Caregiver strain on informal caregivers when providing care for older patients undergoing major abdominal surgery: a longitudinal prospective cohort study.

BACKGROUND: Health-care systems nowadays rely on complementary patient care by informal caregivers. The need for, and burden on, informal caregivers will likely increase in the upcoming years. This study aimed to examine the burden on caregivers when providing care for elderly patients undergoing major abdominal surgery. METHODS: A single-centre longitudinal cohort study was conducted between November 2015 and June 2018 in the Amphia hospital in Breda, the Netherlands. Patients aged 70+ undergoing elective surgery for colorectal carcinoma (CRC) or an abdominal aortic aneurysm (AAA) were included in this study. Informal caregiver burden was assessed and compared over time using the Caregiver Strain Index (CSI) at the outpatient clinic visit, at discharge, 2 weeks post-discharge and after 6 and 12 months. The effects of patient- and caregiver-related factors on the experienced caregiver strain were examined. RESULTS: CSI scores of 248 caregivers were significantly increased at discharge (3.5 vs 2.6; p < 0.001) and 2 weeks post-discharge (3.3 vs 2.6; p < 0.001). After 12 months, scores dropped below baseline scores (1.8 vs 2.6; p = 0.012). The highest strain was observed 2 weeks post-discharge for AAA patients and at discharge for CRC patients. Older age, physical or cognitive impairment and burden of comorbidity were associated with an increased caregiver strain at baseline. Type of surgery was independently associated with the change in mean CSI scores over time; a bigger change in caregiver burden is observed after open surgery. CONCLUSION: In the early postoperative period, perceived caregiver strain was significantly increased. Psychological support for caregivers may be advisable, with timing of this support depending on diagnosis and patient-related factors. TRIAL REGISTRATION: This manuscript was retrospectively registered on 05-04-2016 in the Netherlands Trial Register (NTR5932). http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5932.

Effect of conservative treatment in aortoiliac occlusive disease.

Objective: To determine the effect of primary conservative treatment without revascularization in patients with proven aortoiliac occlusive disease (AIOD) presenting with intermittent claudication (IC).Background: The initial treatment of IC should focus on supervised exercise therapy (SET) and pharmacotherapy. Nowadays, primary endovascular revascularization (EVR) has become increasingly popular in patients with all types of AIOD. But in daily practice, EVR is often performed without initially extensive exercise.Method: This is a single centre retrospective study from December 2012 to September 2017. Primary outcomes were maximum walking distance (MWD) and patient satisfaction. Secondary outcomes were revascularization rate and mortality.Results: Twenty-four patients were included. Mean age was 64 years (SD: 9). Mean follow-up was 28 months (SD: 17). Nineteen patients (80%) had SET. In 18 (75%) patients, the MWD was improved compared to the initial situation. In five (21%) patients, the MWD stayed the same. The MWD of one (4%) patient decreased. Overall satisfaction rate was 87%. Three patients (13%) were not satisfied with the conservative treatment and eventually got an EVR. There was no disease related death.Conclusions: Conservative treatment, especially with SET, has acceptable subjective symptom outcomes in selected patients with AIOD. It could be a good alternative treatment for certain patients with AIOD and IC.

The Role of Delirium and Other Risk Factors on Mortality in Elderly Patients with Critical Limb Ischemia Undergoing Major Lower Limb Amputation.

BACKGROUND: Delirium in patients with critical limb ischemia (CLI) is associated with increased mortality. The main goal of this study was to investigate the association between delirium and mortality in patients undergoing major lower limb amputation for CLI. In addition, other risk factors associated with mortality were analyzed. METHODS: An observational cohort study was conducted including all patients aged ≥70 years with CLI undergoing a major lower limb amputation between January 2014 and July 2017. Delirium was scored using the Delirium Observation Screening Score in combination with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Risk factors for mortality were analyzed by calculating hazard ratios using a Cox proportional hazards model. RESULTS: In total, 95 patients were included; of which, 29 (31%) patients developed a delirium during admission. Delirium was not associated with an increased risk of mortality (hazard ratio [HR] = 0.84; 95 % confidence interval [CI]: 0.51-1.73; P = 0.84). Variables independently associated with an increased risk of mortality were age (HR 1.1; 95% CI 1.0-1.1), cardiac history (HR 3.3; 95% CI 1.8-6.1), current smoking (HR 2.9; 95% CI 1.6-5.5), preoperative anemia (HR 2.8; 95% CI 1.1-7.2), and living in a nursing home (HR 2.2; 95% CI 1.1-4.4). CONCLUSION: Delirium was not associated with an increased mortality risk in elderly patients with CLI undergoing a major lower limb amputation. Factors related to an increased mortality risk were age, cardiac history, current smoking, preoperative anemia, and living in a nursing home.

