An unusual case of bilateral pyoderma gangrenosum with Achilles tendon rupture.

Pyoderma gangrenosum (PG) is a rare, noninfectious, inflammatory disease characterized by neutrophilic infiltration of the dermis and destruction of tissue. PG is a diagnostic challenge, which can lead to late diagnosis, delayed treatment and detrimental surgical interventions. We describe a presentation not previously reported, affecting deep muscle and tendon leading to tendon rupture. Furthermore, we show the multidisciplinary team approach to management of a patient with PG and the reconstructive surgical element. A 31-year-old woman presented with a rapid onset painful, tender, left calf and ankle, which was associated with a mild flare of ulcerative colitis. Investigations revealed a white cell count of 26 × 10(9) cells L(-1) , a C-reactive protein count of 226 mg L(-1) , no deep vein thrombosis on ultrasound, no bone or joint involvement on X-ray and no organisms on joint aspirate. Debridement was undertaken after the left ankle developed a foul-smelling discharging wound. Repeat debridement led to worsening of the condition (pathergy). Intraoperative tissue cultures and microscopy showed no evidence of fungi, bacteria or mycobacteria. Histology showed granulation, inflammatory infiltrate, abscess formation and focal necrotizing vasculitis. Dermatology opinion confirmed PG. Awareness of the diagnosis of PG, and early involvement of dermatology, in a rapidly progressing wound is essential to avoid delayed treatment and prevent worsening through pathergy.

Multivisceral Transplant in a Patient With Portopulmonary Hypertension: A Case Report.

Portopulmonary hypertension, a type of pulmonary arterial hypertension in the setting of cirrhotic or noncirrhotic portal hypertension, is associated with elevated morbidity and mortality during and after transplantation. Uncontrolled portopulmonary hypertension may prevent or delay listing for transplant candidates, and the prognosis without treatment and ultimately transplant is extremely poor. We present a 29-year-old White woman, who had a post-liver transplant at infancy due to biliary atresia. Later on, she developed extensive portal vein thrombosis and portopulmonary hypertension and underwent a multivisceral transplant (liver, stomach, pancreaticoduodenal complex, and small and large intestine). Preoperative mean pulmonary artery pressure was <30 mm Hg with a pulmonary vascular resistance of <300 dynes.s/cm5 on oral sildenafil and intravenous epoprostenol. Intraoperatively, management required comprehensive transfusion protocols, a careful balance between correcting blood loss and preventing thrombosis. Intravenous epoprostenol, sildenafil, milrinone, and inhaled nitric oxide were used to reduce elevated mean pulmonary artery pressure and right ventricular strain associated with vascular clamping, reperfusion, and massive fluid shifts. Nitric oxide and epoprostenol use unleashed antiplatelet effects on a patient already susceptible to coagulopathy. A multimodal and multidisciplinary approach continued throughout the surgery and in the postoperative period, which led to a successful outcome.

A Monte Carlo model of synchrotron radiotherapy shows good agreement with experimental dosimetry measurements: Data from the imaging and medical beamline at the Australian Synchrotron.

Experimental measurement of Synchrotron Radiotherapy (SyncRT) doses is challenging, especially for Microbeam Radiotherapy (MRT), which is characterised by very high dynamic ranges with spatial resolutions on the micrometer scale. Monte Carlo (MC) simulation is considered a gold standard for accurate dose calculation in radiotherapy, and is therefore routinely relied upon to produce verification data. We present a MC model for Australian Synchrotron's Imaging and Medical Beamline (IMBL), which is capable of generating accurate dosimetry data to inform and/or verify SyncRT experiments. Our MC model showed excellent agreement with dosimetric measurement for Synchrotron Broadbeam Radiotherapy (SBBR). Our MC model is also the first to achieve validation for MRT, using two methods of dosimetry, to within clinical tolerances of 5% for a 20×20 mm2 field size, except for surface measurements at 5 mm depth, which remained to within good agreement of 7.5%. Our experimental methodology has allowed us to control measurement uncertainties for MRT doses to within 5-6%, which has also not been previously achieved, and provides a confidence which until now has been lacking in MRT validation studies. The MC model is suitable for SyncRT dose calculation of clinically relevant field sizes at the IMBL, and can be extended to include medical beamlines at other Synchrotron facilities as well. The presented MC model will be used as a validation tool for treatment planning dose calculation algorithms, and is an important step towards veterinary SyncRT trials at the Australian Synchrotron.

