complete response (P<0.05). The effect of in vitro IFN-beta on HCV in PBMC reflects clinical response and would be taken into account as a predictive marker of IFN therapy for chronic hepatitis C.

Investigation of target plasma concentration-effect relationships for olanzapine in schizophrenia.

Olanzapine is an atypical antipsychotic effective in the treatment of schizophrenia. The present study has examined the potential use of target concentration monitoring of olanzapine in plasma as a marker of clinical response and an aid in patient management. Fifty-three patients (mean age 32 years; 40 M, 13 F) with a DSM-IVR diagnosis of schizophrenia completed a 6-week trial of oral olanzapine. Participants received once-daily olanzapine, and their psychotic symptoms were measured with the PANSS (Positive and Negative Symptom Scale) on admission and again after 6 weeks. Responders were classified as having a >/=20% decrease in PANSS scores. Plasma olanzapine was quantified by high-performance liquid chromatography. Receiver operator characteristic (ROC) curve analysis was used to identify a break point in plasma olanzapine that might serve as a surrogate for PANSS classification, and the two methods were compared using the McNemar chi2 test. After 6 weeks the median olanzapine dose was 15 mg/d (range 5-30 mg/d), and the mean plasma olanzapine was 32 micrograms/L at a mean of 13.5 hours after dose. With the PANSS (total), there were 42 responders and 11 nonresponders. ROC curve analysis for total PANSS identified a break point at 23 micrograms/L plasma olanzapine, with the proportions of responders and nonresponders identified by PANSS and the plasma break point being similar. Similar break points were found for the positive, negative, and global PANSS subscores. Nevertheless, these relationships were very modest, and at best the target plasma olanzapine concentration identified only 20% more responders than nonresponders. We suggest that plasma olanzapine monitoring can be used for dose-response optimization, but only to complement the normal clinical evaluation process.

Real-time automated polymerase chain reaction (PCR) to detect Candida albicans and Aspergillus fumigatus DNA in whole blood from high-risk patients

We report the development and evaluation of a real-time PCR assay using the LightCycler instrument for the detection of C. albicans and A. fumigatus DNA in whole blood. Recently published consensus criteria for the diagnosis of invasive fungal infection (IFI) were used for all patient samples. Unique and published primer pairs were developed and assessed for sensitivity, specificity, and reproducibility to detect C. albicans and A. fumigatus DNA in samples spiked with purified DNA, and whole blood samples from 8 high-risk patients and 45 negative controls. The real-time assay demonstrated an analytical sensitivity of 10 fg of purified C. albicans and A. fumigatus DNA and was found to be specific for each species. The standardized approach was highly reproducible and detected C. albicans and A. fumigatus DNA in two patients with proven IFI and in one patient with a possible IFI. In addition, we report for the first time the use of recently published international consensus criteria for the diagnosis of IFI in the evaluation of a mildy invasive fungal diagnostic assay. Standardized clinical criteria and a more standardized approach to detect fungal DNA in less invasive patient samples, may permit a more reliable comparison of future studies. A rapid real-time detection of fungal DNA in whole blood, combined with standard clinical markers of response, may be more useful for monitoring patients at risk of developing IFI than other diagnostic methods currently available.

Quantitating cellular immune responses to cancer vaccines

While the future of immunotherapy in the treatment of cancer is promising, it is difficult to compare the various approaches because monitoring assays have not been standardized in approach or technique. Common assays for measuring the immune response need to be established so that these assays can one day serve as surrogate markers for clinical response. Assays that accurately detect and quantitate T-cell-mediated, antigen-specific immune responses are particularly desired. However, to date, increases in the number of cytotoxic T cells through immunization have not been correlated with clinical tumor regression. Ideally, then, a T-cell assay not only needs to be sensitive, specific, reliable, reproducible, simple, and quick to perform, it must also demonstrate close correlation with clinical outcome. Assays currently used to measure T-cell response are delayed-type hypersensitivity testing, flow cytometry using peptide major histocompatibility complex tetramers, lymphoproliferation assay, enzyme-linked immunosorbant assay, enzyme-linked immunospot assay, cytokine flow cytometry, direct cytotoxicity assay, measurement of cytokine mRNA by quantitative reverse transcriptase polymerase chain reaction, and limiting dilution analysis. The purpose of this review is to describe the attributes of each test and compare their advantages and disadvantages.

