Disease-specific quality of life as part of the long-term follow-up for children born with esophageal atresia in an academic unit in South Africa-a pilot study.

As neonatal mortality rates have decreased in esophageal atresia (EA), there is a growing focus on quality of life (QoL) in these children. No study from Africa has reported on this topic. This pilot study aimed to describe disease-specific QoL in EA children and its applicability as part of long-term follow-up in an academic facility in South Africa. Disease-specific QoL in children born with EA was assessed utilizing the EA-QoL questionnaire for children aged 2-17 years during a patient-encounter. The parent-report for children aged 2-7 years compromised 17 items categorized into three domains: eating, physical health and treatment, and social isolation/stress. The 24-item EA-QL questionnaire for children aged 8-18 (child- and parent-report) explored four domains: eating, body perception, social relationships, and health and well-being. A total of 13 questionnaires for children aged 2-7 years were completed by five parents. A negative perceived impact on their child's eating was reported by 46-92% of parents, and less impact in the other two domains. A total of 27 questionnaires were completed by eight children aged 8-17 years and 10 parents. Similar percentages children and parents reported a negative impact in the eating, social relationships, and body perception domains. More than half reported a negative impact on the child's health and well-being. This study supports the concept that assessment of disease-specific QoL should play a vital role in the comprehensive follow-up approach for children born with EA. We identified that parents of younger children were more likely to report eating disorders, whereas parents of older children were more likely to report health difficulties with different perceptions when it came to the child's scar.

Outcomes of Neonates Requiring Neonatal Intensive Care Admission for Necrotizing Enterocolitis in a Resource-Restricted Hospital in Cape Town, South Africa.

AIM: The aim of this study is to describe the 30-day mortality, neurodevelopmental outcome and composite outcome (mortality or abnormal neurodevelopmental outcome) of neonates with necrotizing enterocolitis (NEC), requiring neonatal intensive care (NICU) admission, in a resource-restricted environment. METHODS: All neonates admitted to Tygerberg Hospital, NICU, with a presumptive diagnosis of NEC Bell stage IIB or more, over a 5-year period, were included. RESULTS: One hundred and thirty-five neonates were included with a mean gestational age of 29 ± 2.7 weeks and mean birth weight of 1185 g ± 446 g. The 30-day mortality was 52%, neurodevelopment abnormalities occurred in 35% of survivors and adverse composite outcome in 63%. The 30-day mortality and adverse composite outcome risk were increased by small for gestational age, shock, metabolic acidosis, inotrope requirement and first feed >9 days after surgery. CONCLUSION: In resource-restricted environments, mortality and abnormal neurodevelopmental outcome of neonates with NEC, remain high. However, outcomes are comparable with international literature. Neonates with NEC, requiring NICU admission and surgery, require neurodevelopmental follow-up.

Necrotizing enterocolitis remains one of the most common gastrointestinal emergencies in neonates. Neonates admitted to a resource-restricted neonatal intensive care unit with a presumptive diagnosis of advanced NEC were reviewed. We were able to identify risk factors associated with a higher chance of death or poor neurodevelopmental outcomes. Our outcomes are comparable with international literature.

Immune checkpoint inhibitors and renal toxicity.

Immune checkpoint inhibitors (ICIs) have transformed the management of a broad spectrum of cancers as metastatic melanoma, non-small lung cancer or renal cell carcinoma. These humanized monoclonal antibodies target immune-regulatory receptors expressed on T lymphocytes, antigen presenting cells and tumor cells and induce an immunological anti-tumor response. If on the one hand these molecules have led to considerable improvement in survival outcomes, on the other hand these therapies can be associated with immune-related adverse effects (irAEs). While these side effects have become well known, the best diagnostic and therapeutic approaches are still under investigation. The authors discuss pathophysiology, clinical presentation and histological features of ICIs renal toxicity. Furthermore, we focus on kidney transplant (KT) recipients, including the therapeutic adaptation approach to immunosuppression and the risk of rejection.