Ultra-fast prompt gamma detection in single proton counting regime for range monitoring in particle therapy.

In order to fully exploit the ballistic potential of particle therapy, we propose an online range monitoring concept based on time-of-flight (TOF)-resolved prompt gamma (PG) detection in a single proton counting regime. In a proof of principle experiment, different types of monolithic scintillating gamma detectors are read in time coincidence with a diamond-based beam hodoscope, in order to build TOF spectra of PG generated in a target presenting an air cavity of variable thickness. Since the measurement was carried out at low beam currents (< 1 proton/bunch) it was possible to reach excellent coincidence time resolutions, of the order of 100 ps (σ). Our goal is to detect possible deviations of the proton range with respect to treatment planning within a few intense irradiation spots at the beginning of the session and then carry on the treatment at standard beam currents. The measurements were limited to 10 mm proton range shift. A Monte Carlo simulation study reproducing the experiment has shown that a 3 mm shift can be detected at 2σ by a single detector of ∼1.4 × 10-3 absolute detection efficiency within a single irradiation spot (∼108 protons) and an optimised experimental set-up.

Arteriovenous fistulae vs. arteriovenous grafts: a retrospective review of 1,700 consecutive vascular access cases.

OBJECTIVE: Vascular access (VA) procedures are rapidly becoming the most prevalent surgery in the United States. It is estimated that there will be over 500,000 VA procedures done this year. Previously, surgeons in the US were attempting many more non-autogenous grafts than autogenous fistulae. In recent years, there has been a great push called 'Fistula First' to promote arteriovenous fistulae (AVF) as the first line of treatment vs. nonautogenous grafts. The goal of this investigation is to determine if too many fistulae are now being performed without attention to specific patient profiles. METHODS: A retrospective review of 1700 consecutive cases was performed by one surgeon at one institution between 1997 and 2005. Patients were categorized by demographics, co-morbidities, previous access procedures, access location, and type of graft. Patency was calculated. Kaplan-Meier, Cox regression and the Log Rank Test were used to analyze data. Access endpoints and complications were also documented. RESULTS: The study reviewed 1700 procedures. The median age was 52 (60.2% male) with 58.7% fistulae and 41.3% grafts. Median patency time was 10 months, with no statistically significant difference between access types. There was no significant difference in length of patency when comparing upper arm (70.1%), lower arm (24.5%) and thigh (5.4%). Graft infection rate was 9.5% and fistula infection rate was 0.9% (p<0.001). The overall infection rate was 4.5%, and decreased patency significantly (4 vs. 11 months). Thrombosis occurred in 24.7% of grafts and 9.0% of fistulae. Thrombosed grafts had better salvage rates (8 vs. 4 months, p<0.001). The data showed diabetes, HTN and HIV have no overall impact on patency. CONCLUSIONS: AVF and grafts are both useful in providing VA for patients requiring hemodialysis. Our data shows that grafts are equivalent in long-term patency. Therefore, it is apparent in those patients who are not candidates for an AV fistula; an AV graft for VA should be placed.

Reproducibility of the Gartland classification for supracondylar humeral fractures in children.

PURPOSE: To evaluate the intra- and inter-observer reproducibility of the Gartland radiographic classification for supracondylar humeral fractures in children. METHODS: Anteroposterior and lateral radiographs of 50 supracondylar humeral fractures in children were graded on 2 separate occasions by 4 orthopaedic surgeons according to the Wilkins modification of the Gartland classification. Data were analysed by calculating the Kappa values for intra- and inter-observer agreement to indicate the reproducibility of the classification. RESULTS: There was moderate inter-observer agreement, except for poor agreement over type I fractures. Type II fractures only showed fair to moderate agreement. Type III fractures and the flexion group showed good to very good agreement. Intra-observer agreement was good to very good. CONCLUSION: Surgeons should treat paediatric supracondylar humeral fractures based on an assessment of the degree of displacement rather than by employing the Gartland classification.

