Evaluating the influence of marine protected areas on surf zone fish.

Marine protected areas (MPAs) globally serve conservation and fisheries management goals, generating positive effects in some marine ecosystems. Surf zones and sandy beaches, critical ecotones bridging land and sea, play a pivotal role in the life cycles of numerous fish species and serve as prime areas for subsistence and recreational fishing. Despite their significance, these areas remain understudied when evaluating the effects of MPAs. We compared surf zone fish assemblages inside and outside MPAs across 3 bioregions in California (USA). Using seines and baited remote underwater videos (BRUVs), we found differences in surf zone fish inside and outside MPAs in one region. Inside south region MPAs, we observed higher abundance (Tukey's honest significant difference [HSD] = 0.83, p = 0.0001) and richness (HSD = 0.22, p = 0.0001) in BRUVs and greater biomass (HSD = 0.32, p = 0.0002) in seine surveys compared with reference sites. Selected live-bearing, fished taxa were positively affected by MPAs. Elasmobranchs displayed greater abundance in BRUV surveys and higher biomass in seine surveys inside south region MPAs (HSD = 0.35, p = 0.0003 and HSD = 0.23, p = 0.008, respectively). Although we observed no overall MPA signal for Embiotocidae, abundances of juvenile and large adult barred surfperch (Amphistichus argenteus), the most abundant fished species, were higher inside MPAs (K-S test D = 0.19, p < 0.0001). Influence of habitat characteristics on MPA performance indicated surf zone width was positively associated with fish abundance and biomass but negatively associated with richness. The south region had the largest positive effect size on all MPA performance metrics. Our findings underscored the variability in species richness and composition across regions and survey methods that significantly affected differences observed inside and outside MPAs. A comprehensive assessment of MPA performance should consider specific taxa, their distribution, and the effects of habitat factors and geography.

Evaluación de la influencia de las áreas marinas protegidas sobre los peces de la zona de rompientes Resumen Las áreas marinas protegidas (AMP) cumplen los objetivos de conservación y manejo de pesquerías a nivel mundial, lo que genera efectos positivos en algunos ecosistemas marinos. Las zonas de rompientes y las playas arenosas, ecotonos importantes que conectan la tierra con el mar, tienen un papel esencial en el ciclo de vida de varios peces y fungen como áreas óptimas para la pesca recreativa y de sustento. A pesar de su importancia, estas áreas están poco estudiadas con respecto a la evaluación del efecto de las AMP. Comparamos la composición de peces del área de rompientes dentro y fuera de las AMP de tres bioregiones de California, EUA. Usamos chinchorros y videos submarinos con carnada (BRUVs) y descubrimos diferencias en los peces de la zona de rompientes dentro y fuera de las AMP en una región. Dentro de las AMP de la región sur observamos una mayor abundancia (diferencia significativa honesta de Tukey [DSH]  =  0.83, p = 0.0001) y riqueza (DSH  =  0.22, p = 0.0001) en los BRUV y una mayor biomasa (DSH  =  0.32, p = 0.0002) en los censos con chinchorro en comparación con los sitios de referencia. Los taxones seleccionados de peces de sustento fueron afectados de manera positiva por las AMP. Los elasmobranquios mostraron una mayor abundancia en los BRUV y una mayor biomasa en los censos con chinchorro dentro de las AMP de la región sur (DSH  =  0.35, p = 0.0003 y DSH  =  0.23, p = 0.008, respectivamente). Aunque no observamos una señal generalizada de las AMP para la familia Embiotocidae, la abundancia de Amphistichus argenteus juveniles y adultos, la especie pescada más abundante, fue mayor dentro de las AMP (prueba K­S D  =  0.19, p < 0.0001). La influencia de las características del hábitat sobre el desempeño de las AMP indicó que el ancho de la zona de rompientes está asociado de forma positiva con la abundancia y biomasa de los peces, pero de forma negativa con la riqueza. La región sur tuvo el mayor tamaño de efecto positivo sobre todas las medidas de desempeño de las AMP. Nuestros hallazgos destacan la variabilidad en la riqueza y composición de especies en todas las regiones y los censos que afectan significativamente las diferencias observadas dentro y fuera de las AMP. Una evaluación completa del desempeño de las AMP debe considerar taxones específicos, su distribución y el efecto de los factores de hábitat y la geografía.

