Laura Merras-Salmio

OVARIAN GRANULOSA CELL TUMORS IN CHILDHOOD

Granulosa cell tumors (GCT) of the ovary are prepubertal in 5% of the patients. In girls less than 20 years old, 80% of GCTs differ from those among adults. These juvenile granulosa cell tumors (JGCTs) are usually benign. GCTs belong to ovarian sex cord-stromal tumors, the more common ovarian tumors being epidermal and germinal. The etiology of GCT remains unknown. Most young children with GCT present with precocious pseudopuberty. Among adolescents GCT often causes menstrual irregularities, virilization, abdominal swelling, and pain. When JGCT is limited to the ovaries the outcome is excellent with only salpingo-oophorectomy. However, more widely spread tumors are difficult to treat and cause mortality. Cisplatin-containing chemotherapy can induce remissions in adult GCTs. Estrogens and peptide hormones, i.e., inhibin, are useful in the follow-up of the patients. The authors describe 3 children with GCT and review current data on this rare tumor from molecular biology to clinical aspects.

Skin reactions during anti-TNFα therapy for pediatric inflammatory bowel disease: a 2-year prospective study.

Background:Although the development of therapy-related skin reactions is common along with an increase in the number of adult patients receiving anti-TNF&agr;, there are few studies on pediatric inflammatory bowel disease; hence, this prospective study focuses on skin reactions related to infliximab therapy. Methods:All pediatric patients with inflammatory bowel disease undergoing infliximab therapy were prospectively screened for the presence of skin manifestations at the time of each infusion between March 1, 2011 and March 31, 2011 at Childrens Hospital, Helsinki, Finland. Blood inflammatory markers and fecal calprotectin levels were measured at the time of infusions. Results:During the study period, 84 children with inflammatory bowel disease (Crohns n = 64) received infliximab infusions (the median duration of therapy 12.2 mo). Almost every other patient (n = 40; 47.6%) presented chronic skin reactions, 23% with lesions considered severe. Most commonly, the patients ear lobes and scalp were affected with psoriasis-like manifestations, followed by their eyelids, perioral and pubic area, trunk, and the extremities. However, an HLA-Cw*0602 genotype associating with psoriasis was rare. Interestingly, most patients with skin reactions had a low degree of intestinal inflammation based on their fecal calprotectin levels (median level, 133 &mgr;g/g versus 589 in unaffected patients; P < 0.016). Seven patients (8.3% of all patients but 17% of those with skin lesions) discontinued the given therapy due to a skin reaction. Conclusions:Skin reactions are common during maintenance therapy with infliximab in pediatric patients. For most patients, skin reactions seem to correlate with a low level of intestinal inflammation. Although potentially harsh, skin lesions mostly allow continuation of infliximab.

Refined Multidisciplinary Protocol-Based Approach to Short Bowel Syndrome Improves Outcomes.

Objective: Management of short bowel syndrome (SBS) has significantly evolved recently. We present our single-center, 25-year experience focusing on the implementation of a refined multidisciplinary SBS care protocol. Methods: This is a retrospective review of the patients with SBS treated at our tertiary center from 1988 to 2014, with either <25% short bowel remaining or duration of parenteral nutrition (PN) >3 months. Patients with primary intestinal motility disorders were excluded. Clinical characteristics, including intestinal anatomy, markers of cholestasis, and catheter-related infections (CRIs), were analyzed. The implementation of a refined modern uniform management protocol in 2009 divided the cohort into 2 subgroups, whose outcomes are compared. Results: Forty-eight patients with SBS were identified (median gestational age 33 weeks). Of them, 22 were born between 2009 and 2014. The main causes of SBS were necrotizing enterocolitis (46%) and midgut volvulus (23%). Median remaining small bowel length was 36 cm. The overall survival was 23 of 26 (88%) before 2009 and 21 of 22 (95%) thereafter, whereas none were transplanted. Duration of PN shortened from a median of 15 to 6 months (P = 0.0015) in the latter cohort, whereas frequency of autologous intestinal reconstruction surgery (31%) remained unchanged. Frequency of neonatal cholestasis was similar in both groups (75%), but cleared in all after 2009. Before 2009, 2 patients died of progressive cholestatic liver failure. The CRI rates decreased from 1.7 to 0.7 per 1000 catheter-days between 2000–2008 and 2009–2014, respectively (P = 0.0178). Conclusions: Uniform refined multidisciplinary approach decreased the duration of PN and CRI rates with high transplant-free survival and avoidance of liver failure, although the frequency of transient neonatal cholestasis remained unchanged.

