Increasing the human chorionic gonadotrophin cut-off to ≤1000 IU/l for starting actinomycin D in post-molar gestational trophoblastic neoplasia developing resistance to methotrexate spares more women multi-agent chemotherapy.

BACKGROUND: A human chorionic gonadotropin (hCG) cut-off of ≤300 IU/l for starting actinomycin D (ActD) in post-molar gestational trophoblastic neoplasia (GTN) patients developing methotrexate resistance (MTX-R) reduced the number of women needing toxic multi-agent chemotherapy (etoposide, MTX and ActD alternating weekly with cyclophosphamide and vincristine; EMA/CO) without affecting survival. Here we assess whether an increased hCG cut-off of ≤1000 IU/l spares more women EMA/CO. PATIENTS AND METHODS: All post-molar GTN patients treated with first-line methotrexate and folinic acid (MTX/FA) were identified in a national cohort between 2009 and 2016. Data collected included age, FIGO score, the hCG levels at MTX-R, and treatment outcomes. RESULTS: In total, 609 GTN patients commenced treatment with MTX/FA achieving a complete response in 57% (348/609). Resistance developed in 25.1% (153/609) at an hCG ≤ 1000 IU/l and switching to ActD achieved remission in 92.8% without any major toxicity with the remaining 7.2% remitting on EMA/CO. Comparative analysis of patients switching at an hCG <100 versus 100-300 versus 300-1000 IU/l revealed a significant fall in the cure rate with second-line ActD from 97% (93/96) to 87% (34/39) to 78% (14/18), respectively, P = 0.009. However, by increasing the hCG cut-off from ≤300 to ≤1000 IU/l, 14 patients were spared EMA/CO chemotherapy. Moreover, in the present series, all post-molar GTN remain in remission. CONCLUSION: This study demonstrates that increasing the hCG cut-off from ≤300 to ≤1000 IU/l for choosing patients for ActD following MTX-R spares more women with GTN from the greater toxicity of EMA/CO without compromising 100% survival outcomes.

Reshaping preoperative treatment of pancreatic cancer in the era of precision medicine.

This review summarises the recent evidence on preoperative therapeutic strategies in pancreatic cancer and discusses the rationale for an imminent need for a personalised therapeutic approach in non-metastatic disease. The molecular diversity of pancreatic cancer and its influence on prognosis and treatment response, combined with the failure of 'all-comer' treatments to significantly impact on patient outcomes, requires a paradigm shift towards a genomic-driven approach. This is particularly important in the preoperative, potentially curable setting, where a personalised treatment allocation has the substantial potential to reduce pancreatic cancer mortality.

The role of laparoscopy and laparoscopic ultrasound in the preoperative staging of pancreatico-biliary cancers--A meta-analysis.

BACKGROUND: Staging laparoscopy (SL) may prevent non-therapeutic laparotomy in patients with otherwise resectable pancreatico-biliary cancers, but evidence is inconclusive. This meta-analysis aims to ascertain the true benefit of SL. METHODS: All studies undertaking SL as a diagnostic sieve were included and data homogenised. Standard meta-analytical tools with emphasis on sensitivity testing and meta-regression to detect the cause for heterogeneity between studies were used. RESULTS: 29 studies satisfied the criteria. 3305 patients underwent SL of which 12 were incomplete. Morbidity (n = 15) and mortality (n = 1) was low. True yield of SL for pancreatic/perpancreatic cancers (PPC) was 25% (95% CI 24-27) with a Diagnostic Odds Ratio (DOR) of 104 (95% CI 48-227). Resection rate improved from 61% to 80%. For proximal biliary cancers (PBC), SL increased the curative resection rate from 27% to 50%, with true yield of 47% (95% CI 42-52) and a DOR 61 (95% CI 19-189). Sub-group analysis for detection of liver and peritoneal lesions demonstrated a sensitivity of 88% (95% CI 83-92) and 92% (95% CI 84-96) for PPC; 83% (95% CI 69-92) and 93% (95% CI 81-99) for PBC, respectively. There was no between-study heterogeneity for peritoneal lesions. However for detection of local invasion, sensitivity was low: 58% (95% CI 51-65) for PPC and only 34% (95% CI 22-47) for PBC. Meta-regression did not reveal any cause for the observed heterogeneity between studies. CONCLUSION: SL offers significant benefit to patients with resectable pancreatico-biliary cancers in avoiding non-therapeutic laparotomy and should be adopted in routine clinical practice in a judicious algorithm.