Review: Quality of life in lower limb peripheral vascular surgery.

PURPOSE: Vascular intervention studies generally consider patency and limb salvage as primary outcomes. However, quality of life is increasingly considered an important patient-oriented outcome measurement of vascular interventions. Existing literature was analyzed to determine the effect of different treatments on quality of life for patients suffering from either claudication or critical limb ischemia. BASIC METHODS: A review of the literature was undertaken in the Medline library. A search was performed on quality of life in peripheral arterial disease. Results were stratified according to treatment groups. PRINCIPAL FINDINGS: Twenty-one articles described quality of life in approximately 4600 patients suffering from peripheral arterial disease. Invasive treatment generally results in better quality of life scores (at a maximum of 2 years of follow-up), compared with non-invasive treatment. In patients with critical limb ischemia, successful revascularization improves quality of life scores. Only one study reported long-term results. CONCLUSIONS: Increase in quality of life scores can be found for any intervention performed for peripheral arterial disease. However, there is scarce information on long-term quality of life after vascular intervention.

Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population.

Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.

Quality of life in perspective to treatment of postoperative edema after peripheral bypass surgery.

BACKGROUND: To examine the effects of peripheral bypass surgery on patients' quality of life (QoL) as well as to compare two treatment modalities to reduce postoperative edema with regard to patients' QoL. METHODS: This was a randomized controlled trial set in the department of vascular surgery in a nonacademic teaching hospital. Ninety-three patients (mean age, 70 years; 33% Rutherford 5-6), enrolled between August 2006 and September 2009, who underwent peripheral bypass surgery (autologous 57, polytetrafluoroethylene 36). Patients were assigned to intermittent pneumatic compression (n = 46) or to compression stockings (n = 47). The main outcome measure was QoL, measured with the World Health Organization Quality of Life assessment instrument (short form: WHOQOL-BREF). RESULTS: QoL improved on the domain of Physical Health by 7.18 points (P < 0.001 [range, 0-100]) after 2 weeks and by 10.03 points (P < 0.001) after 3 months. Patients who received a polytetrafluoroethylene bypass scored 0.45 points (P = 0.0008 [range, 1-5]) lower at baseline on Global QoL than patients who received an autologous bypass. Type of bypass or edema treatment method did not affect the improvements. Edema did not correlate with QoL. CONCLUSION: Improvement in QoL on the domain Physical Health following femoropopliteal bypass surgery was found as soon as 2 weeks after surgery. Improvement in QoL domains was not influenced by the type of bypass reconstruction. No specific effects of edema on QoL were detected.

Evaluation of A-V impulse technology as a treatment for oedema following polytetrafluoroethylene femoropopliteal surgery in a randomised controlled trial.

OBJECTIVE: To investigate the efficacy of A-V impulse technology (A-V) for oedema prevention and treatment following PTFE femoropopliteal surgery. DESIGN: Prospective randomized clinical trial. MATERIALS: 36 patients undergoing PTFE femoropopliteal bypass reconstructions, either being treated postoperatively with a compression stocking (CS) (Group-1, n = 19) or with A-V (Group-2, n = 17). METHODS: Patients in treatment group-1 used a CS postoperatively during 1 week day and night, patients in group-2 were treated with A-V postoperatively at night during one week. The lower leg circumference was measured preoperatively and at five postoperative time points. RESULTS: Limb circumference has increased postoperatively on day 1 (CS 1.5%/A-V 1.4%), on day 4 (5.7%/6.3%), on day 7 (6.6%/6.1%), on day 14 (7.9%/7.7%) and on day 90 (5.8%/5.2%). Differences between treatment groups were not significant. A re-operation gives a significant 3.9% increase in circumference as compared to a first operation (95% CI: 1.5-6.4%; p = 0.002). CONCLUSION: No significant differences were found in the extent of developed edema between the groups following PTFE femoropopliteal bypass surgery. A redo peripheral bypass operation results in significantly more postoperative oedema than a first-time performed bypass operation.

