Patient-reported outcomes before treatment for localized prostate cancer: are there differences among countries? Data from the True North Global Registry.

INTRODUCTION: Similar Patient-Reported Outcomes (PROs) at diagnosis for localized prostate cancer among countries may indicate that different treatments are recommended to the same profile of patients, regardless the context characteristics (health systems, medical schools, culture, preferences…). The aim of this study was to assess such comparison. METHODS: We analyzed the EPIC-26 results before the primary treatment of men diagnosed of localized prostate cancer from January 2017 onwards (revised data available up to September 2019), from a multicenter prospective international cohort including seven regions: Australia/New Zealand, Canada, Central Europe (Austria / Czech Republic / Germany), United Kingdom, Italy, Spain, and the United States. The EPIC-26 domain scores and pattern of three selected items were compared across regions (with Central Europe as reference). All comparisons were made stratifying by treatment: radical prostatectomy, external radiotherapy, brachytherapy, and active surveillance. RESULTS: The sample included a total of 13,483 men with clinically localized or locally advanced prostate cancer. PROs showed different domain patterns before treatment across countries. The sexual domain was the most impaired, and the one with the highest dispersion within countries and with the greatest medians' differences across countries. The urinary incontinence domain, together with the bowel and hormonal domains, presented the highest scores (better outcomes) for all treatment groups, and homogeneity across regions. CONCLUSIONS: Patients with localized or locally advanced prostate cancer undergoing radical prostatectomy, EBRT, brachytherapy, or active surveillance presented mainly negligible or small differences in the EPIC-26 domains before treatment across countries. The results on urinary incontinence or bowel domains, in which almost all patients presented the best possible score, may downplay the baseline data role for evaluating treatments' effects. However, the heterogeneity within countries and the magnitude of the differences found across countries in other domains, especially sexual, support the need of implementing the PRO measurement from diagnosis.

The role of Mediterranean diet on the risk of pancreatic cancer.

BACKGROUND: The Mediterranean diet has been shown to have a beneficial role on various neoplasms, but data are scanty on pancreatic cancer. METHODS: We analysed data from two case-control studies conducted in Italy between 1983 and 2008, including 362 and 326 pancreatic cancer cases and 1552 and 652 hospital-controls, respectively. A Mediterranean Diet Score (MDS) summarising major characteristics of the Mediterranean diet was used in the two studies separately and overall. Two further scores of adherence to the Mediterranean diet were applied in the second study only, the Mediterranean Dietary Pattern Adherence Index (MDP) and the Mediterranean Adequacy Index (MAI). RESULTS: Odds ratios (ORs) for increasing levels of the scores (i.e., increasing adherence) were estimated using multiple logistic regression models. Odds ratio for a MDS score ≥6 compared with <3 was 0.57 (95% confidence interval (CI) 0.34-0.95) in the first study, 0.51 (95% CI 0.29-0.92) in the second study, and 0.48 (95% CI 0.35-0.67) overall. A trend of decreasing risk was observed also for the MDP and MAI the ORs for the highest vs the lowest quintile being 0.44 (95% CI 0.27-0.73) for MDP and 0.68 (95% CI 0.42-1.11) for the MAI. The results were consistent across strata of age, sex, education, body mass index, alcohol drinking, tobacco smoking, and diabetes. CONCLUSION: Our study provides evidence that a priori-defined scores measuring adherence to the Mediterranean diet are favourably associated with pancreatic cancer risk.

Management of incidental durotomies in an integrated Orthopaedic and Neurosurgical Spinal Unit.

Introduction: Incidental durotomy (ID) is an intraoperative event associated to prolonged bed rest and hospital stay, antibiotic use, higher patient dissatisfaction, and leg pain among other complications of its postoperative course. Several repair techniques and postsurgical care have been proposed for its management. This study was designed to develop an agreed protocol in cases of ID among Orthopaedic Surgeons (OS) and Neurosurgeons (NS) integrated into a Spinal Surgery Unit. Research question: Incidental durotomies management protocol. Materials and methods: From 997 eligible cases operated in Hospital del Mar (Barcelona, Spain) from April 2018 to March 2022, demographic, clinical, surgical and postoperative data was collected for statistical analysis from the morbidity and mortality database, with 79 identified IDs. Redo procedures were significantly associated to OS, and cervical and anterior/lateral approaches to NS, both groups were not comparable. Results: ID occurred in 7.9% of cases, more frequently after the lockdown (p=0.03), in females (p=0.04), during posterior approaches (p=0.003), and less frequently in the cervical spine (p=0.009). IDs were linked to postoperative infections (p< 0.001) and nerve root damage (p< 0.001). Patients without ID evolved more satisfactorily during the postoperative period (p=0.002), and those with CSF leak (20/79) spent on bed rest more than twice the time as those without (p<0.001). Multivariable logistic regression showed strong association between posterior approaches and ID, between complicated postoperative courses and ID. Discussion and conclusions: ID is linked to an adverse postoperative recovery, and it should be primarily repaired under microscope, with early mobilization of patients after surgery.