Endoscopic findings in children born with oesophageal atresia in an academic unit in South Africa.

BACKGROUND: Oesophageal atresia (OA) is one of the most common congenital gastrointestinal (GI) abnormalities. Due to advances in multidisciplinary care, early prognosis has improved with emphasis shifting to the long-term impact of this disease. Literature suggests a higher incidence of Barrett's and eosinophilic oesophagitis in these children, with an increased risk of oesophageal carcinoma. Guidelines for adults born with OA include routine endoscopy and lifelong screening of the upper gastrointestinal tract (GIT). Despite this, uncertainty remains regarding the necessity and frequency of endoscopic surveillance for children born with OA. We describe our endoscopic findings in children born with OA. METHODS: A prospective analytic cohort study was undertaken, which included all children born with OA, that were followed-up in our unit between 2020 and 2022. History regarding feeding and GI symptoms were documented after which an endoscopy was performed. RESULTS: During the study period, 37 endoscopies were performed in patients born with OA at a median age of 25 months. The most common clinical appearance on endoscopy was anastomotic strictures followed by oesophagitis. Twelve patients had biopsies taken, with abnormal histology in all but one patient. The most common histological finding was oesophagitis with lymphocytes and chronic gastritis. Two patients had Helicobacter Pylori infection, and one had findings suggestive of eosinophilic oesophagitis. CONCLUSION: All patients with a clinical indication for an endoscopy had abnormal clinical or histological findings, thus concurring with the literature in highlighting the need for regular endoscopy. We recommend regular clinical follow-up and endoscopic surveillance if clinically indicated for children born with OA.

Segmental aganglionosis (zonal aganglionosis or "skip" lesions) in Hirschsprungs disease: a report of 2 unusual cases.

INTRODUCTION: There is accumulating evidence that "skip" lesions or zonal aganglionosis do occur in HSCR disease, albeit rarely. They are of interest because it may cause confusion in interpreting surgical margins as well as understanding the pathophysiology of HSCR disease. Normally described as "a skip area" of normally ganglionated bowel, surrounded proximally and distally by aganglionosis with variations may occur. CASE REPORTS: We report two cases of infants with unusual types of "skip lesions", identified within the last 5 years. RESULTS: One patient had an area of zonal aganglionosis in the transverse colon and recto-sigmoid, bordered by areas of normally enervated bowel in the right and descending colon. In the second patient, the terminal ileum, transverse, descending and sigmoid colons and rectum were histologically aganglionic, but focal patches of ganglion cells were identified in 21 cm of the right ascending colon and the appendix, suggesting some ENS plasticity and possible incomplete apoptosis. CONCLUSION: These cases illustrate the point that the presence of ganglion cells at the resection line is not sufficient to guarantee postoperative function and "skip" lesions may uncommonly confuse the picture. In addition, they raise questions as to its pathophysiology and favor an alternate hypothesis of local changes promoting neuroblast apoptosis as the possible cause.

Outcomes for open and laparoscopic appendicectomy for complicated appendicitis in children.

BACKGROUND: The study aimed to compare the outcomes of paediatric laparoscopic appendectomy (LA) with open appendectomy (OA) for complicated appendicitis (CA). All trainees could perform OA without supervision. METHODS: This is a single-centre, retrospective, non-randomised review of children 4-12 years of age, who had either an OA or LA for CA. The data was collected from August 2012 to June 2016. Nineteen surgical trainees were initially supervised by a consultant until deemed able to perform LA safely. The on-call surgeon decided on operative approach. Intra- and postoperative complications were analysed. Primary endpoint was comparison of infection rates between groups, simultaneous differences between the two procedures performed by surgical trainees and consultants were evaluated. RESULTS: One hundred and fifty-five patients had appendicectomy for CA during the study period. Fourteen patients with incomplete information were excluded. Ninety had OAs and 51 LAs. Both groups were well matched demographically. Postoperative infective complications occurred in 13/51 (25.5%) of the LAs, and in 23/90 (25.6%) of the OA (p = 0.159). Fourteen trainees performed 27 LAs without consultant supervision by the conclusion of the study. The mean duration of LA surgery for surgical trainees was 110.35 minutes (IQR 22.5) and for consultants 93.87 minutes (IQR 35, p = 0.497). CONCLUSION: There is no difference in intra- and postoperative complications between LA and OA for CA. Duration of surgery between surgical trainees and consultants were comparable. This indicates that surgical trainees acquire LA skill over a short period of time and that LA as a laparoscopic teaching procedure merits consideration.