Surgical removal of an infected aortic endoprosthesis using a wire cutter.

The purpose of this study is to report a new method of removing an infected endoprosthesis from the abdominal aorta using a wire cutter. A 65-year-old man with a ruptured abdominal aortic aneurysm was admitted to our hospital. He was treated with an endovascular abdominal endoprosthesis and discharged one week later. Three months after placement, the patient returned with an infection of the aortic endoprosthesis. The endoprosthesis had been fixed with barbs and hooks above the renal arteries and was surgically explanted by using a wire cutter to cut the hooks. The bare suprarenal stent was left in place. The patient was discharged one month after stent removal, and was treated with oral antibiotics for another ten weeks. At one year follow-up the patient showed no clinical, biochemical, or radiological signs of infection. In conclusion, infected endoprostheses should be surgically removed according to the medical literature. We recognize that removing a Zenith endoprostheses requires a dangerous operation because the hooks of the bare stent are engaged into the supra-renal aorta. This case report documents a new technique to safely remove an infected endoprosthesis with the help of a wire cutter.

Risk factors for postoperative delirium after elective major abdominal surgery in elderly patients: A cohort study.

BACKGROUND: Prehabilitation programs have recently been suggested as potentially able to lower the incidence of delirium in elderly patients undergoing major abdominal surgery. For these prehabilitation programs to become successful, it is essential to identify those patients who are most likely to develop a delirium. MATERIAL AND METHODS: A single-centre cohort study was conducted. Inclusion criteria were: age ≥70 years and scheduled for abdominal surgery for colorectal cancer or an abdominal aortic aneurysm between January 2013 and June 2018. Baseline patient, surgical, anaesthesiologic and haematological characteristics were collected. A risk factor analysis was conducted, with postoperative delirium as primary outcome, by performing a multivariable logistic regression analysis. RESULTS: In this study, 627 patients were included, of whom 64 (10%) developed a delirium. Variables that differed significantly between delirious and non-delirious patients were age, burden of comorbidity, renal impairment, hypertension, cognitive impairment, history of delirium, physical and nutritional impairment, open surgery, preoperative anaemia and erythrocyte transfusion. After multivariable logistic regression analysis, risk factors for postoperative delirium after major abdominal surgery were renal impairment (OR 2.2; 95%CI 1.2-4.3), cognitive impairment (OR 4.1; 95%CI 1.8-9.2), an ASA score ≥ 3 (OR 2.0; 95% CI 1.0-3.9), being an active smoker (OR 2.7; 95%CI 1.3-5.8), ICU admission (OR 7.1; 95%CI 3.5-14.3), erythrocyte transfusion (OR 2.4; 95%CI 1.2-4.9) and a diagnosis of colorectal cancer (CRC); (OR 4.0; 95% CI 1.7-9.6). Prehabilitation had a protective effect (OR 0.5; 95% CI 0.3-0.9). CONCLUSION: Postoperative delirium is a frequent complication after major abdominal surgery in the elderly, especially in octogenarians and after open procedures. Renal impairment, cognitive impairment, being an active smoker, ICU admission, erythrocyte transfusion and a diagnosis of CRC are important risk factors for the development of delirium. Prehabilitation lowers the risk of developing a delirium.

Multimodal prehabilitation to reduce the incidence of delirium and other adverse events in elderly patients undergoing elective major abdominal surgery: An uncontrolled before-and-after study.