New genetic associations detected in a host response study to hepatitis B vaccine.

The immune response to hepatitis B vaccination differs greatly among individuals, with 5-10% of healthy people failing to produce protective levels of antibodies. Several factors have been implicated in determining this response, chiefly individual genetic variation and age. Aiming to identify genes involved in the response to hepatitis B vaccination, a two-stage investigation of 6091 single-nucleotide polymorphisms (SNPs) in 914 immune genes was performed in an Indonesian cohort of 981 individuals showing normal levels of anti-HBs versus 665 individuals displaying undetectable levels of anti-HBs 18 months after initial dose of the vaccine. Of 275 SNPs identified in the first stage (476 normal/372 nonresponders) with P<0.05, significant associations were replicated for 25 polymorphisms in 15 genes (503 normal/295 nonresponders). We validated previous findings (HLA-DRA, rs5000563, P-value combined=5.57 x 10(-10); OR (95%CI)=0.61 (0.52-0.71)). In addition, we detected a new association outside of the human leukocyte antigen loci region that passed correction for multiple testing. This SNP is in the 3' downstream region of FOXP1, a transcription factor involved in B-cell development (P-value combined=9.2 x 10(-6); OR (95%CI)=1.38 (1.2-1.6)).These findings might help to understand the biological reasons behind vaccine failure and other aspects of variation in the immune responses of healthy individuals.

A randomised comparison of oral desmopressin lyophilisate (MELT) and tablet formulations in children and adolescents with primary nocturnal enuresis.

AIMS: Desmopressin is a useful treatment for primary nocturnal enuresis (PNE), a common childhood condition that can persist into adolescence. This open-label, randomised, cross-over study evaluated the preference of children and adolescents with PNE for sublingual desmopressin oral lyophilisate (MELT) vs. tablet treatment, and the efficacy, safety, compliance and ease of use associated with each formulation. In total, 221 patients aged 5-15 years who were already receiving desmopressin tablets were randomised 1 : 1 to receive desmopressin treatment in the order MELT/tablet (n = 110) or tablet/MELT (n = 111) for 3 weeks each. Each formulation was administered in bioequivalent doses (0.2/0.4 mg tablets identical with 120/240 microg MELT). Following treatment, patients were questioned regarding treatment preference. Diary card data and 100 mm Visual Analogue Scale scores were also recorded. RESULTS: Overall, patients preferred the MELT formulation to the tablet (56% vs. 44%; p = 0.112). This preference was age dependent (p = 0.006); patients aged < 12 years had a statistically significant preference for desmopressin MELT (p = 0.0089). Efficacy was similar for both formulations (MELT: 1.88 +/- 1.94 bedwetting episodes/week; tablet: 1.90 +/- 1.85 episodes/week). Ease of use of both formulations was high. Compliance (> or = 80%) was 94.5% for MELT patients vs. 88.9% for the tablet (p = 0.059). No serious/severe adverse events were reported. CONCLUSIONS: There was an overall preference for the MELT, and a statistically significant preference for desmopressin MELT in children aged 5-11 years. Desmopressin MELT had similar levels of efficacy and safety at lower dosing levels than the tablet, and therefore facilitates early initiation of PNE treatment in children aged 5-6 years.

Resistance of uropathogens in symptomatic urinary tract infections in León, Nicaragua.

