Safety of hormone replacement therapy in women with a history of cervical adenocarcinoma.

OBJECTIVES: Studies investigating the safety of hormone replacement therapy in cervical cancer have predominantly included patients with squamous disease. Pathological studies have identified estrogen receptor positivity in cervical adenocarcinomas. A recent small case-control study suggested a trend towards reduced survival with hormone replacement therapy in cervical adenocarcinomas. Our objective was to determine if hormone replacement therapy use in patients treated for cervical adenocarcinomas is detrimental to survival. STUDY DESIGN: A retrospective review of all women under the age of 50 with stage 1B-2B cervical adenocarcinomas diagnosed between 1 November 2000 and 24 September 2019. Women were categorised into three groups: ovaries conserved (OVCON); or iatrogenic menopause with (IM-HRT) or without (IM-NOHRT) hormone replacement therapy. Hormone replacement therapy use was defined on an intention to treat basis. Statistical analysis was performed using Kaplan-Meier and Cox proportional hazards methods. MAIN OUTCOME MEASURES: Overall (OS), disease specific (DSS) and progression free (PFS) survival. RESULTS: A total of 58 women (mean age 38.5 ± 6.6) were included in the study of whom 25 (43.1%) had OVCON, 20 (34.4%) had IM-HRT and 13 (22.4%) had IM-NOHRT. No menopause-associated deaths occurred. Although five-year DSS was 73% in IM-NOHRT compared to 95% in IM-HRT and 95% in OVCON, these differences were not statistically significant. Five-year PFS was 68% in IM-NOHRT compared to 90% in IM-HRT and 81% in OVCON but again, these differences were not statistically significant. CONCLUSION: In this small study, hormone replacement therapy does not appear to be detrimental to survival in cervical adenocarcinomas. There is a trend towards improved survival with hormone replacement therapy. Larger studies are required to substantiate these findings.

Folic acid supplementation in postmenopausal women with hot flushes: phase III randomised double-blind placebo-controlled trial.

OBJECTIVE: To assess whether folic acid supplementation ameliorates hot flushes. DESIGN: Double-blind, placebo-controlled randomised trial. SETTING: Nine hospitals in England. POPULATION: Postmenopausal women experiencing ≥50 hot flushes weekly. METHODS: Women (n = 164) were randomly assigned in a 1:1 ratio to receive folic acid 5 mg tablet or placebo daily for 12 weeks. Participants recorded frequency and severity of hot flushes in a Sloan Diary daily and completed Greene Climacteric and Utian Quality of Life (UQoL) Scales at 4-week intervals. MAIN OUTCOME MEASURES: The change in daily Hot Flush Score at week 12 from randomisation based on Sloan Diary Composite Score B calculation. RESULTS: Data of 143 (87%) women were available for the primary outcome. The mean change (SD) in Hot Flush Score at week 12 was -6.98 (10.30) and -4.57 (9.46) for folic acid and placebo group, respectively. The difference between groups in the mean change was -2.41 (95% CI -5.68 to 0.87) (P = 0.149) and in the adjusted mean change -2.61 (95% CI -5.72 to 0.49) (P = 0.098). Analysis of secondary outcomes indicated an increased benefit in the folic acid group regarding changes in total and emotional UQoL scores at week 8 when compared with placebo. The difference in the mean change from baseline was 5.22 (95% CI 1.16-9.28) and 1.88 (95% CI 0.23-3.52) for total and emotional score, respectively. CONCLUSIONS: The study was not able to demonstrate that folic acid had a statistically significant greater benefit in reducing Hot Flush Score over 12 weeks in postmenopausal women when compared with placebo. TWEETABLE ABSTRACT: Folic acid may ameliorate hot flushes in postmenopausal women but confirmation is required from a larger study.

A randomised, placebo-controlled trial of weekly paclitaxel and saracatinib (AZD0530) in platinum-resistant ovarian, fallopian tube or primary peritoneal cancer†.