Oesophageal atresia without tracheo-oesophageal fistula and an anorectal malformation: advantages of a primary laparoscopically assisted anorectal pull-through.

We report on a primary laparoscopically assisted anorectal pull-through (LAARP) performed in a neonate with pure oesophageal atresia and imperforate anus with recto-bulbo-urethral fistula, representing a unique case for the LAARP approach owing to the undistended nature of the bowel and sterile meconium. Further evaluation of the applicability of LAARP in the management of infants with anorectal malformations is needed, but in this case it held major advantages for the patient. A laparoscopically assisted gastrostomy was facilitated during the same procedure, while avoidance of a colostomy and its associated complications also facilitated preservation of the left colon for subsequent use in oesophageal replacement. Long-term outcome remains to be assessed.

A comparison of laparoscopic-assisted (LAARP) and posterior sagittal (PSARP) anorectoplasty in the outcome of intermediate and high anorectal malformations.

INTRODUCTION: Laparoscopic-assisted ano-rectoplasty (LAARP) has gained popularity since its introduction in 2000. Further evidence is needed to compare its outcome with the gold standard of posterior sagittal ano-rectoplasty (PSARP). METHOD: A retrospective review of patients presenting with ano-rectal malformation (ARM) in the period 2000 - 2009. Demographics, associated abnormalities, and operative and post-operative complications were assessed. The functional outcome in children older than 3 years was assessed, applying the Krickenbeck scoring system and, where possible, by interviewing parents. Patients with cloacal abnormalities were excluded. Patients with a LAARP were compared with those managed by PSARP. RESULTS: Seventy-three patients with ARM were identified during the study period. Male to female ratio was 1.6:1. All 32 low ARMs (perineal and vestibular fistulae) were excluded. Thirty-nine had levator or supra-levator lesions. Twenty males presented with recto-bulbar, 3 with recto-prostatic, and 1 with a recto-vesical fistula; 2 had no fistula; and in 2 the data were insufficient to determine the level. Among the females, 6 had recto-vaginal fistulae, 4 had cloacas and 1 had an ARM without fistula. There were 3 syndromic ARMs (2 Trisomy 21 and 1 Baller-Gerald syndrome). One neonate with a long-gap oesophageal atresia had a successful primary LAARP. Seventy-five per cent of all patients had VACTERL associations. Two early deaths after colostomy formation were related to a cardiac anomaly and an oesophageal atresia. In both groups, mean age at anoplasty was 8 months. Twenty of the intermediate/high lesions were treated with LAARP, and 19 by PSARP. There were slightly more complications in the LAARP group; intra-operative injury to the vas deferens and urethra occurred once each. Post-operatively, 2 port-site hernias and 1 case of pelvic sepsis occurred. A poorly sited colostomy caused difficulty in 2 patients. Two patients were converted to laparatomy: severe adhesions in one and a poorly sited stoma in another. Five patients required redo-anoplasty for mucosal prolapse, anal stenosis, incorrect placement of the anus, retraction of the rectum and an ischaemic rectal stricture. Complications in the PSARP group included 2 wound dehiscences, 1 anal stenosis, 3 mucosal prolapses, 1 recurrent fistula and 2 incorrect anal placements requiring redo surgery. The Krickenbeck questionnaire was used in 70% of PSARPs (mean age 5.9 years) and LAARPs (mean age 5.5 years) for a functional assessment. Both groups showed voluntary bowel movements in 14%. Soiling and overflow incontinence was a significant problem. Grade III constipation was less common in the LAARP (14%) than PSARP (21%) group. Four patients in the LAARP group were reliant on regular rectal washouts compared, with 6 in the PSARP group. CONCLUSION: Both LAARP and PSARP can successfully treat ARM but have specific associated problems.