BACKGROUND: Delirium is a common and serious complication in elderly patients undergoing major abdominal surgery, with significant adverse outcomes. Successful strategies or therapies to reduce the incidence of delirium are scarce. The objective of this study was to assess the role of prehabilitation in reducing the incidence of delirium in elderly patients. METHODS: A single-center uncontrolled before-and-after study was conducted, including patients aged 70 years or older who underwent elective abdominal surgery for colorectal carcinoma or an abdominal aortic aneurysm between January 2013 and October 2015 (control group) and between November 2015 and June 2018 (prehabilitation group). The prehabilitation group received interventions to improve patients' physical health, nutritional status, factors of frailty and preoperative anaemia prior to surgery. The primary outcome was incidence of delirium, diagnosed with the DSM-V criteria or the confusion assessment method. Secondary outcomes were additional complications, length of stay, unplanned ICU admission, length of ICU stay, readmission rate, institutionalization, and in-hospital or 30-day mortality. RESULT: A total of 360 control patients and 267 prehabilitation patients were included in the final analysis. The mean number of prehabilitation days was 39 days. The prehabilitation group had a higher burden of comorbidities and was more physically and visually impaired at baseline. At adjusted logistic regression analysis, delirium incidence was reduced significantly from 11.7 to 8.2% (OR 0.56; 95% CI 0.32-0.98; P = 0.043). No statistically significant effects were seen on secondary outcomes. CONCLUSION: Current prehabilitation program is feasible and safe, and can reduce delirium incidence in elderly patients undergoing elective major abdominal surgery. This program merits further evaluation. TRIAL REGISTRATION: Dutch Trial Registration, NTR5932.

Effects of temperature and pH on adsorption of basic brown 1 by the bacterial biopolymer poly(gamma-glutamic acid).

Poly(gamma-glutamic acid) (gamma-PGA), an extracellular polymeric substance (EPS) synthesized by Bacillus species, was explored to study its interaction with the basic brown 1 dye by conducting a systematic batch adsorption study as affected by two critical parameters, temperature and pH. Adsorption isotherms were closely predicted by Temkin equation among the eight isotherm models tested. The rate of adsorption was very rapid attaining equilibrium within 60 min and the kinetics were well described by both modified second-order and pseudo second-order models. Boyd's ion exchange model, which assumes exchanges of ions to be a chemical phenomenon, also fitted the kinetic data precisely. The adsorption rate increased with increasing solution temperature, however, a reversed trend was observed for the adsorption capacity. Changes in enthalpy, entropy and free energy values revealed dye adsorption by gamma-PGA to be an exothermic and spontaneous process involving no structural modification in gamma-PGA, whereas the activation energy of 37.21 kJ/mol indicated dye adsorption to be reaction-controlled. Following a rise in solution pH, the dye adsorption increased and reached a plateau at pH 5, while the maximum release of dye from spent gamma-PGA occurred at pH 1.5, suggesting a possible ion exchange mechanism. Ion exchange adsorption of basic dyes by gamma-PGA was further proved by the presence of two new IR bands at approximately 1600 and 1405.72 cm(-1), representing asymmetric and symmetric stretching vibration of carboxylate anion, for dye-treated gamma-PGA.

Endovascular aneurysm repair with Zenith graft. Complications caused by leg extensions.

AIM: A large amount of Zenith endovascular stent complications is due to problems with the leg extensions. This kind of complication has never been reported in literature. The aim of this study was to monitor the complications of endovascular abdominal aneurysm repair (EVAR) performed with the Zenith endovascular graft occurred in the Amphia Ziekenhuis in Breda to see how many recurrences were due to leg extension. METHODS: The study enrolled all patients (N.=66) treated with the Zenith endograft in the period between October 2000 and September 2006. Mortality, complications and the number of reinterventions were analysed. Average age of the patients was 73.4 years, average follow-up was 24.5 months and average aneurysm size was 61.5 mm. Radiologic follow-up was performed by computed tomography scans and X-rays. RESULTS: Postoperative mortality rate was 0%. The overall mortality rate during follow-up was 3%. Ten patients required a total number of 12 reinterventions (15%). The average time for reintervention was 10 months after the primary operation. Mortality, complication and reintervention rates were comparable with those reported in the literature, but 75% of these reinterventions were related to the leg extensions. CONCLUSION: Authors observed that nine out of 12 complications which required reintervention were due to problems with one of the leg extensions. This is the first study that specifies clearly the percentage of problems with leg extensions in EVAR (75%). When placing a Zenith endovascular graft extra attention should be paid to optimal placement of the leg extensions.

Encapsulation of lycopene extract from tomato pulp waste with gelatin and poly(gamma-glutamic acid) as carrier.