Molecular remission and non-Hodgkin's lymphoma

Non-Hodgkin's lymphomas are highly sensitive to treatment and complete clinical responses are often achieved. However, disease recurrence is common and is caused by the persistence of malignant lymphoma cells at a level below the limits of detection by conventional assessment such as clinical examination, bone marrow morphology and CT scans. This minimal residual disease can be detected using molecular techniques such as the polymerase chain reaction (PCR), and treatments capable of eliminating minimal residual disease are described as producing molecular remission. Molecular assessment is now commonly used as a measure of outcome in clinical trials of novel therapies for the treatment of lymphoma. The evidence for using molecular remission as a surrogate marker of clinical response in this setting is reviewed and the significance of minimal residual disease in determining prognosis and planning treatment strategies is addressed.

HLA class II tetramers: tools for direct analysis of antigen-specific CD4+ T cells.

Immunotherapies for human autoimmune and immune-mediated diseases are proliferating rapidly, and with these changes comes the opportunity to monitor patients for immune responses to therapy based on early surrogate markers for clinical responses. Class II tetramers have the potential to serve as these sorts of markers for immune monitoring, and thereby assist with patient management, therapy selection, and improved outcomes. However, important issues of TCR avidity require resolution, because much is still unknown regarding location, quantitation, and characterization of the human T cell response. Opportunities for application of tetramer technologies in the near future will enable both clinical progress and the development of new insights into human CD4+ T cell biology in vivo.

Urinary calcium excretion in the monitoring of bone metastases from prostatic carcinoma.

One of the greatest problems in treating advanced prostate carcinoma is monitoring the therapeutic response of bone metastases. As these metastases are mainly osteosclerotic and lead to a markedly increased bone calcium requirement that may give rise to an imbalance in calcium homeostasis, the authors investigated whether changes in calcium balance may be useful for evaluating the response of bone metastases to treatment. The study involved 268 prostate carcinoma patients: 142 in Stage A-C2 (International Union Against Cancer [UICC] staging system, 1998) and 126 with bone metastases who had failed to respond to hormone therapy and were receiving chemotherapy. Prostate-specific antigen (PSA), calcium and phosphate metabolism, and the main bone formation and resorption markers were all assayed before and after chemotherapy. Of the 126 patients on chemotherapy, 109 were evaluable for response: according to standard criteria, 25 (23%) had improved, 43 (39.5%) were unchanged, and 41 (37.5%) had worsened. All of the improved and 16 unchanged patients had decreased PSA and bone marker levels and an increased urinary calcium/creatinine ratio (UCa/Cr); the worsened patients had increased PSA and bone marker levels, and their UCa/Cr decreased after only six treatment cycles. PSA and UCa/Cr were the biochemical markers whose changes showed the best agreement with treatment response. The UCa/Cr ratio was the most useful marker of clinical response, mainly because it allowed an early decision to continue or to stop chemotherapy. Furthermore, UCa/Cr and PSA together identified a percentage of patients classified as unchanged on the basis of standard criteria but whose condition had actually improved.

Dyslipidaemia in HIV-infected patients: association with adherence to potent antiretroviral therapy