Long-term outcome of surgically managed necrotizing enterocolitis in a developing country.

UNLABELLED: Necrotizing enterocolitis (NEC) is a serious condition with a high morbidity and mortality commonly affecting premature babies. Data for the impact of the long-term disease burden in developing countries are limited although poor long-term outcome of surgically managed patients has been shown in terms of increased risk of neurodevelopmental delay, increased infectious disease burden and abnormal neurological outcomes in the developed world. PURPOSE: To evaluate the long-term outcome of a pre-human immunodeficiency virus pandemic NEC cohort to characterize common risk factors and outcome in a developing world setting. METHODS: A retrospective review of medical records was carried out on a cohort of 128 premature neonates with surgical NEC (1992-1995). Morbidity, mortality and long-term outcome were evaluated. RESULTS: Data for 119 of 128 sequentially managed neonates with surgically treated NEC was available. Mean gestational age was 32 weeks and average birth weight was 1,413 g. Early (30-day postoperative) survival was 69% (n = 82) overall and 71% in the <1,500 g birth weight group (n = 68; 53%). Overwhelming sepsis (n = 16) or pan-intestinal necrosis (n = 18) accounted for most of the early deaths. Late deaths (>30 days postoperatively, n = 22) resulted from short bowel syndrome (5), sepsis (9), intraventricular hemorrhage (1) and undetermined causes (7). On follow-up (mean follow-up 39 months, 30 for >2 years), long-term mortality increased to 50%. Late surgical complications included late colonic strictures (9), incisional hernias (2) and adhesive bowel obstruction (3). Fifteen patients had short bowel syndrome, of which 10 (66%) survived. Of the long-term survivors, 8 (20%) had severe neurological deficits and 20 (49%) had significant neurodevelopmental delay. Neurological deficits included severe auditory impairment [5 (12%)] and visual impairment [4 (10%)]. Recurrent infections and gastrointestinal tract complaints requiring hospital admission occurred in 16 (39%) of survivors. CONCLUSION: Necrotizing enterocolitis in premature infants impacts morbidity and mortality considerably. A number do well in a developing country, but septic complications may be ongoing and recurrent. The high risk of neurodevelopmental and other problems continue beyond the neonatal period and patients should be "flagged" on for careful follow-up.

Assessment of the delayed repair of uncomplicated inguinal hernias in infants.

BACKGROUND: Potential strangulation of infant inguinal hernias is the main indication for their urgent repair. Lack of theatre time delays repair and prolongs hospitalisation. We report a series of patients with uncomplicated hernias who were discharged home to have their elective surgery at a later stage and assessed the outcomes of this approach. METHODS: A retrospective audit was performed of all infants with an inguinal hernia from January 2010 to June 2015. Incomplete records and infants operated after their first birthday were excluded. Two groups were identified; immediate surgery for infants with uncomplicated hernias, and delayed surgery for infants with uncomplicated hernias. Incarceration/strangulation rates in the interim period were documented for the delayed group, and comparison made between the groups regarding perioperative and anaesthetic complications and length of postoperative hospital stay. RESULTS: The mean time delay between diagnosis and repair was 8.78 weeks. None of the hernias in the delay group strangulated while awaiting repair. There was no significant difference in the perioperative complications between the two groups. Out of the 70 cases in the immediate repair group, there was 7 (10%) surgical and 4 (5.7%) anaesthetic complications. The delayed group (169 infants) had 8 (4.7%) surgical and 6 (3.6%) anaesthetic complications. The incarceration rate after being discharged home was 4.1%. This group of infants had no anaesthetic or surgical complications. Length of hospital stay postoperatively was 1.43 days in the immediate group and 1.3 in the delayed group (p = .485). CONCLUSION: Delayed repair, up to 2 months later, for uncomplicated infant hernia carries a small risk of incarceration but does not increase the rate of strangulation or other complications.