A randomized controlled trial of oral melatonin supplementation and breast cancer biomarkers.

We examined compliance with and the effects of melatonin supplementation on breast cancer biomarkers (estradiol, insulin-like growth factor I (IGF-1), insulin-like growth factor-binding protein 3 (IGFBP-3), and the IGF-1/IGFBP-3 ratio) in postmenopausal breast cancer survivors. In a double-blind, placebo-controlled study, postmenopausal women with a prior history of stages 0-III breast cancer who had completed active cancer treatment (including hormonal therapy) were randomly assigned to either 3 mg oral melatonin (n = 48) or placebo daily for 4 months. Plasma samples were collected at baseline and after the completion of the intervention. The primary endpoints were compliance and change in estradiol and IGF-1/IGFBP-3 levels. Ninety-five women were randomized (48 to melatonin and 47 to placebo). Eighty-six women (91%) completed the study and provided pre- and postintervention bloods. Melatonin was well tolerated without any grade 3/4 toxicity and compliance was high (89.5%). Overall, among postmenopausal women with a prior history of breast cancer, a 4-month course of 3 mg melatonin daily did not influence circulating estradiol, IGF-1, or IGFBP-3 levels. Compliance was comparable between the two groups. Short-term melatonin treatment did not influence the estradiol and IGF-1/IGBBP-3 levels. Effects of longer courses of melatonin among premenopausal women are unknown. Low baseline estradiol levels in our study population may have hindered the ability to detect any further estradiol-lowering effects of melatonin.

Chronic Methamphetamine Self-Administration Dysregulates Oxytocin Plasma Levels and Oxytocin Receptor Fibre Density in the Nucleus Accumbens Core and Subthalamic Nucleus of the Rat.

The neuropeptide oxytocin attenuates reward and abuse for the psychostimulant methamphetamine (METH). Recent findings have implicated the nucleus accumbens (NAc) core and subthalamic nucleus (STh) in oxytocin modulation of acute METH reward and relapse to METH-seeking behaviour. Surprisingly, the oxytocin receptor (OTR) is only modestly involved in both regions in oxytocin attenuation of METH-primed reinstatement. Coupled with the limited investigation of the role of the OTR in psychostimulant-induced behaviours, we primarily investigated whether there are cellular changes to the OTR in the NAc core and STh, as well as changes to oxytocin plasma levels, after chronic METH i.v. self-administration (IVSA) and after extinction of drug-taking. An additional aim was to examine whether changes to central corticotrophin-releasing factor (CRF) and plasma corticosterone levels were also apparent because of the interaction of oxytocin with stress-regulatory mechanisms. Male Sprague-Dawley rats were trained to lever press for i.v. METH (0.1 mg/kg/infusion) under a fixed-ratio 1 schedule or received yoked saline infusions during 2-h sessions for 20 days. An additional cohort of rats underwent behavioural extinction for 15 days after METH IVSA. Subsequent to the last day of IVSA or extinction, blood plasma was collected for enzyme immunoassay, and immunofluorescence was conducted on NAc core and STh coronal sections. Rats that self-administered METH had higher oxytocin plasma levels, and decreased OTR-immunoreactive (-IR) fibres in the NAc core than yoked controls. In animals that self-administered METH and underwent extinction, oxytocin plasma levels remained elevated, OTR-IR fibre density increased in the STh, and a trend towards normalisation of OTR-IR fibre density was evident in the NAc core. CRF-IR fibre density in both brain regions and corticosterone plasma levels did not change across treatment groups. These findings demonstrate that oxytocin systems, both centrally within the NAc core and STh, as well as peripherally through plasma measures, are dysregulated after METH abuse.

Autologous bone-marrow transplantation: host effects of high-dose BCNU.