Management of urinary tract infections (UTI) in Central America and especially Nicaragua, is complicated by the lack of knowledge about the antibiotic resistance of uropathogens. We conducted a prevalence study to gain more insight into the aetiology, bacterial resistance and risk factors for symptomatic UTI in the region of León, Nicaragua. In 2002, all consecutive patients with UTI symptoms and pyuria >/=10 WBC/hpf were admitted to the study. Positive cultures from midstream urine specimens were defined as >/=10(5) cfu/ml of a single uropathogen. Susceptibility tests were performed with disc diffusion tests using the Kirby-Bauer method and broth microdilution using National Committee for Clinical Laboratory Standards criteria both in León and a reference laboratory in Utrecht. A positive culture was present in 62 of 208 study subjects (30%). Escherichia coli (56%), Klebsiella spp. (18%) and Enterobacter spp. (11%) were the most frequent pathogens isolated. Presence of cystocele, incontinence and increasing age were risk factors for bacterial UTI. E. coli was least resistant to ceftriaxone, amikacin and nitrofurantoin (>90% susceptible). We observed high resistance rates in E. coli to amoxicillin (82%, MIC(90) 128 mg/l), trimethoprim-sulphamethoxazole (TMP-SMX) (64%, MIC(90) 32 mg/l), cephalothin (58%, MIC(90), 32 mg/l), ciprofloxacin (30%; MIC(90), 32 mg/l), amoxicillin/clavulanate (21%, MIC(90) 8 mg/l) and gentamicin (12%, MIC(90) 2 mg/l). Our results suggests that community acquired uropathogens in Nicaragua are highly resistant to many antimicrobial agents. The use of amoxicillin, trimethoprim-sulphamethoxazole and cephalothin against uropathogens needs to be reconsidered. High quinolone resistance rates among E. coli in Nicaragua gives cause for great concern.

[Further development of 'Enuresis nocturna' guidelines for children with persistent problems]. / Uitwerking Richtsnoer 'Enuresis nocturna' voor kinderen met hardnekkige klachten.

To achieve dryness in children who suffer from persistent bedwetting, it is important to find out which factors play a role in their bedwetting and why previous treatment has failed. The use of a micturition diary is essential. The child's problems and needs have to be identified and treated individually. The enuresis alarm, with the proper guidance, is the preferred form of initial treatment. Desmopressin is particularly suitable in cases of nocturnal polyuria or if the use of the alarm is unfeasible. If the alarm does not have any effect within two weeks or if a rapid result is important, a combination of desmopressin and the alarm is advisable. Bedwetting combined with daytime micturition problems is often indicative of a small bladder capacity and/or detrusor instability. In these children bladder training and/or treatment with an anticholinergic drug (possibly combined with desmopressin) may be effective.

Controlled balloon dilatation for laparoscopic extraperitoneal bladder neck suspension in patients with previous abdominal surgery.

PURPOSE: The balloon dilator is used in a variety of minimally invasive preperitoneal and retroperitoneal operations. In this study, we compared the ability to create an extraperitoneal cavity using a balloon spacer in patients with and without previous abdominal surgery undergoing laparoscopic bladder neck suspension. PATIENTS AND METHODS: This prospective study included 38 patients in total, 15 of whom had had previous abdominal wall surgery and 23 who had not. A balloon spacer technique was used to develop the extraperitoneal space. RESULTS: In 80% of the patients with previous surgery, the introduction of the balloon spacer was recorded as simple; in 20%, it was considered difficult. In 78% of the patients without previous surgery, the introduction of the balloon spacer was recorded as simple, in 17% it was difficult, and in 4% it failed. In 80% of the patients with previous surgery, the extraperitoneal view was good or acceptable, in 20% it was poor, and in 13% it failed. In 92% of the patients without previous surgery, the extraperitoneal view was good or acceptable, in 4% it was poor, and in 4% dilatation failed. Morbidity was equally divided between the groups. CONCLUSIONS: Previous abdominal surgery is not a contraindication to laparoscopic extraperitoneal surgery using a balloon spacer. The approach carries low morbidity, similar to that in patients without previous abdominal surgery.

Hemodynamics during laparoscopic extra- and intraperitoneal insufflation. An experimental study.