Liver abscess in neonates.

INTRODUCTION: Liver abscesses are rare in neonates with the majority resulting from an ascending infection via the umbilical and portal veins, haematogenous spread, or via the biliary tree, or via direct contiguous spread from neighbouring structures. They may present in unusual ways often presenting with ongoing sepsis and resulting in diagnostic difficulties. We present the clinical and radiological findings on six neonates with hepatic abscesses and underline the association with misplacement of umbilical line, association with hypertonic glucose infusions and TPN. METHODS: A retrospective chart review made of six patients diagnosed with hepatic abscesses between 2000 and 2006. Methods included clinical and radiological review as well as evaluation of potential risk factors. RESULTS: Five of the six patients with neonatal liver abscess were of low birth weight and low gestational age (range 30-34 weeks), but one was post mature (42 weeks). Sex distribution was equal and two were HIV exposed (mother positive), two HIV negative with two having an unknown HIV status. Clinical signs included raised infective markers (CRP) (6) and non-specific signs of septicaemia (4), but a tender hepatomegaly (1) and abdominal distension with ileus (1) were also noted. Five were right-sided abscesses (2 associated with malposition of umbilical line) and one central in position. Predisposing factors included association with a misplaced umbilical line with high concentration glucose infusions (2) and tuberculosis was later diagnosed in one. Infective markers (CRP) remained high with positive blood cultures persisting in all. Causative organisms included Klebsiella (3) Staphylococcus (3) [one a multi-resistant staphylococcus (MRSA)], Gonococcus (1) and Enterobacter (1). Abdominal X-ray demonstrated a mal-positioned umbilical line in three patients (50%). Ultrasound (US) proved a reliable method of diagnosis although some difficulty was encountered in interpreting resolving abscesses and trans-diaphragmatic spread occurred in one. Three patients (50%) responded to antibiotic therapy alone, but interventional drainage was required in the remainder. Needle aspiration was successful in two of these, but one further patient had a radiologically placed pigtail drainage, but later required open drainage. This patient then developed trans-diaphragmatic spread and empyema requiring thoracoscopic decortication. CONCLUSION: Neonatal hepatic abscesses are rare but should enter the differential diagnosis of a neonate with ongoing sepsis. This study serves to draw attention to their association with misplaced central (umbilical) catheters. Failure to respond to antibiotic therapy necessitates interventional drainage.

Use of a single bipolar electrode in the posterior arytenoid muscles for bilateral monitoring of the recurrent laryngeal nerves in thyroid surgery.

The aims were to assess the technical feasibility of using a single electrode in the posterior arytenoid muscles (PAM) for intraoperative monitoring of the recurrent laryngeal nerve (RLN) in thyroid surgery, to validate the new method against the insertion of electrodes placed in the vocal cord muscle, and to report the results of the clinical application of the new concept. A total of 52 patients were enrolled. The handling and safety of RLN monitoring was tested by simultaneous registration of the EMG response from vocal fold electrodes and PAM electrodes. Acoustically and electromyographically we found nearly the same values for the arytenoid muscles as for the vocal folds, although the signals taken from the vocal folds were slightly stronger. PAM recording using a single bipolar electrode is technically feasible and as reliable compared to the standard vocal cord monitoring.

Surgical management of BCG vaccine-induced regional axillary lymphadenitis in HIV-infected children.