Intestinal Rehabilitation of Infantile Onset Very Short Bowel Syndrome

AIM The aim of this study was to evaluate treatment and outcomes of infantile very short bowel syndrome (SBS). METHODS A retrospective review of 42 consecutive children treated for infantile onset SBS defined as remaining small bowel length less than 30% of predicted or more than 3 months of parenteral nutrition (PN) was performed. Surgical treatment and outcomes were compared between very SBS (VSBS, small bowel length less than 25 cm, n=12) and SBS (more than 25 cm, n=30). MAIN RESULTS Median follow-up was 5.7 years (IQR, 2.8 to 11). Absolute initial small bowel length (cm), presence of ileocecal valve (%), and proportion of remaining colon (%) was 15 (10 to 21) vs. 48 (32 to 60) (P<0.0001), 58 vs. 50 (P=0.74), and 95 (76 to 100) vs. 78 (60 to 100) (P=0.27) in VSBS and SBS, respectively. More autologous intestinal reconstruction procedures per patient were performed in SBS group (27/30 vs. 5/12; P=0.002) leading to intestinal autonomy in 2 of 4 VSBS patients in relation to 9 of 11 SBS patients (P=0.52). Cumulative 5-year probability of weaning from PN was 46% (95% CI, 16 to 77) in VSBS and 92% (95% CI, 81 to 100) in SBS (P<0.01). Five-year cumulative survival was 80% (95% CI, 54 to 100) in VSBS and 93% (95% CI, 83 to 100) in SBS (P>0.30). No patients were transplanted. At final follow-up, plasma alanine aminotransferase (29 U/L [21 to 47]), bilirubin (6.0 μmol/L [3.0 to 8.0]), height (-1.4 SD [-2.5 to 0.1]), and relative weight (-5% [-12 to -2]) were similar between the groups. CONCLUSION Although survival, well-preserved biochemical liver function, and growth in VSBS patients are comparable to their counterparts with longer remaining bowel, regaining intestinal autonomy remains challenging in children with the shortest small intestinal remnant.

Surgical rehabilitation of short and dysmotile intestine in children and adults.

Abstract Aims. This is a descriptive study aiming to compare outcomes of intestinal rehabilitation surgery among pediatric and adult intestinal failure (IF) patients with either primary intestinal motility disorders or short bowel syndrome (SBS) treated by our nationwide program. Methods. Medical records of IF patients (n = 31, 71% children) having undergone autologous intestinal reconstructions (AIR) (n = 25), intestinal transplantation (ITx) (n = 5), or being listed for ITx (n = 2) between 1994 and 2014 were reviewed. Results. At surgery, median age was 3.4 (interquartile range, 1.0–22.1) in SBS (n = 22) and 16.5 (3.2–26.7) years in dysmotility patients (n = 9) who received median 60% and 83% of energy requirement parenterally, respectively. Median small bowel length was shorter in SBS than dysmotility patients (34 versus 157 cm, p < 0.001). Following AIR, none of the dysmotility patients achieved permanent intestinal autonomy, whereas 68% of SBS patients weaned off parenteral nutrition (PN) (p = 0.022) and none required listing for ITx. Five dysmotility patients who underwent ITx achieved intestinal autonomy. Regarding both AIR and ITx procedures, no significant difference in PN weaning was observed between the two subgroups. At last follow-up, 3.3 (0.6–8.0) years postoperatively, median plasma bilirubin was 6 (4–16) µmol/l, while liver biopsy showed fibrosis (Metavir stage 1–2) in 50% and cholestasis in 8%. Proportion of PN energy requirement had reduced significantly (p = 0.043) among PN-dependent SBS (n = 7) but not among dysmotility patients (n = 5). Overall survival was 90%. Conclusion. AIR surgery was beneficial among selected SBS patients, whereas in intestinal dysmotility disorders, permanent PN weaning was only achieved by ITx.

