Biomedical subjects

Vicente Valero

Publications and source records attributed to Vicente Valero.

At least 19 recordsLinked to original sources

PubMed2026

Sensitivity to Endocrine Therapy Index Predicts Benefit from Weekly Adjuvant Paclitaxel for Hormone Receptor-Positive Breast Cancer in the GEICAM/9906 Trial.

PURPOSE: To independently validate that low endocrine transcriptional activity measured by the sensitivity to endocrine therapy (SETER/PR) index in hormone receptor-positive (HR+) breast cancer predicts benefit from dose-dense paclitaxel chemotherapy within a second prospective-retrospective biomarker study. EXPERIMENTAL DESIGN: We conducted a blinded, prospective-retrospective biomarker analysis within the GEICAM/9906 trial (NCT00129922), which compared adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by weekly paclitaxel (P) versus six cycles of FEC in lymph node-positive breast cancer. The SETER/PR index was measured in all available HR+/HER2- tumor RNA samples using a prespecified cut point (<0.75). The primary endpoint was the distant recurrence-free interval (DRFI); secondary endpoints were overall survival (OS) and breast cancer-specific survival (BCSS). RESULTS: Of 647 HR+/HER2- tumors, 567 (87.6%) passed assay quality control (279 FEC + P; 288 FEC). A low SETER/PR index was identified in 92 tumors (16.2%). There was a significant interaction between SETER/PR status and treatment on DRFI (P = 0.046). Among patients with a low SETER/PR index, FEC + P significantly improved DRFI [hazard ratio (HR), 0.46; 95% confidence interval (CI), 0.22-0.95; P = 0.035], with similar results after adjustment (HR, 0.48; 95% CI, 0.24-1; P = 0.049). No treatment benefit was observed for SETER/PR ≥0.75 (HR, 1.02; 95% CI, 0.70-1.47; P = 0.931). Differences in OS and BCSS did not reach significance. CONCLUSIONS: Low endocrine transcriptional activity predicts benefit from adding weekly paclitaxel to anthracycline-based adjuvant chemotherapy in HR+/HER2- breast cancer. These findings independently validate the SETER/PR index as a predictive biomarker for paclitaxel-based chemotherapy and support its potential role in guiding regimen selection.

Humans↗

PubMed2007

Tryptophan increases nocturnal rest and affects melatonin and serotonin serum levels in old ringdove.

The sleep promoting functions of melatonin have gained wide scientific attention due to the ability of this indole to provide relief from sleep inefficiency and the temporal relationship between its nocturnal rise in the blood and the "opening of the sleep gate" at night. However, little is known about the effects exerted by its precursor, the amino acid tryptophan. We studied the effect of a 7-day administration of two concentrations of tryptophan (125 and 300 kg b.w.) on the activity/rest rhythms of ringdove, aged 2-3 (young) and 10-12 (old) years, and on the serum levels of serotonin and melatonin. Activity pulses were logged before, during, and up to 5 days after the treatments. The animals received 125 or 300 mg/kg b.w. per animal/day at 09:00 h or at 19:00 h. Subsequently we chose the treatment which gave the best results in terms of nocturnal rest without affecting diurnal activity, i.e., 300 mg/kg b.w. administered to old animals at 09:00 h, 1 h after lights on, for the serotonin and melatonin measurements. During this treatment, the nocturnal and diurnal levels and amplitudes of serotonin and melatonin were all significantly higher than the corresponding levels before and after the treatment. In sum, our results point to an improvement of nocturnal rest in this animal model of old ringdove when administering 300 mg/kg tryptophan 1 h after lights on.

Aging↗

PubMed2007

Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen.

PURPOSE: Findings from our previously published phase III randomized trial showed a high pathologic complete remission (CR) rate in patients with human epidermal growth factor receptor 2-positive breast cancer after the concurrent administration of trastuzumab and paclitaxel, followed by concurrent trastuzumab and 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) preoperative chemotherapy. The safety and efficacy data of initial population were updated, with inclusion of additional experience with the same therapy. STUDY DESIGN: The initial randomized study population of 42 patients were randomly assigned to either four cycles of paclitaxel followed by four cycles of FEC or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. All data were updated through November 2005. RESULTS: Pretreatment characteristics of the initial patients and of the second cohort were similar. In the second cohort, pathologic CR rate was 54.5% (95% confidence interval, 32.2-75.6%) and the pathologic CR rate among all patients treated with chemotherapy plus trastuzumab was 60% (95% confidence interval, 44.3-74.3%). Three patients in the chemotherapy only group have recurred, and one has died. There has been no recurrences in the patients randomized to chemotherapy plus trastuzumab, and the estimated disease-free survival at 1 and 3 years was 100% (P = 0.041). In additional cohort treated with chemotherapy and trastuzumab at the median follow-up of 16.3 months, no patients had recurred. No new safety concerns were observed in this study. CONCLUSION: Our expanded cardiac safety data and the updated efficacy data showed that the natural history of this subset of breast cancer patients can be substantially modified by this treatment approach.