UNLABELLED: There are as yet no clear surgical guidelines for the management of BCG vaccine-induced regional axillary lymphadenopathy. OBJECTIVES: The aim of this study was to evaluate the management of the condition and to suggest possible management strategies. METHODS: A retrospective study was undertaken of 23 cases of suspected ipsilateral BCG adenitis following neonatal BCG inoculation (2001 - 2004). Diagnosis of a BCG infection was confirmed by culture and/or gastric washout. The age of the patient and mode of presentation, imaging findings, and results of tuberculin skin testing (Mantoux test) were documented. Because of a change in management policy the first group of patients treated by primary surgery were compared with those treated by fine-needle aspiration (FNA). The influence of HIV status on outcome was assessed. Surgical complications and outcome were analysed. RESULTS: Twenty-three children under 13 years of age (mean age 8.8 months, male/female ratio 1.9:1) were evaluated. Eighteen patients tested positive for HIV and 5 were HIV-negative. A positive culture for BCG bacillus was identified in 19 cases (83%) - by FNA (N=13, 68%), on pus swab (N=3, 16%), at surgery (N=1, 5%), and by gastric washing (N=2, 11%). Three HIV-negative children had granulomas on histological examination without a positive culture. Forty-five per cent of the 11 patients treated early in the study period by primary surgery (drainage/biopsy) had complications, which included a difficult anaesthetic induction and technical surgical difficulties. The postoperative incidence of wound dehiscence/infection was extremely high in this group and 18.2% developed postoperative cutaneous sinuses. Following a change in management policy, the following 12 patients, with a comparable HIV incidence, treated by initial conservative management, had a much lower incidence of post-procedural complications. CONCLUSION: This study confirms a high perioperative complication rate associated with the primary surgical treatment of BCG lymphadenitis in both HIV-positive and negative patients. Primary surgical treatment (incisional drainage or biopsy) is therefore not considered an ideal form of management in BCG lymphadenitis because of the high fistulisation and poor wound healing, especially in the HIV-positive patient. It should be avoided as the initial approach, with needle aspiration being preferred. Surgery should therefore be confined to the unusual event of real doubt about the underlying diagnosis and the treatment of suppurative complications.

Esophageal stent improves ventilation in a child with a broncho-esophageal fistula caused by Mycobacterium tuberculosis.

The deployment of an esophageal stent to aid in the ventilation of a child who had developed an acquired broncho-esophageal fistula caused by Mycobacterium tuberculosis (MTB) is described. The 12-month-old boy presented with respiratory failure requiring ventilation. The air leak via the fistula led to inadequate mechanical ventilation. The deployment of the stent resulted in successful ventilation, closure of the fistula, and eventual successful treatment.

Practical modifications and applications of the sharpless asymmetric aminohydroxylation in the one-pot preparation of chiral oxazolidin-2-ones.

[reaction: see text] Chiral oxazolidin-2-ones are synthetically valuable as chiral auxiliaries, and many have pharmaceutically interesting biological activity. This communication focuses on a convenient, practical one-pot preparation of chiral 4,5-disubstituted oxazolidan-2-ones in good yield with high enantioselectivities, using a modified Sharpless asymmetric aminohydroxylation of beta-substituted styrene derivatives followed by base-mediated ring closure. This procedure has been demonstrated on both small and large scale, utilizing 1, 3-dichloro-5,5-dimethyl hydantoin as an easily handled, commercially available substitute for tert-butyl hypochlorite.

Neonatal Soave endorectal pull-through for Hirschsprung's disease.

In October 1994 we changed our management of neonatal Hirschsprung's disease from a staged procedure after initial colostomy to a neonatal single-stage Soave endorectal pull-through (SERPT) without a colostomy. We report on our experience with the first 12 neonatal SERPTs, comparing them retrospectively with a consecutive series of 12 patients managed with initial colostomy, followed by a SERPT months later. A neonatal SERPT proved to be an easier and quicker procedure than the same procedure in the older child. Patients could be discharged earlier and fewer complications were encountered; in addition a colostomy was avoided. The cosmetic result and parental acceptance were excellent. At the same time the cost was less than half compared with the staged group. At this stage of follow-up functional results are comparable with previous staged pull-through procedures.

[Missed somatic disease: justified fear or chimera?]. / Das Verpassen somatischer Krankheiten: berechtigte Furcht oder Chimäre?