Tomato pulp waste, a byproduct obtained during the processing of tomato juice, has been shown to be a rich source of lycopene. The objectives of this study were to use gelatin and poly(gamma-glutamic acid) (gamma-PGA) as coating materials for the encapsulation of lycopene extract from tomato pulp waste. Initially, lycopene was extracted with supercritical carbon dioxide, followed by microencapsulation using an emulsion system consisting of 4.5% gelatin, 10% gamma-PGA, and 4.8% lycopene extract. Analysis of differential scanning calorimetry revealed that the thermal stability of the coating material could be up to 120 degrees C, with a mean particle size of 38.7 microm based on Coulter counter analysis. The total weight of microencapsulated powder was 617 microg with the yield of lycopene being 76.5%, indicating a 23.5% loss during freeze drying. During storage of microencapsulated powder, the concentrations of cis-, trans-, and total lycopene decreased along with increasing time and temperature. A fast release of lycopene in the powder occurred at pH 5.5 and 7.0, while no lycopene was released at pH 2.0 and 3.5.

Clinical outcome after re-occlusion of initially successful remote endarterectomy of the superficial femoral artery.

AIM: The clinical consequences of re-occlusion after initially successful arterial revascularization procedures might be as important as patency when it comes to procedure selection. This study evaluates the clinical consequences of re-occlusion after initially successful remote superficial femoral artery endarterectomy (RSFAE), in particular the recurrence and severity of symptoms and the need for re-intervention or amputation. METHODS: A total of 239 successful RSFAEs were performed with a mean endarterectomized segment of 30 cm (10 to 45 cm) between March 1994 and December 2003 in 214 patients (144 males, 163 procedures) with a median age of 63 years (39 to 89 years). Indications for operation were Rutherford category 3 in 174 procedures (73%), Rutherford category 4 in 27 procedures (11%), and Rutherford category 5 in 38 procedures (16%). The incidence and time interval of re-occlusion with the presenting symptoms were recorded as well as the therapeutic consequences. RESULTS: A total of 79 (33%) re-occlusions occurred (40 males, 41 procedures; 34 females, 38 procedures). Eighty percent of patients still had improved or unchanged symptoms following re-occlusion compared to the initial indication for operation, 18% had become worse and 2% were unknown. The mean time between RSFAE and re-occlusion was 17 months (1 day to 88 months). A total of 36 re-interventions were performed: 7 percutaneous recanalisations (one followed by thrombolysis), 5 percutaneous thrombolyses, 1 thrombectomy, 21 venous and 2 prosthetic femoropopliteal bypasses. A further three venous bypasses were planned. Five (14%) of these re-interventions were acute with an overall median time interval between re-occlusion and re-intervention of 41 days (0 to 68 months). Two below-knee amputations were performed: one the same day of re-occlusion, 44 months after RSFAE and one 11 days after re-occlusion, 30 days after RSFAE. CONCLUSION: The clinical consequences of re-occlusion after remote endarterectomy for long occlusive disease of the superfricial femoral artery, from a mixed patient population with 27% ischemic rest pain and gangrene, were mild with 31 elective and only five acute re-interventions and two below-knee amputations.

Effect of pH on binding of mutagenic heterocyclic amines by the natural biopolymer poly(gamma-glutamic acid).

Poly(gamma-glutamic acid) (gamma-PGA), a nontoxic and biodegradable macropolymer, was evaluated for its efficiency in binding three mutagenic heterocyclic amines (HAs), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-p-2), as affected by pH in a batch mode. The maximum HA sorption was attained for pH 3-7 and decreased sharply for pH less than 3. Binding isotherms obtained at pH 2.5 and 5.5 showed different isotherm shapes that belong to S and L types, respectively. The isotherm data at pH 2.5 were well described by a linear form of the Langmuir equation, while at pH 5.5 it showed two distinct curves, which were precisely fitted as multiple Langmuir curves. The deviation of linearity in Scatchard plot proved the multisite HA sorption. The Brunauer-Emmett-Teller equation also fitted better to isotherm data at pH 5.5, suggesting a multisite sorption caused by multimolecular HA layers on gamma-PGA. High HA sorption levels of 1250, 667, and 1429 mg/g at pH 2.5 and 1429, 909, and 1667 mg/g at pH 5.5 were observed for MeIQ, 4,8-DiMeIQx, and Trp-p-2, respectively. Among the HAs studied, the sorption capacity correlated directly with hydrophobicity of HAs and inversely with the number of methyl groups in HA molecules. The plausible binding mechanism of HAs on gamma-PGA may include a combination of hydrophobic, hydrogen-bonding, ionic, and dipole-dipole interactions.