Evaluation of the presence of the bap gene in Staphylococcus aureus isolates recovered from human and animals species.

The implication of biofilm in chronic bacterial infection in many species has triggered an increasing interest in the characterization of genes involved in biofilm formation. The bap gene is a newly identified gene that encodes the biofilm-associated protein, BAP, which is involved in biofilm formation in Staphylococcus aureus. So far the bap gene has only been found in a small proportion of S. aureus strains from bovine mastitis in Spain. In order to study the presence of the bap gene in S. aureus isolates obtained from other species and various locations, a collection of 262 isolates was tested by PCR, using published primers and dot-blot. The results indicated that none of the isolates carried the bap gene suggesting that the prevalence of this gene among S. aureus isolates should be very low.

[Induced mild hypothermia to limit neurological damage after resuscitation]. / Koeling ter beperking van neurologische schade na resuscitatie.

Despite improvements in resuscitation techniques, the prognosis for patients who experience cardiac arrest outside of a hospital remains relatively poor. This is mainly due to brain damage that occurs as a result of global cerebral ischaemia. In 2002, two prospective randomised multicentre studies demonstrated that induced mild hypothermia can increase the chance of good neurologic recovery after out-of-hospital cardiac arrest by at least 40%. For this reason, induced mild hypothermia (32-34 degrees C) was included in the resuscitation guidelines developed by the International Liaison Committee on Resuscitation. Mild hypothermia is relatively easy to apply and has few complications. Compared with normothermia, induced mild hypothermia increases the chance of good neurological recovery by 1.7-fold. A safe and effective method to induce mild hypothermia is the infusion of cold fluids during sedation and mechanical ventilation. Cardiac function, renal function and electrolytes must be monitored closely during induced mild hypothermia. Given the potentially deleterious effects of rapid rewarming, a maximal rewarming rate of 0.5 degrees C per hour is recommended.

[Pyelonephritis during pregnancy: a threat to mother and child]. / Pyelonefritis in de zwangerschap: een bedreiging voor moeder en kind.

Two pregnant women, aged 19 and 40 respectively, were diagnosed with pyelonephritis. The first patient was initially treated with amoxicillin; appropriate antibiotic treatment--consisting of amoxicillin and clavulanic acid--was delayed for 24 hours. The second patient immediately received appropriate treatment (ceftriaxone). The first patient eventually had a nephrostomy and died due to urosepsis with multiple organ failure. The second patient delivered a healthy son and recovered. Approximately 20% of the cases of pyelonephritis during pregnancy progress to urosepsis. Therefore, pregnant women with pyelonephritis should be treated immediately with an intravenous second- or third-generation cephalosporin or the combination ofamoxicillin and clavulanic acid. Treatment of pregnant patients with urosepsis should take place in an intensive care unit and include treatment of the underlying infection as well as support of vital functions. Nephrostomy in a pregnant patient with symptomatic hydronephrosis should only be performed when the symptoms persist despite adequate antibiotic treatment.

[Fatal autointoxication with metformin]. / Een fatale auto-intoxicatie met metformine.

A 39-year-old woman with type-2 diabetes mellitus presented with metabolic acidosis due to an attempted suicide with metformin. Despite treatment with activated charcoal and laxation, she experienced cardiac arrest, which required resuscitation. After transfer to another hospital, she was treated with high-volume continuous venovenous haemofiltration. However, she died due to multiple organ failure. Metformin is the most widely used oral antidiabetic agent in the world and the first-choice treatment for patients with type-2 diabetes mellitus. Metformin overdose can cause lactic acidosis, which usually manifests as abdominal pain, vomiting and diarrhoea. Although rare, metformin-associated lactic acidosis carries a high mortality risk. The treatment of choice is immediate haemodialysis and orally administered activated charcoal. If a patient treated with metformin presents with metabolic acidosis, lactic acidosis due to metformin overdose should be suspected and appropriate treatment should be initiated immediately.

Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based?