The fear to miss the diagnosis of somatic processes in "functional" disorders and the ignorance of the positive criteria for the diagnosis of conversion (physical expression of conflicts) and of psychophysiological disorder (somatic symptoms and signs, accompanying affectivity) lead to diagnosing by exclusion of somatic disorders. Its consequences are extensive, damaging procedures and a postponement of a diagnosis which integrates somatic, psychic and social components by seven to eight years. Based on positive criteria, which had been collected by means of a bio-psycho-social approach to the patient, ten were diagnosed as suffering from conversion and 22 from psychophysiological disorders. Five years later the patients were reassessed. In none of the cases a somatic diagnosis emerged, which would have been responsible for the initial complaints five years earlier. The diagnoses "conversion" and "psychophysiological disorder" proved to be reliable over five years, if they were based on positive criteria. The fear to miss a somatic process turns thus into a chimera.

Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase-Bim axis and reveals glutathione-S-transferase P1 as Achilles' heel.

Glutathione-S-transferase of the Pi class (GSTP1) is frequently overexpressed in a variety of solid tumors and has been identified as a potential therapeutic target for cancer therapy. GSTP1 is a phase II detoxification enzyme and conjugates the tripeptide glutathione to endogenous metabolites and xenobiotics, thereby limiting the efficacy of antitumor chemotherapeutic treatments. In addition, GSTP1 regulates cellular stress responses and apoptosis by sequestering and inactivating c-Jun N-terminal kinase (JNK). Thiazolides are a novel class of antibiotics for the treatment of intestinal pathogens with no apparent side effects on the host cells and tissue. Here we show that thiazolides induce a GSTP1-dependent and glutathione-enhanced cell death in colorectal tumor cell lines. Downregulation of GSTP1 reduced the apoptotic activity of thiazolides, whereas overexpression enhanced it. Thiazolide treatment caused strong Jun kinase activation and Jun kinase-dependent apoptosis. As a critical downstream target of Jun kinase we identified the pro-apoptotic Bcl-2 homolog Bim. Thiazolides induced Bim expression and activation in a JNK-dependent manner. Downregulation of Bim in turn significantly blocked thiazolide-induced apoptosis. Whereas low concentrations of thiazolides failed to induce apoptosis directly, they potently sensitized colon cancer cells to TNF-related apoptosis-inducing ligand- and chemotherapeutic drug-induced cell death. Although GSTP1 overexpression generally limits chemotherapy and thus antitumor treatment, our study identifies GSTP1 as Achilles' heel and thiazolides as novel interesting apoptosis sensitizer for the treatment of colorectal tumors.

Colon cancer cells produce immunoregulatory glucocorticoids.

Glucocorticoids (GC) have important anti-inflammatory and pro-apoptotic activities. Initially thought to be exclusively produced by the adrenal glands, there is now increasing evidence for extra-adrenal sources of GCs. We have previously shown that the intestinal epithelium produces immunoregulatory GCs and that intestinal steroidogenesis is regulated by the nuclear receptor liver receptor homolog-1 (LRH-1). As LRH-1 has been implicated in the development of colon cancer, we here investigated whether LRH-1 regulates GC synthesis in colorectal tumors and whether tumor-produced GCs suppress T-cell activation. Colorectal cancer cell lines and primary tumors were found to express steroidogenic enzymes and regulatory factors required for the de novo synthesis of cortisol. Both cell lines and primary tumors constitutively produced readily detectable levels of cortisol, as measured by radioimmunoassay, thin-layer chromatography and bioassay. Whereas overexpression of LRH-1 significantly increased the expression of steroidogenic enzymes and the synthesis of cortisol, downregulation or inhibition of LRH-1 effectively suppressed these processes, indicating an important role of LRH-1 in colorectal tumor GC synthesis. An immunoregulatory role of tumor-derived GCs could be further confirmed by demonstrating a suppression of T-cell activation. This study describes for the first time cortisol synthesis in a non-endocrine tumor in humans, and suggests that the synthesis of bioactive GCs in colon cancer cells may account as a novel mechanism of tumor immune escape.