Adult↗

PubMed2006

Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma.

BACKGROUND: A single-institution Phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) and define the safety profile of temozolomide and capecitabine when used in combination to treat brain metastases from breast cancer. METHODS: Patients were eligible if they had bidimensionally measurable supratentorial or infratentorial brain metastasis from histologically confirmed breast carcinoma. Patients could have received up to 3 prior chemotherapy regimens. Temozolomide and capecitabine were administered concomitantly to 4 sequential cohorts at different dosing levels on Days 1-5 and Days 8-12, with cycles repeated every 21 days until disease progression. RESULTS: Twenty-four patients with multiple brain lesions were treated, including 14 patients with newly diagnosed brain metastases and 10 patients with recurrent brain metastases. Only 1 patient was chemotherapy-naive. Fatigue and nausea were the most commonly observed toxicities observed at any dose levels. Significant antitumor activity was observed, with a total of 1 complete and 3 partial responses (18% objective response rate) in the brain. The median response duration was 8 weeks (range, 6-64 weeks) and the median time to progression in the brain was 12 weeks (range, 3-70 weeks). Neurocognitive function improved or remained stable in patients with a response or stable disease. CONCLUSIONS: The combination of temozolomide and capecitabine is an active, well-tolerated regimen. The observed antitumor activity warrants further evaluation of this combination as an alternative to or in combination with whole-brain radiation therapy for the treatment of multiple brain metastases.

Adult↗

PubMed2006

A nonreplicating adenoviral vector that contains the wild-type p53 transgene combined with chemotherapy for primary breast cancer: safety, efficacy, and biologic activity of a novel gene-therapy approach.

BACKGROUND: : Primary systemic therapy (PST) is the standard approach to the management of patients with locally advanced breast cancer (LABC). The authors hypothesized that the intratumoral administration of a nonreplicating adenoviral vector (Ad5) that contains the human wild-type p53, AdCMV-p53, combined with chemotherapy, could increase the efficacy of PST as measured by pathologic complete response. METHODS: : In a prospective, open-label, Phase II trial, 13 patients with LABC were treated with 6 3-week cycles of PST, which consisted of intratumoral injections of Ad5CMV-p53 for 2 consecutive days plus docetaxel and doxorubicin followed by surgery. p53 status was determined at baseline and was assessed immediately after the first injection (up to 48 hours). Clinical response was assessed by clinical and radiologic methods. RESULTS: : The trial was terminated early, because none of the patients achieved a pathologic complete response. The median age was 56 years (range, 39-71 years), and the median tumor size was 8 cm (range, 5-11 cm). Eight patients (73%) had a p53 mutation. Serial biopsies showed an increase in p53 messenger RNA (mRNA) and p21(WAF1/Cip1) mRNA. All 12 evaluable patients achieved an objective clinical response. The surgical specimens revealed scattered tumor cells with extensive tumor-infiltrate leukocytes (predominantly T-lymphocytes). At a median follow-up of 37 months (range, 30-41 months), 4 patients (30%) developed systemic recurrence, and 2 patients died. The estimate breast cancer-specific survival rate at 3 years was 84% (95% confidence interval, 65.7-100%). There was no increase in systemic toxicity. CONCLUSIONS: : Ad5CMV-p53 combined with PST is safe, active, and associated with local immunomodulatory effects. The promising clinical activity of this combination deserves further investigation in randomized studies.

Adenoviruses, Human↗

PubMed2006

Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience.