Computer hexapod-assisted orthopaedic surgery provides a predictable and safe method of femoral deformity correction.

AIMS: Computer hexapod assisted orthopaedic surgery (CHAOS), is a method to achieve the intra-operative correction of long bone deformities using a hexapod external fixator before definitive internal fixation with minimally invasive stabilisation techniques. The aims of this study were to determine the reliability of this method in a consecutive case series of patients undergoing femoral deformity correction, with a minimum six-month follow-up, to assess the complications and to define the ideal group of patients for whom this treatment is appropriate. PATIENTS AND METHODS: The medical records and radiographs of all patients who underwent CHAOS for femoral deformity at our institution between 2005 and 2011 were retrospectively reviewed. Records were available for all 55 consecutive procedures undertaken in 49 patients with a mean age of 35.6 years (10.9 to 75.3) at the time of surgery. RESULTS: Patients were assessed at a mean interval of 44 months (6 to 90) following surgery. The indications were broad; the most common were vitamin D resistant rickets (n = 10), growth plate arrest (n = 6) and post-traumatic deformity (n = 20). Multi-planar correction was required in 33 cases. A single level osteotomy was performed in 43 cases. Locking plates were used to stabilise the osteotomy in 33 cases and intramedullary nails in the remainder. Complications included two nonunions, one death, one below-knee deep vein thrombosis, one deep infection and one revision procedure due to initial under-correction. There were no neurovascular injuries or incidence of compartment syndrome. CONCLUSION: This is the largest reported series of femoral deformity corrections using the CHAOS technique. This series demonstrates that precise intra-operative realignment is possible with a hexapod external fixator prior to definitive stabilisation with contemporary internal fixation. This combination allows reproducible correction of complex femoral deformity from a wide variety of diagnoses and age range with a low complication rate. Cite this article: Bone Joint J 2017;99-B:283-8.

Endoscopic palliation of malignant dysphagia: a challenging task in inoperable oesophageal cancer.

BACKGROUND: The main goal when managing patients with inoperable oesophageal cancer is to restore and maintain their oral nutrition. The aim of the present study was to assess the value of endoscopic palliation of dysphagia in patients with oesophageal cancer, who either due to advanced stage of the disease or co-morbidity are not suitable for surgery. PATIENTS AND METHODS: All the endoscopic palliative procedures performed over a 5-year period in our unit were retrospectively reviewed. Dilatation and insertion of self-expandable metal stents (SEMS) were mainly used for tight circumferential strictures whilst ablation with Nd-YAG laser was used for exophytic lesions. All procedures were performed under sedation. RESULTS: Overall 249 palliative procedures were performed in 59 men and 40 women, with a median age of 73 years (range 35-93). The median number of sessions per patient was 2 (range 1-13 sessions). Palliation involved laser ablation alone in 24%, stent insertion alone in 22% and dilatation alone in 13% of the patients. In 41% of the patients, a combination of the above palliative techniques was applied. A total of 45 SEMS were inserted. One third of the patients did not receive any other palliative treatment, whilst the rest received chemotherapy, radiotherapy or chemoradiotherapy. Swallowing was maintained in all patients up to death. Four oesophageal perforations were encountered; two were fatal whilst the other two were successfully treated with covered stent insertion and conservative treatment. The median survival from diagnosis was 10.5 months (range 0.5-83 months) and the median survival from 1st palliation was 5 months (range 0.5-68.5 months). CONCLUSION: Endoscopic interventions are effective and relatively safe palliative modalities for patients with oesophageal cancer. It is possible to adequately palliate almost all cases of malignant dysphagia. This is achieved by expertise in combination treatment.

Combined surgery and chemoradiation as a treatment for the Buschke-Löwenstein tumour.