Thirty-five patients with solid tumors received 44 courses of bis-chlorethylnitrosourea (BCNU) at doses ranging between 600 and 1,400 mg/m2 with cryopreserved or fresh autologous bone-marrow support. Eight patients treated at 600 mg/m2 received no bone-marrow support for their first course of BCNU. Maximum follow-up was 25 months (median, four months). Myelosuppression was severe and dose related but was less prolonged in the marrow-supported groups (p = 0.01) and was not dose limiting. Myelosuppression-related toxicity of infection and hemorrhage occurred in 21 (47%) of 44 courses of treatment. Pulmonary toxicity occurred in seven of 35 patients; abnormal liver function occurred in 18 of 30 patients greater than one month from treatment; and central nervous system symptoms that may have been drug related occurred in six of 35 patients. There was no renal or cardiac toxicity. Except for myelosuppression, toxicity was not dose related. Treatment-related deaths included four with pulmonary toxicity, two with liver toxicity, sepsis in four, and gastrointestinal tract toxicity in one patient. We conclude that the limiting side effect of high-dose BCNU (greater than or equal to 600 mg/m2) is visceral toxicity; the extent of myelosuppression is shortened by the infusion of bone marrow, whether cryopreserved or fresh; and marked tumor regression can be achieved with high-dose BCNU.

Docetaxel administered on a weekly basis for metastatic breast cancer.

PURPOSE: To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m(2)/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis. RESULTS: Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m(2). There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5). CONCLUSION: Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.

Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial.

PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment. PATIENTS AND METHODS: In this double-blind, double-dummy, parallel-group study, postmenopausal patients were randomized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rate, duration of response (DOR), and tolerability. RESULTS: Patients (n = 400) were followed for a median period of 16.8 months. Fulvestrant was as effective as anastrozole in terms of TTP (hazard ratio, 0.92; 95.14% confidence interval [CI], 0.74 to 1.14; P =.43); median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole. OR rates were 17.5% with both treatments. Clinical benefit rates (complete response + partial response + stable disease > or = 24 weeks) were 42.2% for fulvestrant and 36.1% for anastrozole (95% CI, -4.00% to 16.41%; P =.26). In responding patients, median DOR (from randomization to progression) was 19.0 months for fulvestrant and 10.8 months for anastrozole. Using all patients, DOR was significantly greater for fulvestrant compared with anastrozole; the ratio of average response durations was 1.35 (95% CI, 1.10 to 1.67; P < 0.01). Both treatments were well tolerated. CONCLUSION: Fulvestrant was at least as effective as anastrozole, with efficacy end points slightly favoring fulvestrant. Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy.

Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

In vitro proliferation of hemopoietic stem cells in long-term marrow cultures: principles in mouse applied to man.

The continuous in vitro marrow culture system for proliferation of mouse pluripotent hemopoietic stem cells (CFUs) and granulocyte-macrophage progenitor cells (CFUc) as initially described by T. M. Dexter, depended upon a 25% concentration of special lots of horse serum and addition of fresh "recharging" marrow after 3-4 weeks. This system has been modified to permit longer hemopoiesis in non-recharged cultures over 25-30 weeks. Addition of 10(-7)M hydrocortisone sodium hemi-succinate during weekly feeding and switch from horse to 25% fetal calf serum with corticosteroid at week 4, maintains stability of the adherent marrow stromal cells, decreases lipogenesis (which is deleterious after 10 weeks) and increases proliferation of hemopoietic cells over longer duration. Stem cells removed from 8 week old primary NIH/Swiss marrow cultures reconstituted hemopoiesis in lethally irradiated mice. While 16 week old cultures produced total numbers of CFUc equivalent to 8 week cultures, these cells could not prevent marrow death following similar total body irradiation. Thus, stem cells moved progressively from a pluripotent to a committed CFUc compartment between weeks 8-16. Human femur marrow required thyroxine in addition to hydrocortisone for sustained CFUc maintenance over a shorter 8 week period. Improved technology for mouse long-term marrow cultures should further aid in developing a usable human "Dexter-system".

Differential cyclic AMP responses to calcitonin among human ovarian carcinoma cell lines: a calcitonin-responsive line derived from a rare tumor type.