PURPOSE: To evaluate the cardiac safety of long-term trastuzumab therapy in patients with human epidermal growth receptor 2 (HER2) -overexpressing metastatic breast cancer (MBC) treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX). PATIENTS AND METHODS: Among 218 MBC patients treated with trastuzumab-based therapy for at least 1 year, 173 patients were assessable for cardiac toxicity. Cardiac events (CEs) were defined as follows: asymptomatic decrease of left ventricular ejection fraction (LVEF) below 50%; decrease of 20 percentage points in LVEF compared with the baseline; or signs or symptoms of congestive heart failure (CHF). RESULTS: The median cumulative time for trastuzumab administration was 21.3 months. The median follow-up was 32.6 months (range, 11.8 to 79.0 months). Forty-nine patients (28%) experienced a CE: three patients (1.7%) had an asymptomatic decrease in the LVEF of 20 percentage points, 27 patients (15.6%) experienced grade 2 cardiac toxicity, and 19 patients (10.9%) experienced grade 3 cardiac toxicity. All but three patients had improved LVEF or symptoms of CHF with trastuzumab discontinuation and appropriate therapy. There was one cardiac-related death (0.5%). Baseline LVEF was significantly associated with CE (hazard ratio, 0.94; P = .001). The hazard of a CE among patients taking concomitant taxanes was higher early in the follow-up period but declined during the course of follow-up. CONCLUSION: The risk of cardiac toxicity of long-term trastuzumab-based therapy is acceptable in this population, and this toxicity is reversible in the majority of the patients. In patients who have experienced a CE, additional treatment with trastuzumab can be considered after recovery of cardiac function.

Adult↗

PubMed2006

Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer.

PURPOSE: We developed a multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases. PATIENTS AND METHODS: One hundred thirty-three patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with oligonecleotide microarrays on fine-needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases. RESULTS: Overall pCR rate was 26% in both cohorts. In the training set, 56 probes were identified as differentially expressed between pCR versus residual disease, at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross-validation. Many predictors performed equally well. A nominally best 30-probe set Diagonal Linear Discriminant Analysis classifier was selected for independent validation. It showed significantly higher sensitivity (92% v 61%) than a clinical predictor including age, grade, and estrogen receptor status. The negative predictive value (96% v 86%) and area under the curve (0.877 v 0.811) were nominally better but not statistically significant. The combination of genomic and clinical information yielded a predictor not significantly different from the genomic predictor alone. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant. CONCLUSION: A 30-probe set pharmacogenomic predictor predicted pCR to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12 of 13 patients) and all but one of those who were predicted to have residual disease had residual cancer (27 of 28 patients).

Adult↗

PubMed2006

Prospective study of incidence and severity of epiphora and canalicular stenosis in patients with metastatic breast cancer receiving docetaxel.

PURPOSE: To determine the incidence and severity of epiphora and canalicular stenosis in patients receiving docetaxel weekly or every 3 weeks. PATIENTS AND METHODS: In this prospective trial, each patient underwent an ophthalmologic examination and probing and irrigation of the lacrimal drainage apparatus at baseline and every 4 to 6 weeks after initiation of docetaxel. During each visit, epiphora and canalicular stenosis were graded. Patients with epiphora were treated with tobramycin and dexamethasone drops. If epiphora worsened or if findings on probing and irrigation suggested further canalicular narrowing, silicone intubation was offered. RESULTS: Twenty-eight patients received docetaxel weekly, and 28 patients received docetaxel every 3 weeks. Eighteen patients (64%) who received weekly docetaxel developed epiphora. Epiphora was mild in seven patients, moderate in five, and severe in six. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Nine patients had worsened canalicular stenosis; six underwent surgery. The median cumulative docetaxel dose was 496.5 mg at onset of epiphora and 889.5 mg at surgery. Eleven patients (39%) who received docetaxel every 3 weeks developed epiphora. The median cumulative docetaxel dose at onset of epiphora in this group was 420 mg. Epiphora was mild in nine patients, moderate in one, and severe in one. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Two patients underwent surgery. CONCLUSION: Epiphora occurred in 64% of patients in the weekly group and in 39% of patients in the every-3-weeks group. Moderate or severe canalicular stenosis was seen in about one-third of patients in the weekly group and in none of the patients in the every-3-weeks group.

Adult↗

PubMed2006

Randomized pilot test of a lifestyle physical activity intervention for breast cancer survivors.