BACKGROUND: The Buschke-Löwenstein tumour (BLT) or giant condyloma acuminata is a rare disease which affects the anogenital region. Although histologically benign, it behaves in a malignant fashion, infiltrating the surrounding tissues. The morbidity and mortality from this tumour is high, as is the risk of recurrence following treatment. It lies on the continuum between the benign condylomata acuminata and squamous cell carcinoma. The human papillomavirus is implicated in its aetiology. Treatment is controversial, with topical chemotherapy, radiotherapy, immunotherapy and radical surgery all having been employed. Chemoradiation remains the mainstay of treatment for anal cancers but has not been routinely employed in the management of the BLT without squamous cell carcinoma transformation. METHODS: Two cases of extensive perineal BLT treated with chemoradiation and subsequent surgical excision are presented. RESULTS: The first patient had a good symptomatic response to the chemoradiation but unfortunately died of recurrent disease following surgery. The second patient had a macroscopically complete response to chemoradiation and remains well following abdominoperineal excision. CONCLUSION: Pre-operative chemoradiation has proved to be useful in management for histologically proven benign BLT

Routes of early enteral nutrition following oesophagectomy.

Introduction Oesophagectomy for cancer is a challenging procedure with a five-year overall survival rate of 15-20%. Early enteral nutrition following oesophagectomy is a crucial component of the postoperative recovery and carries a significant impact on the outcome. Different methods of enteral feeding were conducted in our unit. The aim of this study was to examine the efficacy and safety of nasojejunal tube (NJT), jejunostomy tube (JT) and pharyngostomy tube (PT) feeding after oesophagectomy. Methods A retrospective review was carried out of prospectively collected data on patients with oesophageal cancer who underwent an oesophagectomy between 2011 and 2014. The primary outcome was feeding tube related complications such as occlusion, dislocation and leak. The secondary outcomes were length of stay and 30-day morbidity. Results A total of 90 oesophagectomies were included in the study. A NJT was inserted in 41 patients (45.6%), a JT was used in 14 patients (15.5%) and a PT was the route for enteral nutrition in 35 patients (38.9%). In total, five patients (5.5%) developed tube related complications. There were no tube related complications in the NJT group but one JT patient (7.1%) developed tube related cellulitis (p=0.189) and four PT patients (11.4%) developed tube related haemorrhage (p=0.544), tube dislocation (p=0.544) or cellulitis (p=0.189). The median length of stay and 30-day postoperative morbidity were similar between the groups. Conclusions NJT feeding is a less invasive, feasible route for early enteral nutrition following oesophagectomy. A randomised controlled trial is recommended to verify these findings.

Absolute dosimetry on a dynamically scanned sample for synchrotron radiotherapy using graphite calorimetry and ionization chambers.

The absolute dose delivered to a dynamically scanned sample in the Imaging and Medical Beamline (IMBL) on the Australian Synchrotron was measured with a graphite calorimeter anticipated to be established as a primary standard for synchrotron dosimetry. The calorimetry was compared to measurements using a free-air chamber (FAC), a PTW 31 014 Pinpoint ionization chamber, and a PTW 34 001 Roos ionization chamber. The IMBL beam height is limited to approximately 2 mm. To produce clinically useful beams of a few centimetres the beam must be scanned in the vertical direction. In practice it is the patient/detector that is scanned and the scanning velocity defines the dose that is delivered. The calorimeter, FAC, and Roos chamber measure the dose area product which is then converted to central axis dose with the scanned beam area derived from Monte Carlo (MC) simulations and film measurements. The Pinpoint chamber measures the central axis dose directly and does not require beam area measurements. The calorimeter and FAC measure dose from first principles. The calorimetry requires conversion of the measured absorbed dose to graphite to absorbed dose to water using MC calculations with the EGSnrc code. Air kerma measurements from the free air chamber were converted to absorbed dose to water using the AAPM TG-61 protocol. The two ionization chambers are secondary standards requiring calibration with kilovoltage x-ray tubes. The Roos and Pinpoint chambers were calibrated against the Australian primary standard for air kerma at the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA). Agreement of order 2% or better was obtained between the calorimetry and ionization chambers. The FAC measured a dose 3-5% higher than the calorimetry, within the stated uncertainties.