BACKGROUND: We investigated whether the Src inhibitor saracatinib (AZD0530) improved efficacy of weekly paclitaxel in platinum-resistant ovarian cancer. PATIENTS AND METHODS: Patients with platinum-resistant ovarian, fallopian tube or primary peritoneal cancer were randomised 2 : 1 to receive 8-week cycles of weekly paclitaxel (wPxl; 80 mg/m(2)/week ×6 with 2-week break) plus saracatinib (S; 175 mg o.d.) or placebo (P) continuously, starting 1 week before wPxl, until disease progression. Patients were stratified by taxane-free interval (<6 versus ≥6 months/no prior taxane). The primary end point was progression-free survival (PFS) rate at 6 months. Secondary end points included overall survival (OS) and response rate (RR). RESULTS: A total of 107 patients, median age 63 years, were randomised. Forty-three (40%) had received >2 lines of prior chemotherapy. The 6-month PFS rate was 29% (wPxl + S) versus 34% (wPxl + P) (P = 0.582). Median PFS was 4.7 versus 5.3 months (hazard ratio 1.00, 95% confidence interval 0.65-1.54; P = 0.99). RR (complete + partial) was 29% (wPxl + S) versus 43% (wPxl + P), P value = 0.158. Grade 3/4 adverse events were 36% versus 31% (P = 0.624); the most frequent G3/4 toxicities were vomiting (5.8% saracatinib versus 8.6% placebo), abdominal pain (5.8% versus 0%) and diarrhoea (4.3% versus 5.7%). Febrile neutropenia was more common in the saracatinib arm (4.3%) than placebo (0%). Response, PFS and OS were all significantly (P < 0.05) better in patients with taxane interval ≥6 months/no prior taxane (n = 85) than those <6 months (n = 22), regardless of randomisation. CONCLUSIONS: Saracatinib does not improve activity of weekly paclitaxel in platinum-resistant ovarian cancer. Taxane-free interval of ≥6 months/no prior taxane was associated with better outcome in both groups. TRIALS REGISTRATION: Clinicaltrials.gov NCT01196741; ISRCTN 32163062.

Nonalcoholic Fatty liver disease in renal transplant recipients proven by transient elastography.

BACKGROUND: The increasing recognition of the importance of nonalcoholic fatty liver disease (NAFLD) and its strong association with the metabolic syndrome has stimulated interest in the putative role of NAFLD in the development and progression of cardiovascular disease. Furthermore, recent studies investigated the association of NAFLD and chronic kidney disease. We analyzed the incidence of NAFLD diagnosed by transient elastography (TE) in renal transplant recipients (RTRs). We also assessed whether TE-defined NAFLD is associated with decreased graft function in RTRs. METHODS: Our study included 73 RTRs with a functioning graft for more than 1 year. Liver stiffness was used to assess liver fibrosis and the controlled attenuation parameter (CAP) was used to detect and quantify liver steatosis by using TE (Fibroscan, Echosense, Paris, France). Therefore, with CAP being implemented on TE, both steatosis and fibrosis could be evaluated simultaneously. According to this evaluation, NAFLD was defined by the presence of steatosis with CAP values ≥ 238 dB.m(-1) regardless of presence or absence of any stage of fibrosis. RESULTS: According to the TE findings, NAFLD was present in 57.5% of RTRs. We have found that the severity of liver steatosis was positively correlated with serum creatinine levels (r = 0.664; P < .0001) and negatively correlated with estimated glomerular filtration rate (eGFR; r = -0.692; P < .0001) levels. The severity of liver fibrosis was positively correlated with the serum creatinine, serum iron, and C-reactive protein levels indicating a more severe form of NAFLD in those patients. None of the investigated liver tests showed any differences between those RTR patients who had NAFLD compared to those without NAFLD. CONCLUSION: Our results showed that RTRs have high prevalence of TE-defined NAFLD which possibly contributes to graft dysfunction. Measuring aminotransferase levels would not be a useful tool for NAFLD detection in RTRs. Our study showed the value of TE as an effective, noninvasive screening method for the diagnosis of NAFLD in RTRs.

Non-alcoholic fatty liver disease; a part of the metabolic syndrome in the renal transplant recipient and possible cause of an allograft dysfunction.