Removal of cationic dyes from aqueous solution using an anionic poly-gamma-glutamic acid-based adsorbent.

Natural polymeric materials are gaining interest for application as adsorbents in wastewater treatment due to their biodegradable and non-toxic nature. In this study, a biopolymer, poly-gamma-glutamic acid (gamma-PGA) derived from bacterial sources (Bacillus species) was evaluated for its efficiency in removing basic dyes from aqueous solution. Sorption studies under batch mode were conducted using C.I. Basic blue 9 (BB9) and C.I. Basic green 4 (BG4) as test dyes. Equilibrium process conformed well with the Redlich-Peterson isotherm equation and the monolayer sorption capacity obtained from the Langmuir model was 352.76 and 293.32mg/g for BB9 and BG4 dyes, respectively. The kinetic studies of dye sorption on gamma-PGA gave high coefficients of determination (>0.98) for a pseudo second-order equation. An ion-exchange model, which assumes adsorption as a chemical phenomenon, was also found to fit the kinetic data precisely. The dye sorption largely depended on the initial pH of the solution with maximum uptake occurring at pH above 5. About 98% of the dye adsorbed on gamma-PGA could be recovered at pH 1, which facilitates the reuse of spent gamma-PGA.

Progestins inhibit the growth of MDA-MB-231 cells transfected with progesterone receptor complementary DNA.

Because progesterone exerts its effects mainly via estrogen-dependent progesterone receptor (PgR), the expression of progesterone's effects may be overshadowed by the priming effect of estrogen. PgR expression vectors were transfected into estrogen receptor (ER)-alpha and PgR-negative breast cancer cells MDA-MB-231; thus the functions of progesterone could be studied independent of estrogens and ERs. Eight stable transfectant clones expressing both PgR isoform A and B were studied for their growth response to progesterone and its analogues. Although progesterone had no effect on growth in the control transfectant, the hormone markedly inhibited DNA synthesis and cell growth in all of the PgR-transfectants dose-dependently from 10(-12)-10(-6) M. This growth inhibition was associated with an arrest of cells in the G0/G1 phase of the cell cycle. Progestins medroxyprogesterone acetate, Org2058, and R5020 also strongly inhibited DNA synthesis, and their doses required for maximal inhibition of 60-70% were 10(-17) M, 10(-13) M, and 10(-7) M, respectively. Antiprogestin ZK98299 alone had no effect, but the compound was capable of counteracting the inhibitory effect of progesterone. In contrast, RU486 inhibited DNA synthesis, and it showed no further effects when it was used concurrently with progesterone. These results indicate that progestins are per se antiproliferative via a PgR-mediated mechanism in breast cancer cells. More importantly, we have shown that progestins may exert effective inhibitory control over the cell growth if the PgR expression is reactivated in ER- and PgR-negative breast cancer cells.

Founder mutation in the BRCA1 gene in Malay breast cancer patients from Singapore.

The mutation spectrum of the BRCA1 gene among ethnic groups from Asia has not been well studied. We investigated the frequency of mutations in the BRCA1 gene among Malay breast cancer patients from Singapore, independent of family history. By using the protein truncation test (PTT) and direct sequencing, BRCA1 mutations were detected in 6 of 49 (12.2%) unrelated patients. Four novel missense mutations in exon 11, T557A (1788A>G), T582A (1863A>G), N656S (2086A>G) and P684S (2169C>T) were identified in one patient. Two patients had missense mutations in exon 23, V1809A (5545T>C), which has been previously detected in individuals from Central and Eastern Europe. Three unrelated patients had the deleterious 2846insA frameshift mutation in exon 11. Methylation specific PCR (MSP) of the promoter region of the BRCA1 gene detected hypermethylation of tumor DNA in an additional 2 patients. Haplotype analysis using the microsatellite markers D17S855, D17S1323 and D17S1325 revealed a common haplotype for the three unrelated patients and their three relatives with the 2846insA mutation. These findings strongly suggest that the 2846insA mutation, the most common deleterious mutation in this study, may possibly be a founder mutation in breast cancer patients of Malay ethnic background.