BACKGROUND: Total extraperitoneal laparoscopic surgery is an alternative to the laparoscopic transperitoneal route; however, its effects on hemodynamics have not been adequately studied. This experimental study compared the effects of intraperitoneal insufflation and extraperitoneal insufflation on hemodynamics and oxygen transport. METHODS: Sixteen pigs were randomly assigned for intraperitoneal insufflation or extraperitoneal insufflation with 15 mmHg carbon dioxide. Hemodynamic and oxygen transport parameters were taken during an hour of insufflation and analyzed for statistical differences. RESULTS: During extraperitoneal CO2 pneumoperitoneum central venous filling pressures (central venous pressure, pulmonary capillary wedge pressure and mean pulmonary arterial pressure) and end-tidal CO2 increased slower but to a similar magnitude in comparison to intraperitoneal insufflation. Cardiac output and indices of oxygen consumption and oxygen delivery were equally affected by both types of insufflation. Arterial CO2 pressure increased significantly more during intraperitoneal insufflation. CONCLUSION: The data from this study suggest that extraperitoneal insufflation might result in less cardiovascular impairment than intraperitoneal insufflation.

[Laparoscopic pelvic lymph node dissection valuable in the staging of clinically localized prostate carcinoma]. / Laparoscopische pelvine lymfeklierdissectie goed bruikbaar voor de stadiëring van klinisch gelokaliseerd prostaatcarcinoom.

OBJECTIVE: To assess the value of laparoscopic lymph node dissection of the obturator fossa in patients with prostate carcinoma with high risk of lymph node metastases. DESIGN: Prospective descriptive study. SETTING: Department of Urology, University Hospital Nijmegen, the Netherlands. METHOD: Prior to curative therapy for prostate carcinoma a bilateral laparoscopic pelvic lymph node dissection was performed in 25 patients, with a high risk of lymph node metastases on the basis of tumour size, tumour grade or serum prostate specific antigen. RESULTS: In 52% (13/25) of the patients lymph node metastases were found. Once a laparotomy was performed for an arterial bleeding. A mean of 11.6 lymph nodes were removed during bilateral dissection of the obturator fossa. Three quarter of the patients were discharged one day postoperatively. CONCLUSION: A laparoscopic lymph node dissection is a valuable tool for the evaluation of pelvic lymph nodes in patients with a clinically localised prostate carcinoma and a high risk of lymph node metastases.

Measurement of the blood supply to the abdominal testis by means of near infrared spectroscopy.

Cryptorchidism is the most common male sexual disorder. In the case of an abdominal testis there is no objective criterion to choose between autotransplantation or orchiopexy after ligation of the spermatic vessels with subsequent development of collateral blood supply. By combining near infrared spectroscopy (NIRS) with pulse oximetry the active testicular blood volume (ATBV) before and after occlusion of the spermatic vessels can be calculated in an animal model. NIRS is a noninvasive continuous optical technique that measures tissue oxygenation and hemodynamics. Ten boars with one non-palpable testis each were selected. The spermatic vessels and vas deferens were separately prepared and atraumatic occluders were placed around the vessels. ATBV was measured before and after occlusion of the spermatic vessels. The calculated ATBV was 18.3 +/- 2.3 ml/100 g of testicular tissue, not corrected by division by the path length factor, accounting for light scattering in the tissue. In 5 of 10 boars no significant ATBV was found after occlusion of the spermatic vessels, suggesting subsequent atrophy. NIRS combined with pulse oximetry provides us with reproducible quantification of ATBV. The method can be used to investigate the viability of a testis after (temporary) occlusion of the spermatic vessels.

[Craniotomy; a ,much-alive tradition with the Kisii (Kenya)]. / Craniotomie; een springlevende traditie bij de Kisii (Kenia).

From 1981 until 1986 the authors witnessed traditional craniotomies being performed in the Kisii tribe in South West Kenya. The indication is the prevention or reduction of headache after trauma capitis. The frequency of the operation is estimated at 1 per 1000 persons a year. The aim is to remove part of the skull around the 'traumatic burst'. After shaving off the hair, the 'omobari omotwe' ('surgeon of the head') makes an incision at the place of the trauma or the headache. The bleeding is stopped with crushed leaves. With primitive instruments the bone is scraped away until the dura mater is reached, which is left untouched very carefully. The operation is carried out without anaesthesia, takes an average of 45 min and is sometimes completed by putting fat on the wound. A postoperative recovery period of 6-12 weeks is usual. The operation is highly regarded and seems to have few complications. Reoperations are frequent: one patient underwent the operation 26 times.

Outcome analysis of the psychosexual and socioeconomical development of adult patients born with bladder exstrophy.