OBJECTIVES: Critical illness increases the tendency to both coagulation and bleeding, complicating anticoagulation for continuous renal replacement therapy (CRRT). We analyzed strategies for anticoagulation in CRRT concerning implementation, efficacy and safety to provide evidence-based recommendations for clinical practice. METHODS: We carried out a systematic review of the literature published before June 2005. Studies were rated at five levels to create recommendation grades from A to E, A being the highest. Grades are labeled with minus if the study design was limited by size or comparability of groups. Data extracted were those on implementation, efficacy (circuit survival), safety (bleeding) and monitoring of anticoagulation. RESULTS: Due to the quality of the studies recommendation grades are low. If bleeding risk is not increased, unfractionated heparin (activated partial thromboplastin time, APTT, 1-1.4 times normal) or low molecular weight heparin (anti-Xa 0.25-0.35 IU/l) are recommended (grade E). If facilities are adequate, regional anticoagulation with citrate may be preferred (grade C). If bleeding risk is increased, anticoagulation with citrate is recommended (grade D(-)). CRRT without anticoagulation can be considered when coagulopathy is present (grade D(-)). If clotting tendency is increased predilution or the addition of prostaglandins to heparin may be helpful (grade C(-)). CONCLUSION: Anticoagulation for CRRT must be tailored to patient characteristics and local facilities. The implementation of regional anticoagulation with citrate is worthwhile to reduce bleeding risk. Future trials should be randomized and should have sufficient power and well defined endpoints to compensate for the complexity of critical illness-related pro- and anticoagulant forces. An international consensus to define clinical endpoints is advocated.

[The guideline 'Treatment of acute carbon-monoxide poisoning' from doctors in clinics with a tank for hyperbaric ventilation]. / Richtlijn 'behandeling koolmonoxide-intoxicatie' van artsen uit klinieken met een hyperpressietank.

The guideline 'Treatment of acute carbon-monoxide poisoning' from doctors in clinics with a tank for hyperbaric ventilation Carbon-monoxide (CO) poisoning is a potentially life-threatening emergency. Its prognosis is determined by prompt recognition and treatment. CO is toxic because it binds to haemoglobin (Hb), thus impairing oxygen transport and causing tissue hypoxia. The most important symptoms are headache and altered consciousness, ranging from somnolence to coma. The diagnosis is based on a history ofCO exposure combined with an elevated carboxyhaemoglobin (HbCO) level in the blood. On the basis of the available literature, it is recommended that patients with a HbCO level > or = 10% should always be treated. In patients requiring artificial ventilation, 100% oxygen for 8 hours is recommended. In pregnant women and in patients who are or have been comatose, hyperbaric oxygen can be considered. In all other symptomatic patients, use of a non-rebreathing mask with 100% oxygen for 8 hours is recommended.

Recurrence after a surgically induced remission.

In December 1976, an 18-year-old woman had symptoms typical of Cushing's syndrome. Laboratory evaluations and roentgenograms documented pituitary-dependent Cushing's disease in a patient with a pituitary microadenoma. In May 1977, she underwent transsphenoidal pituitary exploration. A 2-mm pituitary microadenoma was removed. The patient improved, and laboratory evaluation documented remission of the disease. In June 1978, she again complained of symptoms compatible with Cushing's disease. Laboratory evaluation confirmed a pituitary-dependent hypercortisonism. This case report marks the first recurrence of Cushing's disease in a patient previously cured by transsphenoidal resection of a pituitary tumor.

Diabetes mellitus and neuropathy following Vacor ingestion in man.

Two patients ingested Vacor, a rodenticide containing the active ingredient N-3 pyridylmethyl-N'-p-nitrophenyl urea. Both patients developed ketosis-prone diabetes mellitus and severe autonomic neuropathy. Niacinamide therapy given nine hours after Vacor ingestion in one patient and 14 hours after ingestion in the other was not successful in preventing these sequelae. Physicians need to be aware of the toxicity of Vacor, and the potential therapeutic benefit of early niacinamide therapy.

Ketoconazole-induced increase in estradiol-testosterone ratio. Probable explanation for gynecomastia.

Ketoconazole, an antifungal drug, causes gynecomastia in some patients. It also inhibits androgen and glucocorticoid synthesis. In four volunteer male subjects, 600-mg doses of ketoconazole depressed serum testosterone concentrations markedly, but serum estradiol to a much lesser degree. The bound and free percentages of both hormones were not significantly altered. The net result was a significant elevation of the estradiol-testosterone ratio, expressed as either total circulating hormone or free hormone. In five male patients receiving long-term high-dose ketoconazole therapy, the testosterone concentrations fell, but the effect on estradiol was variable. In these patients the estradiol-testosterone ratio was persistently increased. Since gynecomastia appears to be the result of an elevated estradiol-testosterone ratio, the selective hormonal effect demonstrated may explain the side effect of gynecomastia after ketoconazole therapy.