OBJECTIVE: This paper will report the results of a pilot test of a 6-month, 21-session intervention to increase breast cancer survivors' physical activity by teaching them to incorporate short periods of moderate activity into their daily routines (lifestyle intervention). The effect of the intervention on physical performance, quality of life, and physical activity are reported. METHODS: Sixty breast cancer survivors were randomized to either a lifestyle intervention or a standard care control group. Physical performance, quality of life (Medical outcomes study short form-36 [SF-36]), and physical activity (7-day recall and motivation readiness), were assessed at baseline and 6 months. RESULTS: The lifestyle group had significantly better performance in the 6-min walk task than the controls (p=0.005) at 6 months. The intervention had positive effects on the bodily pain (p=0.020) and general health (p=0.006) subscales from the SF-36. The lifestyle group had a greater motivational readiness for physical activity at 6-month than standard care, but no significant differences were seen between the two in terms of number of minutes of moderate or more intense physical activity or number of days on which they did > or =30 min of moderate or more intense activity. CONCLUSIONS: Despite the small sample size, the lifestyle intervention showed promise for improving physical functioning and quality of life and increasing physical activity, and should be tested in a larger randomized trial. PRACTICE IMPLICATIONS: If the lifestyle approach is shown to be effective in a larger trial, it represents a highly feasible intervention that it can be delivered to cancer survivors by health care institutions or community organizations without dedicated exercise facilities and equipment.

Activities of Daily Living↗

PubMed2006

Randomized trial of high-dose chemotherapy and autologous hematopoietic stem cell support for high-risk primary breast carcinoma: follow-up at 12 years.

BACKGROUND: The authors previously reported results from a randomized trial of standard-dose chemotherapy with combined 5-fluorouracil (1000 mg/m2 per cycle), doxorubicin (50 mg/m2 per cycle), and cyclophosphamide (500 mg/m2 per cycle) (FAC) versus FAC followed by high-dose chemotherapy (HDCT) and autologous stem cell support (ASCS) for patients with high-risk primary breast carcinoma. After a median follow-up of 6.5 years, no significant differences were observed in recurrence-free survival (RFS) or overall survival (OS) between the 2 arms. This report updates the survival analyses. METHODS: Patients with >or=10 positive axillary lymph nodes after primary surgery or >or=4 positive lymph nodes at surgery after neoadjuvant chemotherapy were eligible. All patients were to receive 8 cycles of FAC. Patients were assigned randomly to receive either no further chemotherapy or 2 cycles of combined high-dose cyclophosphamide (5250 mg/m2 per cycle), etoposide (1200 mg/m2 per cycle), and cisplatin (165 mg/m2 per cycle) with ASCS. Primary endpoints were RFS and OS. RFS and OS were calculated by using the Kaplan-Meier method. The log-rank statistic was used to compare treatment arms. RESULTS: Between 1990 and 1997, 78 patients were registered, and 39 patients were assigned randomly to each arm. The median follow-up for all patients who were alive at last follow-up was 142.5 months (range, 45-169 months). An intention-to-treat analysis showed no significant difference between the 2 arms in terms of RFS (at 10 years: 40% with FAC vs. 26% with FAC plus HDCT; P=.11) or OS (at 10 years: 47% with FAC vs. 42% with FAC plus HDCT; P=.13). CONCLUSIONS: With a median follow-up of nearly 12 years for patients who remained alive, this trial continued to demonstrate no RFS or OS advantage for patients with high-risk primary breast carcinoma treated with HDCT after standard-dose FAC chemotherapy.

Adult↗

PubMed2006

Prognosis and management of patients with node-negative invasive breast carcinoma that is 1 cm or smaller in size (stage 1; T1a,bN0M0): a review of the literature.