Since sonographic evaluation of the fetus became routine, prenatally established diagnosis of multiple or severe malformations raises the question of whether a pregnancy should be terminated. To answer this question properly, all aspects concerning the life of a child born with a serious malformation, such as exstrophy of the bladder, must be considered. Therefore, more than ever an evaluation of the quality of life of these patients is necessary to be able to make a solid based decision. We studied the psychosexual and socioeconomic development of 22 adult exstrophy patients (11 men and 11 women) by a standardized personal interview, evaluation of a standard performance test SCL-90 (symptom checklist 1990) and an adapted personality score test. The latter 2 tests are well established and provide reproducible results. Based on several large scale investigations, standard scores are available. Nine women (82%) and 10 men (91%) scored better or in accordance with the standard scores. Exstrophy of the bladder does influence the psychosexual and socioeconomic development. The quality of life is hardly ever considered so poor that termination of pregnancy is a realistic alternative.

[Transurethral microwave-thermotherapy in the treatment of benign prostatic hyperplasia]. / Transurethrale microgolf-thermotherapie bij de behandeling van benigne prostaathyperplasie.

OBJECTIVE: Determining the therapeutic efficacy of transurethral microwave thermotherapy (TUMT) in benign prostatic hyperplasia (BPH). DESIGN: Prospective. SETTING: Department of Urology, University Hospital Nijmegen, the Netherlands. METHOD: In the outpatient clinic, 130 BPH patients (mean age: 65.9 years (SD: 6.9); mean prostatic volume 50.2 cm3 (SD: 18.4)) received TUMT in a single session lasting 60 min. The prostate was heated to above 45 degrees C by a microwave antenna in a urethral catheter, resulting in tissue necrosis. In the first year after treatment the Madsen symptom score, maximal flow, residual volume, prostatic volume and concentration of prostate-specific antigen in blood were collected. RESULTS: After 1 year 98 patients could be evaluated; of the other 32, 16 withdrew from follow-up, 10 underwent transurethral prostate resection and 6, other treatment. The maximal flow increased by 1.2 ml/s (SD: 4.0). The residual volume decreased by 15.8 ml (SD: 55.6). Symptom scores improved by 5.9 points (SD: 5.0). A 50% increase in symptom score was seen in 49.5% of all patients; 24.3% showed no improvement of complaints. There was no change in prostatic volume, whereas PSA concentration showed a transient increase in the first week after TUMT. Preliminary results after 6 months' follow-up of a randomised placebo-controlled study in 50 patients showed subjective and objective improvement of miction. CONCLUSION: TUMT results in distinct subjective improvement. Urodynamic findings show a less pronounced improvement.

Transurethral microwave thermotherapy (TUMT) in benign prostatic hyperplasia: placebo versus TUMT.

OBJECTIVES: A prospective, randomized placebo-controlled study was designed to exclude a placebo response in transurethral microwave thermotherapy (TUMT). METHODS: During a sham procedure, the microwave applicator was installed in the urethra as in the real TUMT treatment and a complete procedure was simulated by the microwave delivery system (Prostatron). Any patient who entered this study had the option to request a second real TUMT treatment if, 3 months after the initial procedure, his condition had not improved. RESULTS: A total of 48 patients were available for evaluation at 3 months and 28 at 6 months. The TUMT group had an average decrease of 7.3 points (from 13.2 to 5.9) in the Madsen symptom score, an average increase in flowrate of 3.4 mL/s (9.6 to 13.0), and an increase in voiding percentage of 9.6% (81.7 to 91.3). All improvements were statistically significant. In the sham group, the average Madsen score decreased from 12.1 to 8.2 points, the average flowrate decreased from 9.7 to 9.5 mL/s, and the voiding percentage increased from 80.8% to 84.3%. Only the change in symptom score was significant. In both groups, observations at the 3-month follow-up were similar to those after 6 and 12 months. Patients who had TUMT after sham treatment showed similar significant changes in symptom score and peak flow as observed in the original TUMT group. Patients who did not respond favorably to a first TUMT did not experience improvement after a second TUMT. CONCLUSIONS: A placebo effect, although minimal, exists. This placebo response, however, accounts for little of the observed benefit of TUMT.