Despite all improvements in transplant medicine, renal transplant recipients have a high risk for cardiovascular mortality. A high prevalence of cardiovascular complications in renal transplant recipients (RTR) is explained by cardiovascular risk factors present before transplantation, in addition to the development of new risk factors as well as worsening of preexisting risk factors after transplantation. A majority ot these patients develop metabolic syndrome within a year after the transplantation. The metabolic syndrome (MS) is associated with impaired renal allograft function and increased insulin resistance. Non alcoholic fatty liver disease (NAFLD) represents a liver manifestation of metabolic syndrome and it development is strongly associated with all components of MS in general population. The current importance of NAFLD and its link to the MS has encouraged an interest in its possible role in the development of atherosclerosis in recent years. Considering the fact that all components of MS are more common among renal transplant recipients compared to general population, it would be expected that RTR may have a much higher incidence of NAFLD compared to general population. We propose that the presence of NAFLD in RTR could be a strong predictor in cardiovascular morbidity and mortality. Also, according to the recent investigations about the possible link between NAFLD and chronic kidney disease, we hypothesis that NAFLD may be associated with deteriorating graft function, causing a chronic allograft nephropathy and graft loss. Common factors underlying the pathogenesis of NAFLD and chronic allograft dysfunction may be insulin resistance, oxidative stress, activation of rennin-angiotensin system, and inappropriate secretion of inflammatory cytokines by steatotic and inflamed liver.

A phase II trial evaluating two schedules of sagopilone (ZK-EPO), a novel epothilone, in patients with platinum-resistant ovarian cancer.

BACKGROUND: Sagopilone, the first fully synthetic epothilone, has shown promising preclinical activity in tumour models. This open-label randomised phase II study investigated two infusion schedules of sagopilone in women with ovarian cancer. PATIENTS AND METHODS: Women with ovarian cancer recurring within 6 months of end of last platinum-containing treatment received sagopilone 16 mg/m(2) as a 3- or 0.5-h i.v. infusion every 21 days for up to 6 weeks. RESULTS: Sixty-three patients received sagopilone as a 3-h (n=38) or 0.5-h (n=25) infusion. There were nine confirmed tumour responses [by modified RECIST (n=8) and by Gynecologic Cancer Intergroup CA-125 criteria (n=1)] in 57 patients assessable for efficacy overall [three (13%) with 0.5-h and six (18%) with 3-h infusions]. The 0.5-h arm was closed when it failed to meet its target efficacy. Main drug-related adverse events were peripheral sensory neuropathy (73%; 16% grade 3), nausea (37%; 2% grade 3), fatigue (35%; 3% grade 3) and arthralgia (30%; 5% grade 3). Overall incidence of peripheral sensory neuropathy was similar in both treatment arms, with no grade 4 neuropathy events. No acute allergic infusion reactions were observed. CONCLUSION: Sagopilone is effective, with balanced tolerability, in patients with recurrent platinum-resistant ovarian cancer.

Triple A syndrome: genotype-phenotype assessment.

The triple A or Allgrove syndrome is an autosomal-recessive disease (MIM*231550) characterized by the triad of achalasia, alacrima and adrenocorticotropic hormone (ACTH)-resistant adrenal insufficiency. Associated features of the syndrome are neurological and dermatological abnormalities. Until the discovery of the AAAS gene as the responsible gene in triple A syndrome, the diagnosis was based on characteristic clinical features. Here we present the clinical and molecular genetic data which demonstrated the marked phenotypic variability in three unrelated patients with triple A syndrome. The final diagnosis of triple A syndrome was confirmed by molecular analysis. In one patient with isolated achalasia, the diagnosis of triple A syndrome could only be made on the basis of the molecular genetic analysis of the AAAS gene. We therefore suggest that the diagnosis of triple A syndrome should be considered in patients who exhibit only one or two of the main symptoms (i.e. alacrima, achalasia or adrenal insufficiency). These patients require careful neurological investigation, and mutation analysis of the AAAS gene should be performed.

Dermatitis herpetiformis in a 30-month-old child.

Dermatitis herpetiformis is commonly observed in adults and adolescents. We report one of the youngest cases seen so far-a 30-month-old boy. After clinical investigations an asymptomatic gluten-sensitive enteropathy was diagnosed. Skin lesions resolved with gluten-free diet. Dermatitis herpetiformis should be considered in differential diagnosis of chronic dermatitis in early childhood as well. Monitoring for prevention of complications is the greatest problem at this age.

[Familial adenomatous colonic polyposis]. / Obiteljska adenomatozna polipoza crijeva.

We described two patients (brother and sister) with familial adenomatous polyposis of the colon. It is an inherited disease with autosomal dominant pattern of inheritance. The incidence is 1:8.000, with usual onset of polyps development late in the first decade of life or during adolescence, and malignant alteration up to the fourth decade of life. APC gene located on long arm of chromosome 5 is responsible for occurrence of the disease that presents with onset of multiple adenomatous polyps in the colon (from some of them to 1000). The treatment includes chemoprevention by sulindac or aspirin that prevents or reverse process of carcinogenesis. Surgical approach is preventive colectomy up to 20 (25) years of life. APC gene mutation (deletion at codon 1309-1311) was proven by DNA analysis from blood and polyp in both patients. There was no evidence of mutations of genes p53 and K-ras. Preventive colectomy is planned as soon as possible.