PURPOSE: Mammographic screening has led to an increase in the number of small, node-negative breast cancers being diagnosed. Node-negative breast cancers that are < or = 1 cm are stage T1a,bN0M0. Controversy surrounds the prognosis of these patients with locoregional therapy only and the need for adjuvant systemic therapy. METHODS: We performed a comprehensive review of the literature describing outcome and prognostic factors in stage T1a,bN0M0 breast cancer. We also reviewed current guidelines for systemic therapy in these patients. RESULTS: Early studies reported 10-year relapse-free survival (RFS) rates higher than 90% without adjuvant systemic therapy, but some more recent data suggest inferior outcomes. High tumor grade is the most consistent factor associated with poor prognosis. Other adverse prognostic factors are younger age, lymphovascular invasion (LVI), high Ki-67, and larger tumors within the T1a,b subgroup. Patients with high-grade tumors and/or LVI may have 10-year RFS rates of less than 75% in the absence of systemic therapy. The prognostic significance of hormone receptor status is unclear. Current guidelines for the systemic management of early-stage breast cancer differ when applied to stage T1a,bN0M0, reflecting the controversial nature of the issue. CONCLUSION: Adjuvant systemic therapy is advisable for most patients with stage T1a,bN0M0 breast cancer who have grade 3 tumors and/or LVI. Other T1a,bN0M0 cases should be considered for systemic therapy based on clinicopathologic factors with known prognostic significance and assessment of the risk-benefit ratio. More reliable tools are needed to assess the prognosis of patients with stage T1a,bN0M0 breast cancer and their potential to benefit from specific therapeutic agents.

Breast Neoplasms↗

PubMed2006

Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial.

PURPOSE: To evaluate the effectiveness of patient-controlled methylphenidate as compared with placebo in cancer patients with fatigue, as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). PATIENTS AND METHODS: Patients with a fatigue score of at least 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) and hemoglobin level of at least 10 g/dL were included. Patients were randomly assigned to receive 5 mg methylphenidate or placebo every 2 hours as needed (maximum of four capsules a day), for 7 days. Patients completed a daily diary including study drug record and fatigue intensity. A research nurse telephoned patients daily to assess toxicity and fatigue level. All patients were offered open-label methylphenidate for 4 weeks. FACIT-F and the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 15, and 36. The FACIT-F fatigue subscore on day 8 was considered the primary end point. RESULTS: Of 112 patients randomly assigned, 52 patients in the methylphenidate and 53 in the placebo group were assessable for analysis. Fatigue intensity improved significantly on day 8 in both the methylphenidate and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .31) or ESAS (P = .14) between groups. In open-label phase, fatigue intensity maintained low as compared with baseline. No significant toxicities were observed. CONCLUSION: Both methylphenidate and placebo resulted in significant symptom improvement. Methylphenidate was not significantly superior to placebo after 1 week of treatment. Longer study duration is justified. The role of daily telephone calls from a research nurse should be explored as a palliative care intervention.

Adult↗

PubMed2006

Disease-free and overall survival after pathologic complete disease remission of cytologically proven inflammatory breast carcinoma axillary lymph node metastases after primary systemic chemotherapy.

BACKGROUND: Breast carcinoma axillary lymph node (ALN) pathologic complete response (pCR) after primary chemotherapy is associated with significantly higher recurrence-free survival (RFS) and overall survival (OS) rates. The purpose of the current study was to determine long-term outcome in patients achieving a pCR of cytologically proven inflammatory breast carcinoma ALN metastases after primary chemotherapy. METHODS: Patients with cytologically documented ALN metastases from inflammatory breast carcinoma were treated in three prospective primary chemotherapy trials. After surgery, patients were subdivided into those patients with and those patients without residual ALN carcinoma. Survival was calculated using the Kaplan-Meier method. RESULTS: Of 175 patients treated, 61 had cytologically confirmed ALN metastases. Fourteen patients (23%) achieved a pCR of the ALNs after primary chemotherapy. The 5-year OS and RFS rates were found to be improved in those patients achieving a pCR of the ALNs (82.5% [95% confidence interval (95% CI), 62.8-100%] and 78.6% [95%CI, 59.8-100%], respectively, vs. 37.1% [95%CI, 25.4-54.2%] and 25.4% [95%CI, 15.5-41.5%], respectively) (P = 0.01 [for OS] and P = 0.001 [for RFS]). Combination anthracycline and taxane-based primary chemotherapy resulted in significantly more patients achieving an ALN pCR (45% vs. 16%; P = 0.01). CONCLUSIONS: pCR of ALN metastases is associated with an excellent prognosis in patients with inflammatory breast carcinoma. The rates of ALN pCR are nearly 50% in patients with inflammatory breast carcinoma who are treated with anthracyclines and weekly paclitaxel before surgery. However, those patients with residual ALN disease at the time of surgery greatly require the introduction of novel therapeutic strategies.

Adult↗

PubMed2006

Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors.