Limb-sparing therapy of extremity soft tissue sarcomas: treatment outcome and long-term functional results.

The purpose of this study is to assess the long-term success rate and functional results of limb-sparing therapy in a group of 156 patients with soft tissue sarcomas of the extremities in the Netherlands Cancer Institute, treated according to a standard protocol of surgery and radiotherapy, if indicated. The patients (79 females and 77 males) were treated between 1977 and 1983 by an intended wide local excision with a margin of at least 2 cm. Postoperative radiotherapy was applied in 117 patients; 26 patients had surgery only, including 13 patients who had to be treated by amputation. The total dose was 60 Gy, with 40 Gy to a large volume and a boost of 20 Gy to the tumour bed at 2 Gy per fraction, five fractions per week. Most sarcomas were located in the proximal part of the lower extremity (51%). The group comprised 50 liposarcomas, 47 malignant fibrous hystiocystoma (MFH) and 59 other histologies; 69 (44%) had high-grade tumours. Three treatment groups with limb-sparing treatment were defined: group I (n = 26) patients who had a complete excision receiving no further treatment, group II (n = 64) with narrow surgical margins and radiotherapy and group III (n = 53) with incomplete resection and radiotherapy. The 10-year actuarial overall survival and local control rate for all patients was 63 and 81%, respectively. Multivariate analysis showed that histological grade (P < 0.0001), age (P = 0.0005) and location deep to the fascia (P = 0.0008) were independent prognostic factors for survival, while local control was predicted by grade (P = 0.0014) and treatment group (p = 0.028). Patients with surgery only (group I) had 81% 5-year local control as compared to 92% with radiotherapy after narrow surgery (group II) and 74% with incomplete surgery and radiotherapy (group III). Limb preservation when attempted was achieved in 90% of the patients. After limb-sparing treatment, 7% had severe impairment of mobility, 3% had lymph oedema and 16% marked fibrosis. Fractures in the irradiated bone occurred in 6% of the patients. The combination of limited surgery followed by radiotherapy resulted in a high local control rate with good functional results. Ultimately limb sparing treatment was successful in 83% of all patients with extremity sarcomas.

Serum IGF-binding protein-6 and prostate specific antigen in breast cancer.

OBJECTIVE: Recent studies have demonstrated the presence of the IGF-binding proteins (IGFBPs) and prostate specific antigen (PSA), an IGFBP protease. in human breast tissue. We sought to investigate the differences in serum IGFs, IGFBP-1, -3 and -6, and PSA between patients with surgically proven breast cancer and patients with benign breast disease. DESIGN AND METHODS: Concentrations of IGFs, IGFBP-1, -3 and -6, and PSA were determined in the sera from 57 patients with breast cancer (CA), and 46 women with benign breast disease (BBD) using immunoassays for IGFs and IGFBPs and an ultrasensitive ELISA for PSA. RESULTS: The mean (+/- S.E.M.) serum IGFBP-6 level in the CA group, 127 (16) ng/ml, was statistically significantly lower than in the BBD group, 157 (10) ng/ml (P = 0.016). Patients with CA had an elevated geometric mean serum PSA level of 0.018 (range: 0.0015-0.107) ng/ml, compared with 0.007 (range: 0.0015-0.019) ng/ml in women with BBD (P = 0.025). Mean serum IGFBP-1 concentrations were significantly lower in the CA group, 16 (2) ng/ml, versus 37 (4) ng/ml in the BBD group (P = 0.001). Mean serum IGFBP-3 concentrations were also lower in the CA group versus the BBD group, at 1981 (65) ng/ml, versus 2603 (140) ng/ml (P = 0.002) respectively. In the CA group, statistically significant correlations between PSA and IGFBP-6 (r = 0.413; P = 0.001), and between PSA and IGFBP-1 (r = -0.329; P = 0.021) were seen. Differences in IGF-I and -II between the two groups were not statistically significant. CONCLUSION: Lower serum concentrations of IGFBP-6, -3 and -1, but higher PSA concentrations were seen in the breast cancer group, and collectively these would suggest that there is an increase in bioavailable IGF-I in breast cancer.