Long-term health-related quality of life of patients with pediatric onset intestinal failure

BACKGROUND Despite improved survival rates of patients with pediatric intestinal failure (IF), data on health-related quality of life (HRQoL) of IF patients are still scarce. We hypothesized that I) continued parenteral nutrition, underlying intestinal motility disorder, abdominal pain and problematic bowel function would be associated with poorer HRQoL and higher parental stress levels, and II) the time intervals since the latest bowel operation, the latest episode of sepsis, and the latest inpatient care episode would be associated with better HRQoL and lower parental stress. METHODS Patients with pediatric onset IF and their parents answered questionnaires on HRQoL, parental stress, and bowel-related symptoms. Clinical data were gathered by chart review. Controls matched for age and sex were randomly chosen by the Population Register Centre of Finland. RESULTS Thirty-six (73%) IF patients participated at a median age of 9years. Overall HRQoL was similar to healthy peers, and frequent abdominal pain was the only factor associated with poorer HRQoL. Abdominal pain and stool frequency >3 times per day were associated with higher levels of parental stress, whereas longer time intervals since the latest bowel operation or hospitalization were associated with lower parental stress levels. CONCLUSION Long-term HRQoL of pediatric IF patients is comparable to that of healthy peers. Time often eases parental stress, but frequent abdominal pain presents a challenge to the well-being of some patients and requires medical attention.

Small Bowel Dilatation Predicts Prolonged Parenteral Nutrition and Decreased Survival in Pediatric Short Bowel Syndrome.

Objective: To analyze risk factors and prognostic significance of small bowel (SB) dilatation in children with short bowel syndrome (SBS). Background: In SBS, the remaining SB may dilate as part of intestinal adaptation. The impact of dilatation on parenteral nutrition (PN) dependence and survival has not been studied systematically. Methods: SB diameter of SBS children (n = 61) was measured in contrast SB series (n = 169, median age 0.94, range 0.32–2.7 years) during 2002 to 2015, and expressed as millimeters (SB width) and as ratio to L5 vertebra height (SB diameter ratio). Linear regression was used to examine risk factors for dilatation. PN weaning and survival were analyzed with Cox proportional hazards regression. Results: Maximal SB diameter ratio during follow-up was predicted by PN dependence and SB atresia, while maximal absolute SB width by birth weight, age, PN duration, and remaining bowel length. Weaning off PN was 14-fold more likely in patients with maximal SB diameter ratio <2.00 compared with >3.00 (P = 0.005), and 5.4-fold more likely when maximal SB width was <20 mm compared with >30 mm (P = 0.023). After adjustment for age, remaining SB length, and the presence of ileocecal valve, both estimates of maximal SB dilatation remained significant independent predictors for weaning off PN. When all measurements were included, the cumulative survival was worse if SB diameter ratio exceeded 2.00 (P = 0.002–0.042). Conclusions: SB dilatation predicts prolonged PN duration and decreased survival in SBS children. Measurement of maximal SB diameter standardized to L5 vertebra height may be a valuable objective tool for patient follow-up and assessment of prognosis.

Cow's Milk-Associated Gastrointestinal Symptoms Evaluated Using the Double-Blind, Placebo-Controlled Food Challenge