PURPOSE: To evaluate whether hormonal receptor (HR) status can influence the prognostic significance of pathologic complete response (pCR). PATIENTS AND METHODS: This retrospective analysis included 1,731 patients with stage I to III noninflammatory breast cancer treated between 1988 and 2005 with primary chemotherapy (PC). Ninety-one percent of patients received anthracycline-based PC, and 66% received additional taxane therapy. pCR was defined as no evidence of invasive tumor in the breast and axillary lymph nodes. RESULTS: Median age was 49 years (range, 19 to 83 years). Sixty-seven percent of patients (n = 1,163) had HR-positive tumors. A pCR was observed in 225 (13%) of 1,731 patients; pCR rates were 24% in HR-negative tumors and 8% in HR-positive tumors (P < .001). A significant survival benefit for patients who achieved pCR compared with no pCR was observed regardless of HR status. In the HR-positive group, 5-year overall survival (OS) rates were 96.4% v 84.5% (P = .04) and 5-year progression-free survival (PFS) rates were 91.1% v 65.3% (P < .0001) for patients with and without pCR, respectively. For the HR-negative group, 5-year OS rates were 83.9% v 67.4% (P = .003) and 5-year PFS rates were 83.4% v 50.0% (P < .0001) for patients with and without pCR, respectively. After adjustment for adjuvant hormonal treatment, HR status, clinical stage, and nuclear grade, patients who achieved a pCR had 0.36 times the risk of death. CONCLUSION: pCR is associated with better outcome regardless of HR status in breast cancer patients who receive PC.

Adult↗

PubMed2006

Comparative study of the activity/rest rhythms in young and old ringdove (Streptopelia risoria): correlation with serum levels of melatonin and serotonin.

Aging is characterized by changes in the circadian rhythms of melatonin, serotonin, and sleep/wakefulness, alterations that affect sleep quality. The authors studied the circadian rhythms of serotonin and melatonin in young and old ringdoves (Streptopelia risoria) (2-3 and 10-12 yrs old, respectively), animals that are characterized by being monophasic and active by day, like humans. The aim was to correlate the indole rhythms with the animals' activity/rest periods. The animals were kept under a 12:12 h light/dark cycle, fed ad libitum, and housed in separate cages equipped for activity recording. Activity pulses were recorded with one actometer per animal (two perpendicular infrared transmitters) and were logged every 15 min by a computer program (DAS 16) throughout the experiment. Melatonin was measured by radioimmunoassay and serotonin by ELISA at intervals of 3 h (from 09:00 to 18:00 h) and 1 h (from 21:00 to 06:00 h), respectively. The results showed a reduction in nocturnal vs. diurnal activity of 89% and 61% in the young and old animals, respectively, with 100% considered to be the diurnal activity of each group. The amplitude of a cosine function fit to the melatonin concentrations of the old animals was half that of the young birds. The acrophase and nadir were at 02:00 and 14:00 h in the young and 01:00 and 13:00 h in the old animals, respectively. The amplitude of the corresponding cosine function fit to the serotonin concentrations in the old birds was one-third that of the young animals. The acrophase and nadir were at 15:00 and 03:00 h in the young and 16:00 and 04:00 h in the old animals, respectively. For both melatonin and serotonin, the concentrations in the young animals were significantly higher than in the old at most of the measurement times. There was a clear negative correlation between the circadian rhythms of activity and the serum melatonin levels in both young and old animals. The equivalent correlation for serotonin was positive, and stronger in the case of the young animals. The results suggest a possible relationship between the observed decline in the amplitude of the old animals' melatonin and serotonin rhythms and the lower percentage reduction in their nocturnal relative to diurnal activity pulses compared to the young animals. In conclusion, the circadian rhythms of melatonin and serotonin undergo alterations with age that could be involved in the changes in age-associated sleep.

Aging↗

PubMed2005

Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy.