Metabolic complications are being increasingly recognized among HIV-infected patients treated with potent combination antiretroviral therapies. We sought to assess the association of dyslipidaemia with adherence to protease inhibitor (PI) therapy and with the markers of clinical response to antiretroviral therapy (CD4 count, HIV RNA viral level) through a prospective, cross-sectional cohort study. Fifty-six HIV-infected patients who were already on, or who were started on PI-containing antiretroviral therapy were monitored for the development of dyslipidaemias. Therapy with PI-containing antiretroviral therapy was significantly associated with elevated serum triglyceride level (>250 mg/dl) (52% vs 8%, P=0.001). Patients with an adherence rate of at least 80% to a PI-containing regimen were significantly more likely to have elevated low density lipoprotein (LDL) cholesterol level as compared to patients with an adherence rate of <80% (79% vs 26%, P=0.03). Patients with an adherence rate of at least 80% to a PI-containing regimen were also significantly more likely to have severe hypertriglyceridaemia (>800 mg/dl) as compared to patients with an adherence rate of <80% (21% vs 4%, P=0.04). Viral load at the last study visit did not correlate with total cholesterol (r=-0.39, P=0.30), LDL cholesterol (r=0.57, P=0.30), or triglyceride level (r=0.55, P=0.20). However, there was a significant correlation between the last viral load and high density lipoprotein (HDL) cholesterol (r=0.79, P=0.035), i.e. lower viral load was associated with higher HDL cholesterol level. In conclusion, dyslipidaemia in patients with HIV infection was significantly associated with adherence to PI-containing antiretroviral therapy. Patients who are adherent to PI-containing regimens at least 80% of the time warrant close monitoring for the development of dyslipidaemia.

Application of the enrichment approach to identify putative markers of response to 5-fluorouracil therapy in advanced colorectal carcinomas.

A wide range of tumor response is seen amongst patients with the same stage of colorectal cancer, even with the use of uniform chemotherapy. The significant economic and personal impact of chemotherapy provides the impetus for the identification of markers of response for use in guiding patient treatment. However, practical constraints prevent evaluation of all putative markers in a definitive manner. In this study, the enrichment approach was evaluated by examining the expression of a panel of putative response markers in selected patient populations with advanced colorectal cancer (i.e., those demonstrating the best and the poorest clinical response to a standardized 5-fluorouracil/folinic acid chemotherapy regimen). Patients showing a good response had a significantly increased survival when compared with poor responders (P=0.0013). Markers were then ranked for clinical importance based on differences in expression between the two groups. This allows for the relatively rapid and inexpensive investigation of multiple markers, using defined patient groups. Bcl-2 overexpression in primary colorectal tumor specimens was found to correlate with clinical response of metastatic deposits to chemotherapy (P=0.044), as did the site of the primary tumor (P=0.011). However, no clear association was observed between response status and the other examined factors (p53, PCNA, TP, MMPs 1, 2 or 9, TIMPs 1 or 2, TS, Dukes' stage at initial diagnosis, histological grade, sex or age). This approach has allowed prioritization of markers of clinical response on which larger, statistically definitive studies will be performed.

Pretreatment plasma HVA and haloperidol response in acute mania

Introduction: Pretreatment plasma homovanillic acid (HVA) levels have been reported to be a correlate of clinical response to typical antipsychotics for schizophrenic, bipolar manic, and mixed groups of psychotic patients. Biological markers of clinical response to antipsychotics could be useful for optimizing drug treatment. Method: Thirty-one consenting acute inpatient subjects between ages 19 and 66 years with a DSM-III-R clinical diagnosis of bipolar disorder, manic with psychotic features were entered into this double-blind study and were randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg for the 3-week study. Subjects also received one of the following concomitant medications: standard lithium, lorazepam 4 mg/day, or placebo. Results: The primary multiple regression analysis, including all subjects on both haloperidol doses, yielded a significant main effect for pretreatment plasma HVA ( n=31, F=5.7, P=0.025), indicating that higher pretreatment plasma HVA was predictive of better clinical response. In addition, the interaction between haloperidol dose and pretreatment plasma HVA was also significantly associated with clinical response ( F=12.59, P=0.0015). When the two haloperidol doses were analyzed separately, we found that pretreatment plasma HVA was only correlated with clinical response in the low haloperidol 5 mg/day group ( n=18, F=11.73, P=0.0038) and was unrelated to clinical response to the high haloperidol 25 mg/day group. Limitations: The sample size was small. Results may have been confounded by prior antipsychotic treatment and concomitant use of lithium or lorazepam. Discussion: These results suggest that pretreatment plasma HVA could be useful for dosing antipsychotics. Patients with high plasma HVA levels would be good candidates for low-dose treatment because they are more likely to improve on such a dose, while patients with low plasma HVA levels might warrant more rapid dosage escalation.