Several human tumor cell lines have been reported to have specific receptors for calcitonin (CT) and CT-responsive adenylate cyclase. In order to correlate patterns of responsiveness to CT, parathyroid hormone (PTH) and prostaglandin E2 (PGE2) with tumor morphology and intermediate filament protein expression, we examined four human ovarian tumor cell lines (BIN-16, BIN-22, BIN-53, BIN-67) which had been cultured from cells of metastatic foci. In two cell lines (BIN-53 and -16) there were small increases in cAMP content after exposure to CT and in three cell lines (BIN-53, -16, and -22) larger increases with PGE2. There was no cAMP response in any of the cells to PTH. In BIN-67 cells, however, CT induced a striking (greater than 20-fold) increase in cAMP content. Histologically, the CT-nonresponsive tumor lines were derived from serous adenocarcinomas while the CT-responsive tumor line was from a rare small cell carcinoma. Gel electrophoretic and immunofluorescence microscopic analyses had previously disclosed that the CT-nonresponsive cell lines contained high levels of simple epithelial keratins and no or very low levels of vimentin (characteristic of ovarian surface epithelial cells), while the CT-responsive cell line contained almost exclusively vimentin. Thus, cells cultured from a rare type of ovarian tumor were CT-responsive and were distinguishable from CT-nonresponsive ovarian tumor cells by initial tumor histology and intermediate filament protein expression.

High dose methotrexate with leucovorin rescue. Rationale and spectrum of antitumor activity.

Methotrexate (MTX) in high doses (3 to 7.5 g/m2) with leucovorin rescue (HDMTX-LCV) can be delivered on a weekly basis in a setting of proper pharmacologic monitoring. Myelosuppression occurs in 28 per cent of the patients and in 8 per cent of the courses and usually results from delayed MTX excretion secondary to mild reversible nephrotoxicity. The incidence of tumor regression was 50 per cent in head and neck cancer; 59 per cent in non-Hodgkin's lymphoma; 40 per cent in small cell lung cancer; 24 to 50 per cent in breast cancer and 50 per cent in osteogenic carcinoma, for an over-all response rate of 39 per cent (70 of 178) in patients with disseminated cancer. HDMTX-LCV is not recommended for the conventional treatment of metastatic cancer because of the potential for toxicity and the fact that the response rates cited are probably not superior to those which can be achieved by conventional doses of MTX. However, the relative lack of myelosuppression and mucositis, when compared to conventional unrescued MTS, and the achievement of therapeutic concentrations of MTX in the central nervous system with the HDMTX-LCV program have led to its incorporation into clinical trials of combination chemotherapy.

Prolonged cryopreservation of human bone marrow.

We tested the viability of human bone marrow stored for 40 to 42 months in the vapor phase of liquid nitrogen. A median of 2 X 10(10) nucleated cells obtained from eight patients were concentrated to 1.3 X 10(10) using discontinuous centrifugation. These were stored in polyolefin bags in volumes of 100 to 500 ml using 10% dimethyl sulfoxide (DMSO) as cryoprotectant. Cell number and granulocyte - monocyte colony - forming cell (CFU-c) plating efficiency were determined before freezing and after thawing, after dilution and removal of DMSO, and after 2 to 4 hr of additional incubation. The median difference in cell number and CFU-c plating efficiency after this prolonged storage was -9 and +2%, respectively. Dilution, washing, and a 2-hr incubation were associated with cell losses of 24, 24, and 19% and increases in CFU-c plating efficiency, ranging from 22 to 79%. The number of viable CFU-c was never significantly lower than the number of CFU-c stored or initially thawed. Vapor phase storage appears to be adequate for prolonged human bone marrow cryopreservation using CFU-c viability as a determinant.

Sildenafil for iatrogenic serotonergic antidepressant medication-induced sexual dysfunction in 4 patients.

OBJECTIVE: To evaluate the effect of sildenafil on iatrogenic serotonergic antidepressant-induced sexual dysfunction. METHOD: Four outpatients (2 men, 2 women) who developed sexual dysfunction (erectile impotence, anorgasmia) during treatment with a serotonin reuptake inhibitor antidepressant for psychiatric disorder were selected. Each subject was initially prescribed sildenafil 50 mg to be taken approximately 1 hour before sexual activity. The dose was increased to 100 mg for a partial or failed response. RESULTS: Four cases are detailed in case report fashion. All 4 had rapid reversal of their sexual dysfunction, usually with the first dose. Reversal equates to 1 successful use of sildenafil in each of 2 patients and 3 uses in 2 patients. CONCLUSION: Sildenafil may be an effective treatment for serotonergic antidepressant-induced sexual dysfunction and deserves further evaluation in randomized placebo-controlled studies.