PURPOSE: Pathologic complete remission (pCR) of primary breast tumors after primary chemotherapy (PCT) is associated with higher relapse-free survival (RFS) and overall survival (OS) rates. The purpose of this study was to determine long-term outcome in patients achieving pCR of cytologically proven axillary lymph node (ALN) metastases. METHODS: Patients with cytologically documented ALN metastases were treated in five prospective PCT trials. After surgery, patients were subdivided into those with and without residual ALN carcinoma. Survival was calculated by the Kaplan-Meier method. RESULTS: Of 925 patients treated, 403 patients had cytologically confirmed ALN metastases. Eighty-nine patients (22%) achieved ALN pCR after PCT. Compared with the group without ALN pCR, 5-year OS and RFS were improved in patients achieving ALN pCR (93% [95% CI, 87.5 to 98.5] and 87% [95% CI, 79.7 to 94.3] v 72% [95% CI, 66.5 to 77.5] and 60% [95% CI, 54.1 to 65.9], respectively; P < .0001). Residual primary tumor did not affect outcome of those with ALN pCR. Combination anthracycline/taxane-based PCT resulted in significantly more ALN pCRs, although outcome after ALN pCR was not improved by taxanes. We constructed a nomogram demonstrating that patients who do not benefit from neoadjuvant anthracyclines are unlikely to benefit from subsequent taxanes. CONCLUSION: ALN pCR is associated with an excellent prognosis, even with a residual primary tumor, pointing to biologic differences between primary and metastatic cells. ALN pCR represents an early surrogate marker of long-term outcome. Response to initial PCT has important potential as a guide to subsequent therapy.

Adult↗

PubMed2005

Nomograms to predict pathologic complete response and metastasis-free survival after preoperative chemotherapy for breast cancer.

PURPOSE: To combine clinical variables associated with pathologic complete response (pCR) and distant metastasis-free survival (DMFS) after preoperative chemotherapy (PC) into a prediction nomogram. PATIENTS AND METHODS: Data from 496 patients treated with anthracycline PC at the Institut Gustave Roussy were used to develop and calibrate a nomogram for pCR based on multivariate logistic regression. This nomogram was tested on two independent cohorts of patients treated at the M.D. Anderson Cancer Center. The first cohort (n = 337) received anthracycline; the second cohort (n = 237) received a combination of paclitaxel and anthracycline PC. A separate nomogram to predict DMFS was developed using Cox proportional hazards regression model. RESULTS: The pCR nomogram based on clinical stage, estrogen receptor status, histologic grade, and number of preoperative chemotherapy cycles had good discrimination and calibration in the training and the anthracycline-treated validation sets (concordance indices, 0.77, 0.79). In the paclitaxel plus anthracycline group, when the predicted pCR rate was less than 14%, the observed rate was 7.5%; for a predicted rate of > or = 38%, the actual rate was 85%. For a predicted rate between 14% to 38%, the observed rates were 50% with weekly and 27% with 3-weekly paclitaxel. This indicates that patients with intermediate chemotherapy sensitivity benefit the most from the optimized schedule of paclitaxel. Patients unlikely to achieve pCR to anthracylines remain at low probability for pCR, even after inclusion of paclitaxel. The nomogram for DMFS had a concordance index of 0.72 in the validation set and outperformed other prediction tools (P = .02). CONCLUSION: Our nomograms predict pCR accurately and can serve as a basis to integrate future molecular markers into a clinical prediction model.

Anthracyclines↗

PubMed2005

Squamous cell carcinoma of the breast.

PURPOSE: Squamous cell carcinoma (SCC) of the breast is rare and generally aggressive. In this study, we analyzed 33 patients treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) and a series of 137 patients identified through the Surveillance, Epidemiology, and End Results (SEER) database to make therapy recommendations. METHODS: Records of The University of Texas M.D. Anderson Cancer Center were searched for patients diagnosed with breast SCC from 1985 to 2001. All biopsy material was reviewed by a dedicated breast pathologist who performed immunohistochemistry for hormone receptors and the epidermal growth factor receptor (EGFR). We searched the SEER database for patients with breast SCC diagnosed between 1988 and 2001. RESULTS: We identified 33 patients with breast SCC, of whom two patients had metastatic disease at diagnosis. The median relapse-free survival (RFS) of 31 patients with localized disease was 20 months (range, 1 to 108 months), with a 26% RFS rate at 5 years. The median overall survival in these patients was 37 months (range, 12 to 108 months), with 40% surviving at 5 years. Median survival from the time recurrent disease was recognized was 14 months (range, 2 to 86 months). Tumors were usually hormone receptor-and HER2/neu-negative, though EGFR was frequently overexpressed. Information from the SEER database was consistent with most of our findings. CONCLUSION: SCC of the breast is aggressive and often treatment-refractory. The role of platinum salts, EGFR inhibitors, and other novel agents needs to be explored.

Adult↗