Absorbed dose determination in kilovoltage X-ray synchrotron radiation using alanine dosimeters.

Alanine dosimeters from the National Physical Laboratory (NPL) in the UK were irradiated using kilovoltage synchrotron radiation at the imaging and medical beam line (IMBL) at the Australian Synchrotron. A 20 × 20 mm2 area was irradiated by scanning the phantom containing the alanine through the 1 mm × 20 mm beam at a constant velocity. The polychromatic beam had an average energy of 95 keV and nominal absorbed dose to water rate of 250 Gy/s. The absorbed dose to water in the solid water phantom was first determined using a PTW Model 31014 PinPoint ionization chamber traceable to a graphite calorimeter. The alanine was read out at NPL using correction factors determined for 60Co, traceable to NPL standards, and a published energy correction was applied to correct for the effect of the synchrotron beam quality. The ratio of the doses determined by alanine at NPL and those determined at the synchrotron was 0.975 (standard uncertainty 0.042) when alanine energy correction factors published by Waldeland et al. (Waldeland E, Hole E O, Sagstuen E and Malinen E, Med. Phys. 2010, 37, 3569) were used, and 0.996 (standard uncertainty 0.031) when factors by Anton et al. (Anton M, Büermann L., Phys Med Biol. 2015 60 6113-29) were used. The results provide additional verification of the IMBL dosimetry.

The reliability of lymph-node staging in rectal cancer after preoperative chemoradiotherapy.

AIMS: To determine the prognostic significance of the nodal stage and number of nodes recovered in the surgical specimen after preoperative synchronous chemoradiation (SCRT) and surgery for locally advanced or unresectable rectal cancer. MATERIALS AND METHODS: One hundred and eighty-two consecutive patients with locally advanced or unresectable (T3/T4) rectal carcinomas were entered on a prospective database and treated in this department with preoperative chemoradiation, followed 6-12 weeks later by surgical resection. Most patients received chemotherapy in the form of low-dose folinic acid and 5-fluorouracil (5-FU) 350 mg/m2 via a 60-min infusion on days 1-5 and 29-33 of a course of pelvic radiotherapy delivered at a dose of 45 Gy in 25 fractions over 33 days to a planned volume. After resection, patients with a positive circumferential margin (< or = 1 mm), extranodal deposits or Dukes' C histology received adjuvant 5-FU-based-chemotherapy (n = 40). RESULTS: After SCRT, 161 patients underwent resection. Twenty-one patients remained unresectable or refused an exenterative operation. Median follow-up is 36 months. Down-staging was achieved in most patients, with 19 having a complete pathological response (pT0). The median number of lymph nodes recovered for all patients was five (range 0-21). The 3-year survival rate for node-positive patients is 47%, for node-negative patients with less than three lymph nodes recovered is 62% and for node-negative patients with three or more lymph nodes recovered is 70%. Compared with node-positive patients, simple regression models revealed a reduced hazard ratio (HR) of 0.72 (0.36-1.43) for node-negative patients with less than three nodes recovered and 0.48 (0.26-0.89) for node-negative patients with three or more lymph nodes recovered. In a multivariate model, including nodal status, excision status, age and sex only positive excision margins significantly predicted a poor outcome: HR = 3.05 (1.55-5.97). CONCLUSIONS: The number of nodes found after preoperative chemoradiation is a significant prognostic factor by univariate analysis. In this study, patients with node-negative histology, and at least three nodes recovered, had better long-term survival than patients in whom two or less nodes were recovered or with positive nodes. This effect was attenuated by the inclusion of excision status in multivariate models.

High spatial resolution dosimetric response maps for radiotherapy ionization chambers measured using kilovoltage synchrotron radiation.