Distribution, Isolation and Sequence Analysis of the C-Terminal Heptapeptide of Pro-Enkephalin A (YGGFMRF) from the Ovine Median Eminence.

Abstract Using a polyclonal antiserum raised against the C-terminal heptapeptide of pro-enkephalin A, we have isolated the opioid heptapeptide Tyr-Gly-Gly-Phe-Met-Arg-Phe (MERF) from ovine median eminence and mapped its distribution in that structure. MERF-immunoreactivity was confined to the pars externa (neurosecretory zone) where it colocalized with corticotrophin-releasing factor in the majority of terminals. No larger, N-terminally extended forms of MERF were detected in median eminence extracts suggesting that pro-enkephalin is fully processed to its constituent enkephalin congeners, and that the bioactive products, including MERF, act at the level of the hypothalamus in regulating anterior pituitary function.

High-dose BCNU with autologous bone marrow rescue for recurrent glioblastoma multiforme.

Eleven patients with recurrent malignant glioma were treated with single high doses of BCNU ranging from 600 to 1400 mg/sq m. To prevent the characteristic late myelosuppression observed after conventional doses of BCNU, autologous bone marrow harvested just before drug treatment was infused 24 to 36 hours after therapy. Higher doses of BCNU causes earlier and more profound myelosuppression; one patient died on pancytopenia, breakdown of the gut epithelium, and Clostridium septicemia 10 days after receiving 1400 mg/sq m of BCNU. All patients experienced transient emesis; four developed transient elevation of hepatic enzymes, two reversible interstitial pulmonary infiltrates, and two who received 1400 mg/sq m BCNU suffered irreversible cortical damage. Eight patients receiving 600 to 1200 mg/sq m demonstrated reconstitution of polymorphonuclear leukocytes an platelets within at least 30 days after treatment. With a follow-up time of up to 19 months, four patients improved, three stabilized, and three deteriorated and died. The median survival time was 7 months. Computerized tomography performed on patients receiving constant corticosteroids showed diminished contrast enhancement and mass effect in eight patients. High-dose BCNU at doses up to 1200 mg/sq m with marrow rescue is a feasible approach to the treatment of patients with glioblastoma.

Results of radical radiotherapy for inflammatory breast cancer.

We performed a retrospective review of 65 patients with nonmetastatic clinical inflammatory breast carcinoma treated with radical radiotherapy as the sole local treatment between 1968 and 1986. Chemotherapy was given to 47 patients (72%). The median total radiation dose to the target volume was 6,984 cGy. With a median follow-up in survivors of 41 months, the 5-year actuarial probability of relapse-free survival was 17% and the overall survival was 28%. Thirty patients experienced failure in the treated breast, skin, or draining lymph nodes, for a crude, uncensored local recurrence rate of 46%. Of the factors analyzed, only the response to initial chemotherapy was predictive of local recurrence. Local recurrence was noted in 0 of 3 patients with a complete response (CR) to initial chemotherapy, 5 of 17 patients with a partial response (PR), and 12 of 17 patients with less than a partial response (CR/PR versus less than PR, p = 0.009). We conclude that conventional radical radiotherapy in unselected patients is insufficient to manage the local tumor burden presented by inflammatory breast cancer, even when high doses are employed.

Maturation of the posterolateral spinal fusion and its effect on load-sharing of spinal instrumentation. An in vivo sheep model.