Objective: The aim of this study was to evaluate the suspicion of cows-milk allergy in infants with unspecific gastrointestinal (GI) symptoms using the double-blind, placebo-controlled food challenge. Methods: A prospective cohort study, which recruited 57 consecutive children with gastrointestinally manifested symptoms suspected of cows-milk allergy. All patients underwent a 5-day double-blind, placebo-controlled food challenge for cows milk. Results: The median age of the patients was 8.7 months. None had measurable cows-milk–specific IgE. The food challenge was positive in 18 (32%) cases, with symptoms manifesting within 48 hours in 17 of 18 cases. The only symptom that correlated with the positive challenge was loose stools, reported as a presenting symptom in 78% of challenge-positive and in 46% of challenge-negative children (P = 0.043). During active challenge, the respective proportions were 82% and 2% (P < 0.0001). No serious adverse effects were manifested during the challenges. In the challenge-negative group, significant placebo reactions occurred in 18 (46%) patients. In the challenge-negative children, adult-type hypolactasia genotype CC frequency was higher (31%, P = 0.033) than national prevalence of 18%. Conclusions: In an infant with unspecific GI symptoms suspected of cows-milk allergy, this diagnosis is seldom confirmed. Other reasons for the troublesome GI symptoms should also be identified.

Clinical Use of Infliximab Trough Levels and Antibodies to Infliximab in Pediatric Patients With Inflammatory Bowel Disease.

Objectives: Optimizing infliximab (IFX) treatment in pediatric patients with inflammatory bowel disease (IBD) by using serum infliximab (S-IFX) trough levels and antibodies to IFX is recommended. There is need for studies assessing this strategy in clinical practice. Methods: We retrospectively identified all pediatric patients with IBD (n = 146, median age 14.8 years) treated with IFX at our tertiary referral center from 2003 to 2014. All were analyzed for IFX trough levels (S-IFX, n = 475), and IFX antibody (IFX-Ab, n = 219) titers were included. Both were analyzed using enzyme-linked immunosorbent assay. We correlated these parameters with concurrently analyzed fecal calprotectin levels and the treatment outcome. Results: If IFX had no efficacy, or a loss of response occurred, 40 of 64 (63%) had trough levels <2.0 mg/L, with negative IFX-Ab in 37 of 59 (63%). If the S-IFX was very low (<0.2 mg/L), 4 of 36 still had negative IFX-Ab. Concurrent azathioprine therapy did not relate to IFX-Ab. Fecal calprotectin was significantly lower in patients with clinical remission or ongoing therapy compared with those with subsequent loss of efficacy: medians 95 &mgr;g/g (33–308) and 670 &mgr;g/g (264–1473), P < 0.0001. The S-IFX median was substantially higher in patients with either remission or ongoing therapy, compared with those with no or loss of efficacy: 3.7 mg/L (1.8–5.4) and 1.2 mg/L (0.03–4.4, P = 0.01), respectively. Conclusions: Measuring IFX trough levels and fecal calprotectin has a potential impact on the treatment strategies and should be included in clinical routine. Low IFX trough levels associate with increased antibodies to IFX in most, but not in all cases.

Fecal calprotectin in the prediction of postoperative recurrence of Crohn's disease in children and adolescents.

BACKGROUND Fecal calprotectin (FC) correlates with endoscopic recurrence of Crohns disease (CD) in adults but has not been studied among children postoperatively. We aimed to analyze whether FC relates with postoperative CD recurrence in children. METHODS Altogether 51 postoperative endoscopies and FC measurements from 22 patients having undergone surgery for CD at age ≤18years were included. RESULTS Ileocecal resection (n=15), small bowel resection (n=6), or left hemicolectomy (n=1) was performed at median age of 15.1 (interquartile range 14.4-17.6) years. Following surgery, FC decreased significantly (659 vs. 103μg/g, p=0.001). During median follow-up of 5.7 (4.2-7.7) years, either endoscopic or histological recurrence occurred in 17 patients (77%). FC >139μg/g at time of endoscopy or FC increase of 79μg/g compared to first postoperative value was suggestive of endoscopic recurrence (Rutgeerts score i2-i4), while FC >101μg/g or increase of 21μg/g indicated histological recurrence. Best accuracy for prediction of recurrence was obtained by combining FC at endoscopy and the postoperative increase of FC. The corresponding AUROC values were 0.74 (95% 0.58-0.89) for endoscopic recurrence whereas 0.81 (95% CI 0.67-0.95) for histological recurrence. CONCLUSION FC is a useful surrogate marker of postoperative recurrence also in pediatric CD patients.