Small circular beams of synchrotron radiation (0.1 mm and 0.4 mm in diameter) were used to irradiate ionization chambers of the types commonly used in radiotherapy. By scanning the chamber through the beam and measuring the ionization current, a spatial map of the dosimetric response of the chamber was recorded. The technique is able to distinguish contributions to the large-field ionization current from the chamber walls, central electrode and chamber stem. Scans were recorded for the NE 2571 Farmer chamber, the PTW 30013, IBA FC65-G Farmer-type chambers, the NE 2611A and IBA CC13 thimble chambers, the PTW 31006 and 31014 pinpoint chambers, the PTW Roos and Advanced Markus plane-parallel chambers, and the PTW 23342 thin-window soft x-ray chamber. In all cases, large contributions to the response arise from areas where the incident beam grazes the cavity surfaces. Quantitative as well as qualitative information about the relative chamber response was extracted from the maps, including the relative contribution of the central electrode. Line scans using monochromatic beams show the effect of the photon energy on the chamber response. For Farmer-type chambers, a simple Monte Carlo model was in good agreement with the measured response.

Long term exposure to dopamine reverses the inhibitory effect of endothelin-1 on prolactin secretion.

This study was undertaken to assess the possibility that endothelin-1 (ET-1) and dopamine (DA) can act in concert to modulate PRL secretion. Enzymatically dispersed anterior pituitary cells obtained from random cycling female rats were perifused with Dulbecco's Modified Eagle's Medium supplemented with 0.2% BSA and 100 microM ascorbic acid. In the absence of dopamine, ET-1 (applied at 20 nM for 60 min) rapidly evoked a small transient elevation of PRL release, followed by a sustained inhibitory phase. Overnight perfusion with 500 nM DA-supplemented medium did not change the basic character of ET-1's effects on PRL secretion. Continuation of DA exposure for 48 h dramatically shifted the responsiveness of the lactotrophs to ET-1; the fast stimulatory response was robustly enhanced, whereas the inhibitory phase was replaced by a modest secondary elevation of basal PRL secretion. The stimulatory effect of ET-1 on PRL secretion after DA pretreatment was blocked by an ETA receptor antagonist, BQ-123. The effect of DA can be mimicked completely by a specific D2 receptor agonist (+/-)-2-(N-phenyl-N-propyl)amino-5-hydroxytetraline hydrochloride, whereas pretreatment with a D1 agonist, SKF-39393, failed to change the responsiveness of lactotrophs to ET-1. Our data indicate that persistent activation of D2 receptors, a condition most closely resembling the in vivo environment of the lactotrophs, uncouples the inhibitory signaling pathway from the ETA receptor while synergistically affecting signal transduction, which mediates the ET-induced stimulation of PRL secretion.

Structural relationships between the isoenzymes of human placental alkaline phosphatase: a serum factor converts M-PLAP to A- and B-PLAP.

A protein factor has been found in serum which converts the M form of placental alkaline phosphatase (PLAP) to the A and B forms. The identity of the conversion products has been confirmed by analysis of their dimers and polypeptides. Proteolysis is not implicated in this phenomenon. This report establishes microvillous M-PLAP as the precursor of the A and B forms.

Detection of the mRNA to placental alkaline phosphatase by in vitro translation and immunoprecipitation.

RNA prepared from human placental syncytiotrophoblast tissue was analysed by in vitro translation and immunoprecipitation. The major polypeptide synthesized from syncytiotrophoblast mRNA was human placental lactogen, accounting for 15-20 per cent of the translated polypeptides. Immunoprecipitation using antibodies to placental alkaline phosphatase (PLAP) specifically precipitated polypeptides of 56 kD and 58 kD. The possible relationship between these polypeptides and those of placental microvillus PLAP is discussed.

A review of the cytogenetics of 58 pediatric brain tumors.

We describe the cytogenetic results of 58 pediatric central nervous system (CNS) tumors of variable histology, investigated between 1992 and 2000. Successful cytogenetics were obtained for 53 patients, with clonal chromosome abnormalities demonstrated in 25. Notable findings included (1) 2p abnormality in four primitive neuroectodermal tumors (PNET); (2) 1p loss in four low-grade gliomas and two PNET; (3) telomeric associations in one pilocytic astrocytoma; (4) chromosome 7 gain in four astrocytomas and two PNET; (5) 17p loss in four PNET; (6) double minutes in one PNET and three glioblastomas; and (7) chromosome 10 loss in four PNET. Higher grade tumors demonstrated greater karyotype complexity. Low-grade tumors showed either minimal simple chromosome changes or a normal karyotype. Chromosome abnormalities were more frequent in supratentorial tumors than their infratentorial counterparts. Our results add weight to the limited existing body of cytogenetic documentation for pediatric CNS tumors and provide further evidence that 2p loss is a consistent region of chromosome involvement in PNET. We advocate further studies of CNS tumors, in particular, to evaluate the importance of 2p changes and to compare cytogenetic results for supratentorial tumors and their infratentorial counterparts.