Alveolar rhabdomyosarcoma metastatic to the breast: long-term survivor.

The case history is described of an adolescent girl with alveolar rhabdomyosarcoma of the maxillary sinus, who was treated with radical radiotherapy and adjuvant chemotherapy. She relapsed in the breast and, after incomplete excision, received radical radiotherapy resulting in long-term survival with breast conservation. The characteristics of patients with metastatic rhabdomyosarcoma with breast involvement are discussed. In adolescent girls, the breast is postulated to be a preferential metastatic site.

[Nodular lymphoid hyperplasia of the colon and terminal ileum. Case report]. / Nodularna limfoidna hiperplazija kolona i terminalnog ileuma. (Prikaz bolesnika).

A patient admitted to our hospital because of diarrhea and hematochesia is presented. These complaints appeared eight months before, and were not accompanied by other disturbances. All hematological, biochemical and microbiological findings were normal, but endoscopic, x-ray and histologic examination of the gastrointestinal tract showed nodular lymphoid hyperplasia of the colon and terminal ileum. Since an immunological derangement was not verified, this seems to be a rare benign disorder as a response to repeated antigenic stimuli. In our patient these were recurrent parasitoses. The treatment is not needed, but due to the possibility of late onset hypogammaglobulinemia. Long-term patient follow up is required.

[Therapeutic dilemmas in children with esophageal achalasia]. / Terapijske dileme u djece s ahalazijom jednjaka.

Two patients with oesophageal achalasia are presented. The first patient, a 22-month-old girl, had medical, endoscopic and surgical treatment. The effectiveness of drug therapy with nifedipine was good but short in duration. Endoscopic bougienage dilatation has not been definitely successful. Operative treatment, two years after the first symptoms, permanently resolved the problem of spastic lower oesophageal sphincter. The second girl, 13.5 years old, responded very well to nifedipine therapy during hospitalisation. Because of inadequate drug usage, oesophageal myotomy was performed relatively soon. In follow-up both girls were in good health condition. The treatment of oesophageal achalasia in children is still controversial. Therapeutic approach and decision on the treatment strategy depend primarily on patient's age, duration and severity of clinical signs and symptoms Etiology, pathogenesis, and possibilities of achalasia treatment are discussed.

[Adenocarcinoma of the colon in a 14-year-old boy]. / Adenokarcinom debelog crijeva u 14-godisnjeg djecaka.

We report the case of a 14-year-old boy with adenocarcinoma of the colon. The diagnosis was established 3 months following the initial symptoms. The tumor was located in the region of the descending colon and was of Dukes B stage. The patient underwent left hemicoloctomy followed by chemotherapy and irradiation. In the follow-up period of two years the patient has been well. It is concluded that early diagnosis, adequate monitoring of patients by the determination of carcinoembryonic antigen and regular follow-up visits could lead to better prognosis.

[Liver cirrhosis caused by alpha-1-antitrypsin deficiency]. / Ciroza jetre uzrokovana deficitom alfa-1-antitripsina.

The authors present 2 patients with cirrhosis of the liver associated with alpha-1-antitrypsin deficiency. The patients are two children (brother and sister aged 4 and 13). The manifestation of the disease in these two children was a prolonged neonatal icterus. The symptoms of a decompensated cirrhosis of the liver appeared at the age of 2 and 4 years. There were several attacks of obstructive bronchitis etiologically associated with the same cause. The boy died at the age of four of hepatic coma preceded by several bleedings from esophageal varices. Splenectomy was performed in the girl on account of distinct signs of hyperplenism and two and a half years later mesentericocaval shunt because of the extensive bleeding from esophageal varices and the fundus of the stomach. The diagnosis of alpha-1-antitrypsin deficiency was made on the basis of low values in the serum and on the basis of liver biopsö and findings of typical PAS positive inclusions in the endoplasmic reticulum of hepatocytes. The values of A1A parents are also lower. The finding of Pi phenotypification is significant--the SZ phenotype was found in two patients (brother and sister), which is seldom described in patients with cirrhosis of the liver.