UNLABELLED: We investigated the temporal relationship among the biomechanical, radiographic, and histological properties of a posterolateral spinal fusion mass to elucidate the changes in load-sharing of the spinal instrumentation and that of the fusion mass throughout the healing process. Destabilization of the posterior spinal column and transpedicular screw fixation at the segments between the third and fourth and the fifth and sixth lumbar vertebrae was performed in twenty-four sheep. A posterolateral spinal arthrodesis with use of autologous corticocancellous bone graft was done randomly at one of the two segments; the other segment (without bone graft) served as the instrumented control. Six animals each were killed at four, eight, twelve, and sixteen weeks postoperatively. Biomechanical testing showed that the posterolateral fusion mass had increased mechanical stiffness after the fourth week. The strain on the hardware, measured with use of rods instrumented with strain-gauges, decreased significantly (p < 0.01) beginning at eight weeks. Radiographically, three independent observations of each of the six animals at each time-period showed that, although all of the fusion masses were considered solid unions at sixteen weeks, bridging of trabecular bone was noted during only ten of eighteen observations at twelve weeks, three of eighteen observations at eight weeks, and none of eighteen observations at four weeks. Computerized tomography and histomorphometric analyses demonstrated that mineralization in the fusion mass increased in a linear fashion even after eight weeks. Histologically, the fusion mass consisted predominantly of woven bone at eight weeks; thereafter, it was gradually trabeculated. CLINICAL RELEVANCE: We found a great discrepancy between biomechanical stability and histological maturation of the posterolateral fusion mass. The biomechanical properties of a stable spinal fusion preceded the radiographic appearance of a solid fusion by at least eight weeks, suggesting that immature woven bone provided substantial stiffness to the fusion mass. The spinal instrumentation was subjected predominantly to bending stress rather than to axial stress, and the load-sharing of the spinal instrumentation decreased concurrently with the development of the spinal fusion.

Endocrine and cytotoxic therapies for the management of advanced local breast cancer. Current clinical investigation.

There is a need for more clinical investigation in advanced local breast cancer. Both chemotherapy and endocrine therapy improve disease-free and overall survival and are now a routine part of standard patient care. Dose-intensive chemotherapy should be reserved for younger patients in large, controlled clinical trials. For operable patients, adequate surgical therapy of the breast and axilla remains a standard of care and provides the most important piece of prognostic information (i.e., the number of involved axillary lymph nodes). Tamoxifen treatment of the estrogen receptor-positive postmenopausal patient remains the standard, although chemotherapy may add a further increment to disease-free survival.

The outcome of posterolateral fusion in highly selected patients with discogenic low back pain.

STUDY DESIGN: A prospective analysis of the clinical outcome of a consecutive series of patients treated with posterior lumbar arthrodesis. Preoperative data were collected retrospectively by chart review. OBJECTIVES: To measure by independent review the clinical outcome of posterolateral intertransverse fusion as a treatment for discogenic low back pain in a highly selected group of patients. SUMMARY OF BACKGROUND DATA: Although numerous studies have reported on the surgical management of degenerative disc disease, they have been difficult to interpret because they lack patient-oriented outcome assessment and objective pain measurement criteria, independent review, and include patients with diagnoses other than degenerative disc disease. METHODS: Between 1991 and February 1993 all patients seen by a single surgeon, evaluated with magnetic resonance imaging and discography, and treated with posterolateral lumbar fusion were reviewed by independent investigation. Outcome was assessed in the areas of radiographic fusion, pain, function, and patient satisfaction. RESULTS: Twenty-three patients (12 women, 11 men; 100% follow-up an average of 47 months after surgery [range, 24-84 months]) met the inclusion criteria. Overall, 39% had a good or excellent result, 13% fair, and 48% poor. Nine of 10 patients receiving worker's compensation had a poor result, four of five patients with radiographic pseudarthrosis had a poor result. Statistically significant improvement in the visual analogue scale was noted in the good and excellent group (P = 0.0001) and the fair group (P = 0.002) with no change in the poor group. Patients out of work more than 3 months before surgery tended to have poor results. Overall, 56% of patients were extremely satisfied with the result of their surgery. CONCLUSION: Posterolateral intertransverse fusion can be used to successfully manage chronic discogenic back pain. However, patient selection remains a challenge, and successful outcome appears to be limited in the subset of patients receiving worker's compensation and those chronically disabled. Prospective and randomized study with objective pain criteria, independent review, and patient-oriented outcome is recommended.

Static and fatigue biomechanical properties of anterior thoracolumbar instrumentation systems. A synthetic testing model.