Randomised trial comparing prednimustine with combination chemotherapy in advanced ovarian carcinoma.

A total of 76 patients with advanced epithelial ovarian carcinoma were randomised to receive 6 months of treatment with either a combination of hexamethylmelamine, 5-fluorouracil, cisplatin and prednimustine or prednimustine alone following initial surgery. Pathologically confirmed response rates were 35% for combination chemotherapy and 28% for prednimustine, and the overall survival was identical for the two groups. Seven patients achieved a pathologically defined complete response, one of whom relapsed at 8 months; the others remain disease-free 18-36 months (median, 23 months) after presentation. The extent of initial surgery significantly affected the survival of patients receiving prednimustine but not of those receiving combination chemotherapy. Prednimustine can produce durable responses in advanced ovarian cancer using a schedule that results in negligible toxicity.

Ovarian steroids influence the activity of neuroendocrine dopaminergic neurons.

The secretion of prolactin (PRL) from the anterior lobe (AL) of the pituitary gland is tonically inhibited by dopamine (DA) of hypothalamic origin. While ovarian steroids play a role in the regulation of the secretion of PRL, their effect on all three populations of hypothalamic neuroendocrine dopaminergic neurons is not fully understood. In this study we describe the effects of ovarian steroids on regulation of the release of DA from tuberoinfundibular dopaminergic (TIDA), tuberohypophyseal dopaminergic (THDA) and periventricular-hypophyseal dopaminergic (PHDA) neurons. Adult female rats were bilaterally ovariectomized (OVX) and, 10 days following ovariectomy (day 0), injected with corn oil (vehicle), estrogen, or estrogen plus progesterone (day 1). Animals were sacrificed every 2 h from 09.00 to 21.00 h by rapid decapitation. Trunk blood was collected and the concentration of PRL in serum was determined by radioimmunoassay. The median eminence (ME) and the AL, intermediate (IL) and neural (NL) lobes of the pituitary gland were dissected and the concentration of DA and DOPAC in each was measured by HPLC-EC. OVX rats presented small but significant increases in the secretion of PRL at 15.00 and 17.00 h. Replacement of estrogen or estrogen plus progesterone increased the basal concentration of PRL. Moreover, injection of estrogen only, or estrogen plus progesterone increased the concentration of PRL in serum at 15.00 h through 19.00 h, respectively, followed by a decrease to baseline thereafter. The turnover of DA in the ME and NL of OVX rats increased at 13.00 and returned to low levels. Turnover of DA in the IL of OVX rats increased in the morning by 11.00 h and remained elevated before decreasing by 17.00 h. The turnover of DA in the ME, IL and NL of OVX rats increased by 19.00 h. Injection of estrogen advanced the increase of TIDA activity by 2 h in the ME compared to OVX rats. Moreover, administration of estrogen suppressed the activity of THDA and PHDA neurons in the afternoon compared to OVX rats. In estrogen plus progesterone-treated rats, the activity of hypothalamic neuroendocrine dopaminergic neurons terminating in the ME, IL, and NL was inhibited prior to the increase in the secretion of PRL. The concentration of DA in the AL diminished prior to the estrogen-induced increase of PRL. Administration of progesterone, in concert with estrogen, delayed the increase of PRL in serum and the decrease of DA in the AL, compared to estrogen-treated rats, by 4 h. These data suggest a major role for ovarian steroids in controlling increases in the secretion of PRL by not only stimulating PRL release from lactotrophs, but also by inhibiting the activity of all three populations of hypothalamic neuroendocrine DAergic neurons.