The nonpalpable testis and the changing role of laparoscopy.

OBJECTIVE: To show the reliability of laparoscopic procedures in case of cryptorchidism. It also shows the growing possibilities of laparoscopic manipulations of the cryptorchid testis obviating in a great percentage the need for open operative procedures. METHODS: Starting from the standard diagnostic laparoscopic procedure we gradually extended its use to a full operative procedure. The standard procedure is extensively elucidated in the way we used it in sixty-one laparoscopic procedures for seventy-four non-palpable testes. RESULTS: All laparoscopies were technically successful. Forty testes (60.3%) were found intra-abdominally. Four testes (5.5%) were found lying in the inguinal canal or in an ectopic position. Twenty-five testes were absent. The diagnosis of a vanishing testis could be established in most of these cases. In the beginning period the following open procedures were done after the diagnostic laparoscopy: sixteen open explorations, ten formal standard orchidopexies; nine orchiectomies, nine autotransplantations, and three Fowler-Stephens procedures. In recent years we proceeded with laparoscopic manipulation, performing eleven laparoscopically assisted orchidopexy procedures (LAOPs), six extended laparoscopic explorations, and two laparoscopic orchiectomies. CONCLUSIONS: Laparoscopy is not only a safe and reliable method in diagnosing the presence of a nonpalpable testis, but also thanks to more sophisticated instruments allows us more and more to perform the complete treatment. It can facilitate the placement of surgical incisions or obviate the need for further open intervention if no spermatic vessels are visualized in the abdomen.

Laser ablation of the prostate: experience with an ultrasound guided technique and a procedure under direct vision.

Twenty-four patients with benign prostatic hyperplasia were treated with the Nd:YAG laser. We review our experience with two different techniques: the ultrasound-guided transurethral laser-induced prostatectomy (TULIP) and the visual laser ablation of the prostate (VLAP). Our experience with these two different laser systems shows that the treatment is relatively simple, speedy and performed with virtually no blood loss. The results, of both the TULIP and VLAP procedures, are excellent. The symptom scores decrease from 43 to 19 (TULIP) and 48 to 9 (VLAP). Furthermore, there is a marked increase in average uroflow from 7.9 to 18.6 ml/s (TULIP) and from 8.1 to 18.0 ml/s (VLAP). The patients with the TULIP procedure, however had more pronounced posttreatment complaints. These patients more often received antibiotics. Laser therapy of the prostate, although still in its infancy, gives excellent results and has substantial advantages over conventional transurethral resection of the prostate (TURP). Laser therapy may replace TURP within several years.

[Diagnostic laparoscopy in non-palpable testis]. / Diagnostische laparoscopie bij een niet-palpabele testis.

In this article we present our experience with diagnostic laparoscopies in 45 patients with a total of 48 impalpable testes. Laparoscopy was performed before surgical exploration, in the same operative set-up. No complications were seen. One laparoscopy was a technical failure. In six children and one adult no testis, no deferent duct or spermatic vessels were found. The diagnosis of testicular absence was made. In 14 children no testis was found. In 13 cases atrophic spermatic vessels were seen, in one case histologically proven testicular tissue was found. In one case a blind-ending deferent duct was seen. In 27 patients an intra-abdominal testis was found, mostly 2-3 cm before the internal annulus. We performed an orchidectomy 10 times, an orchidopexy 3 times and an autotransplantation of the testis 9 times. Laparoscopy proved to be an easy, safe and reliable method to localise an impalpable testis. It is the method of choice in our clinic.

Clinical results with microwave thermotherapy of benign prostatic hyperplasia.

Since October 1990, 414 patients with micturition complaints due to benign prostatic hyperplasia were treated with transurethral microwave thermotherapy (TUMT). In this study 130 patients are presented who were treated according to a strict protocol. The technique of treatment as well as the inclusion and exclusion criteria for TUMT treatment are discussed. With a follow-up period of 1 year after TUMT, a clear subjective improvement was seen in 63% of the patients. Objective improvement, however, is less pronounced. The main complication of TUMT is a urinary retention, which can be treated with a transurethral catheter. This catheter can be removed in most patients after 1 week.