STUDY DESIGN: A mechanical testing standard for anterior thoracolumbar instrumentation systems was introduced, using a synthetic model. Twelve recent instrumentation systems were tested in static and fatigue modes. OBJECTIVES: To establish the testing standard for anterior thoracolumbar instrumentation systems using a synthetic model and to evaluate the static and fatigue biomechanical properties of 12 anterior thoracolumbar instrumentation systems. SUMMARY OF BACKGROUND DATA: Although numerous studies have been performed to evaluate the biomechanics of anterior spinal instrumentation using a cadaveric or animal tissue, problems of specimen variation, lack of reproducibility, and inability to perform fatigue testing have been pointed out. In no studies has a precise synthetic testing standard for anterior thoracolumbar instrumentation systems been described. METHODS: An ultra-high-molecular-weight polyethylene cylinder was designed according to the anatomic dimensions of the vertebral body. Two cylinders spanned by spinal instrumentation simulated a total corpectomy defect, and a compressive lateral bending load was applied. The instrumentation assembly was precisely standardized. The static destructive and fatigue tests up to 2 million cycles at three load levels were conducted, followed by the failure mode analysis. Twelve anterior instrumentation systems, consisting of five plate and seven rod systems were compared in stiffness, bending strength, and cycles to failure. RESULTS: Static and fatigue test parameters both demonstrated highly significant differences between devices. The stiffness ranged from 280.5 kN/m in the Synthes plate (Synthes, Paoli, PA) to 67.9 kN/m in the Z-plate ATL (SofamorDanek, Memphis, TN). The Synthes plate and Kaneda SR titanium (AcroMed, Cleveland, OH) formed the highest subset in bending strength of 1516.1 N and 1209.9 N, respectively, whereas the Z-plate showed the lowest value of 407.3 N. There were no substantial differences between plate and rod devices. In fatigue, only three systems: Synthes plate, Kaneda SR titanium, and Olerud plate (Nord Opedic AB, Sweden) withstood 2 million cycles at 600 N. The failure mode analysis demonstrated plate or bolt fractures in plate systems and rod fractures in rod systems. CONCLUSIONS: The biomechanical testing standard for anterior thoracolumbar instrumentation systems was successfully designed. It provided a repeatable and consistent experimental condition and controlling dimensional and surgical factors. The comparison of 12 instrumentation systems highlights the importance of mechanically balanced device design without a weak link in the development of instrumentation.

The effects of rigid spinal instrumentation and solid bony fusion on spinal kinematics. A posterolateral spinal arthrodesis model.

STUDY DESIGN: Spinal kinematics after the implementation of rigid spinal instrumentation or the achievement of a solid fusion was studied using a sheep posterolateral spinal arthrodesis model. OBJECTIVE: To investigate the effects of rigid spinal instrumentation or solid fusion on spinal kinematic parameters. SUMMARY OF BACKGROUND DATA: Numerous studies have attempted to define spinal instability in terms of kinematics. Recent in vitro studies have documented the neutral zone, or a measure of spinal laxity, as more sensitive to spinal instability than the range of motion. METHODS: Seven skeletally mature sheep underwent a single-level posterolateral lumbar arthrodesis using autologous bone graft augmented with transpedicular screw fixation. The animals were killed 4 months after surgery. The identical surgical procedures were performed in seven sheep cadaveric spines, which served as acute postoperative controls. Each functional spinal unit was tested biomechanically before and after hardware removal. The experimental control groups consisted of destabilized spines and spines that underwent transpedicular screw fixation alone, whereas the fusion groups included spines that underwent posterolateral fusion alone or posterolateral fusion with instrumentation. RESULTS: Rigid instrumentation and solid fusion significantly decreased the neutral zone and range of motion in all testing modes. In axial rotation and lateral bending, solid fusion reduced the range of motion significantly more than transpedicular screw fixation alone. However, in all testing modes, the neutral zones showed no statistical difference between transpedicular screw fixation alone and fusion groups. CONCLUSIONS: The range of motion was an equivalent or better indicator of fixation or fusion stability compared with the neutral zone. Moreover, the immediate postoperative fixation stability, even if using transpedicular screw fixation, was less than the stability present after a solid fusion.