High-dose ketoconazole therapy and adrenal and testicular function in humans.

Ketoconazole, an oral antifungal, when given in conventional doses, transiently blocks testosterone synthesis and adrenal response to corticotropin. Higher therapeutic doses (ie, 800 to 1,200 mg/day), even once daily, caused more prolonged blockade. In some men, the serum testosterone concentrations were always subnormal. Bound and free testosterone values were equally diminished. Oligospermia and azospermia after prolonged therapy were noted. Impotence and decreased libido were found. Gynecomastia appeared more common than with lower doses. Depressed response to corticotropin was pronounced. Urine cortisol excretion was depressed. The blockade appeared related to the serum ketoconazole concentration. Instances of normal hormone levels or responsiveness were associated with low ketoconazole concentrations. The hormonal effects were generally unrelated to duration of therapy, although there may have been partial reversal with continued therapy. These effects appeared reversible with discontinuation of therapy. Patients receiving ketoconazole should be considered potentially unable to mount an adrenal stress response and may require testosterone supplementation.

Ketoconazole blocks testosterone synthesis.

Ketoconazole, a new oral drug used to treat systemic and superficial mycoses, inhibits sterol synthesis in fungi. The development of gynecomastia in two patients prompted us to investigate the effect of the drug on testosterone production. After a 200-, 400-, or 600-mg dose, volunteer male testosterone serum concentrations fell markedly, but returned toward baseline eight to 24 hours later as ketoconazole serum concentrations waned. A marked but transient drop in testosterone levels occurred in patients receiving long-term therapy, and continuous testosterone depression was noted in one. A block of synthesis was demonstrated in vitro. Ketoconazole at concentrations achievable in serum with currently used doses blocked basal and gonadotropin-stimulated testosterone production by rat Leydig cells. The diminution of testosterone synthesis could be significant as further therapeutic trials may use larger doses or more than once-daily administration. The paucity of reports of endocrinologic toxicity may relate to the "escape" from the block demonstrated in vivo.

[Masquelet technique for the treatment of large dia- and metaphyseal bone defects]. / Die Masquelet-Technik zur Behandlung großer dia- und metaphysärer Knochendefekte.

OBJECTIVE: Treatment of large dia- and metaphyseal bone defects (> 3 cm) with two surgical interventions with an interval of 4-8 weeks. INDICATIONS: Dia- and metaphyseal bone defects predominantly of the lower extremity. CONTRAINDICATIONS: Intraarticular bone defects, persisting bone infection or osteomyelitis, insufficient soft tissue coverage in the region of the bone defect, osteoporosis. SURGICAL TECHNIQUE: First surgical intervention: thorough bone debridement and soft tissue coverage, implantation of a cement spacer into the bone defect for the induction of a synovial foreign-body membrane, internal or external fixation. Second surgical intervention: removal of the cement spacer and filling of the bone defect with autologous cancellous bone graft, optionally internal fixation after initial external fixation. POSTOPERATIVE MANAGEMENT: Partial to full weight-bearing after the first surgical intervention depending on pain. Partial weight-bearing (max. 15 kg) after the second surgical intervention, until radiological signs of a remodeling of the regenerate bone occur. Usually no implant removal. RESULTS: A total of 6 patients (4 men, 2 women) aged 15-66 years with average bone defects of 7 cm (range 4-10 cm) were treated using the Masquelet technique. There were 2 aseptic femoral nonunions and 4 tibial nonunions (2 septic and 2 aseptic nonunions). One case was a periprosthetic tibial bone defect. Bone stabilization after debridement was performed using ring fixators on the tibia and an intramedullary nail and a locking plate on the femur, respectively. The second surgical intervention was performed after 6-9 weeks. In 3 of the 4 tibial cases, internal fixation was performed during this intervention. The iliac crest and the RIA (reamer-irrigator-aspirator) technique were used for cancellous bone grafting. Amputation after breakage of the plate was necessary in the patient with the periprosthetic bone defect. Nonunion at the docking site required cancellous bone grafting in 1 patient. All 5 patients were able to perform full weight-bearing without pain after 6 months. The Ilizarov fixator was removed 5 months after the second surgical intervention in a 15-year-old patient. None of the other implants were removed.

Acromegaly and Zollinger-Ellison syndrome secondary to an islet cell tumor: characterization and quantification of plasma and tumor human growth hormone-releasing factor.

A young woman with acromegaly and Zollinger-Ellison syndrome associated with a GH-releasing factor (GRF)- and gastrin-secreting metastatic islet cell carcinoma was studied by means of specific antisera which recognize various regions of the GRF molecule. Using specific immunohistochemical techniques, the tumor cells were shown to contain GRF, gastrin, and gastrin-releasing peptide, but not GH. During a 4-h period, plasma GRF levels averaged 5.6 +/- 1.4 ng/ml (+/- SD), while GH levels averaged 148 +/- 71 ng/ml. GH secretion was pulsatile and increased after TRH administration. GRF RIAs may be useful in establishing the diagnosis of acromegaly secondary to the ectopic secretion of GRF.

Recombinant nematode anticoagulant protein c2, an inhibitor of tissue factor/factor VIIa, attenuates coagulation and the interleukin-10 response in human endotoxemia.

The tissue factor-factor (F)VIIa complex (TF/FVIIa) is responsible for the initiation of blood coagulation under both physiological and pathological conditions. Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent inhibitor of TF/FVIIa, mechanistically distinct from tissue factor pathway inhibitor. The first aim of this study was to elucidate the pharmacokinetics and pharmacodynamics of a single intravenous (i.v.) dose of rNAPc2. The second aim was to study its effect on endotoxin-induced coagulation and inflammation. Initially, rNAPc2 was administered to healthy volunteers in three different doses. There were no safety concerns and the pharmacokinetics were consistent with previous studies, in which rNAPc2 was administered subcutaneously. rNAPc2 elicited a dose-dependent reduction of the endogenous thrombin potential and a selective prolongation of prothrombin time. Subsequently, the effect on endotoxin-induced coagulation and inflammation was studied. The administration of rNAPc2 completely blocked the endotoxin-induced thrombin generation, as measured by plasma prothrombin fragment F1+2. The endotoxin-induced effect on fibrinolytic parameters such as plasmin-antiplasmin complexes and plasminogen activator inhibitor type 1 was not affected by rNAPc2. The administration of rNAPc2 attenuated the endotoxin-induced rise in interleukin (IL)-10, without affecting the rise in other cytokines. In conclusion, rNAPc2 is a potent inhibitor of TF/FVIIa, which was well tolerated and could safely be used intravenously in this Phase I study in healthy male volunteers. A single i.v. dose rNAPc2 completely blocked endotoxin-induced thrombin generation without affecting the fibrinolytic response. In addition, rNAPc2 attenuated the endotoxin-induced rise in IL-10, without affecting the rises in other cytokines.

Inhibition of cholesterol synthesis by ketoconazole.

To determine if ketoconazole influences cholesterol metabolism in humans, plasma lipid levels were studied in seven men with advanced prostate cancer who were being treated with high-dose ketoconazole. Additionally, the effects of ketoconazole on cholesterol synthesis in cultured normal human fibroblasts were studied. High-dose ketoconazole therapy caused a 27 percent reduction in total serum cholesterol values without affecting serum triglyceride levels. The reduction in serum cholesterol levels was maintained for five months in six of seven patients. The fall in total cholesterol levels was due to a 38 percent reduction in low-density lipoprotein cholesterol levels without associated changes in high-density lipoprotein cholesterol levels. Serum lanosterol levels increased 46 percent during ketoconazole treatment. Studies in cultured normal human fibroblasts showed that ketoconazole inhibited cholesterol synthesis by blocking the conversion of lanosterol to cholesterol. These results establish that ketoconazole is a potent inhibitor of cholesterol production in vivo and in vitro.

Metastatic islet cell tumor in von Hippel-Lindau disease.

A 56-year-old woman with many unusual manifestations of von Hippel-Lindau syndrome is described. In addition to retinal hemangioblastomas, pheochromocytoma, renal cell carcinoma, and multiple organ cysts, she had a cerebellar astrocytoma, pancreatic exocrine insufficiency, diabetes mellitus, thyrotoxicosis, and a metastatic calcitonin-secreting islet cell carcinoma. This case report documents the first example of a metastatic islet cell tumor in a patient with von Hippel-Lindau disease. The possible relationship between this disorder, the other neurocutaneous syndromes, and the multiple endocrine neoplasia syndromes is discussed.