A 2-year dyadic longitudinal study of mothers' and fathers' marital adjustment when caring for a child with cancer.

OBJECTIVE: Studies examining interrelationships within parental couples confronted with pediatric cancer are scarce. This study explored dyadic longitudinal associations between both partners' family functioning and mood at diagnosis, and marital adjustment 2 years later. METHOD: Parents of children (n = 47 couples) with acute lymphoblastic leukemia (ALL) completed the Family Well-Being Assessment and Profile of Mood States-Bipolar Form at diagnosis, and the Locke-Wallace Marital Adjustment Test 2 years post diagnosis. Multilevel linear models using the actor-partner interdependence model (APIM) and controlling for baseline marital adjustment were conducted to evaluate within subject and dyadic longitudinal effects. RESULTS: For mothers, better marital adjustment 2 years post diagnosis was associated with perception of greater family support and less role conflict and role overload at diagnosis. For fathers, better marital adjustment 2 years post-diagnosis was associated with perception of less role conflict, greater role ambiguity, and being more tired at diagnosis, as well as their partner's perception of less role conflict at diagnosis. CONCLUSIONS: These findings highlight the importance of considering both partners' perspectives in understanding marital adjustment across treatment phases in parents of children with ALL. Early interventions for couples should be tailored to meet each partner's needs in order to foster resilience within the couple.

Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia.

Multidrug resistance-related proteins (MRPs) 2, 3 and 5 are involved in the efflux of drugs used in acute lymphoblastic leukemia (ALL) treatment. Polymorphisms of these genes were investigated for an association with treatment responses in 273 childhood ALL patients. The MRP3 A-189 allele of the regulatory AT polymorphism was associated with reduced event-free survival (P=0.01). The results remained significant after adjustment for multiple comparisons and in the multivariate analysis. Among patients with an event, the A-189 carriers had significantly higher methotrexate plasma levels (P=0.03). MRP3 A-189 also conferred four times higher risk of a relapse in central nervous system (P=0.01). Patients with this allele tended to have lower frequency of thrombocytopenia grade 2 (P=0.06). Gene reporter assay showed that the haplotype tagged by the A-189 had higher promoter activity (P≤0.01). In conclusion, MRP3 A-189 T polymorphism was associated with treatment responses in ALL, likely due to the change in MRP3 efflux.

Development of reconstructive surgery services in the Gaza Strip, Palestine.

Plastic surgery involves the restoration, alteration or reconstruction of the human body. It includes reconstructive and aesthetic surgery. This paper discusses the authors' experience introducing new reconstructive, microsurgical and aesthetic surgeries in the Gaza Strip. We analyzed 192 cases of reconstruction carried out in the Al-Alamy Burns Center in Al-Shifa Hospital from August 2017 to July 2018 and at the European Gaza Hospital during a one-month delegation, as well as 38 aesthetic surgeries performed in the author's private clinic. We highlight challenges hindering the development of reconstructive and plastic practices in the Gaza Strip and propose solutions. Plastic surgeries have greatly evolved at Al-Shifa Hospital. Despite obstacles limiting the development of reconstructive surgery, we were able to treat complicated cases requiring microsurgical procedures. In one year we performed 192 reconstructive surgeries, in addition to 38 hair transplants. Overall success rate was 97.8%, with five failed flaps documented. Wound infection was the main cause of failure. However, the failed flaps were repaired by various approaches. The hair transplant patients went home the same day with no complications. Plastic surgeries have improved significantly and staff competencies have increased with frequent exposure to different cases. Moreover, the physicians' skills and knowledge have been imbedded in practice following the educational development of the authors. Establishing specialized training programs in plastic and reconstructive surgery is crucial to enhancing and reinforcing the physicians' skills and knowledge and guaranteeing high quality care.

Incluant les chirurgies reconstructrice et esthétique, la chirurgie plastique a pour but la restauration, la transformation ou la reconstruction du corps humain. L'auteur expose ici son expérience de mise en place de chirurgies reconstructive, de microchirurgie et de chirurgie esthétique dans la bande de Gaza. Nous avons analysé 192 cas de reconstruction réalisées dans le CTB Al Alamy de l'hôpital Al Shifa et l'hôpital européen de Gaza entre août 2017 et juillet 2018 ainsi que 38 interventions esthétiques réalisées en secteur privé. Nous soulignons les contraintes obérant le développement de la chirurgie plastique et reconstructrice dans la bande de Gaza et proposons des solutions. La chirurgie plastique a largement évolué à Al Shifa. Malgré les difficultés organisationnelles, nous avons traiter des cas compliqués nécessitant de la microchirurgie. En 1 an, nous avons réalisé 192 interventions reconstructrices et 38 transplantations de cheveux. Avec 5 échecs de lambeaux (qui ont pu être récupérés par diverses techniques), le taux de succès est de 97,8%. L'infection de site opératoire était la principale cause d'échec. Les transplantations de cheveux ont été réalisées en ambulatoire et ne se sont pas compliquées. Les techniques se sont significativement améliorées, concomitamment à l'accroissement de l'expérience des équipes, sous l'influence de l'auteur. Des programmes d'éducation spécifiques à la chirurgie plastique et reconstructives sont indispensables à l'acquisition et au développement des connaissances des professionnels afin de garantir un haut niveau de qualité de soins.

Safety and pharmacokinetics of temozolomide using a dose-escalation, metronomic schedule in recurrent paediatric brain tumours.

The aims of this study were to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetics of oral temozolomide administered over 42 d in children with recurrent/refractory brain tumours. Cohorts of 3-6 patients were treated for 42 d, followed by a 7-d rest period for a maximum of 6 cycles. Patients were stratified as heavily pre-treated (HPT) and non-heavily pre-treated (NHPT). Starting doses were 50 mg/m2 (HPT) or 75 mg/m2 (NHPT). Out of 28 patients enrolled, 20 were evaluable for toxicity and 19 for pharmacokinetics. Three patients in the NHPT group developed grade 3/4 haematological toxicity, 2 experienced dose-limiting toxicity (thrombocytopenia) at 100 mg/m2, and 9/20 developed grade 3 lymphopenia. MTD in both strata was 85 mg/m2. Responses were observed in 4 patients: 2 complete responses (CR) in medulloblastoma and supratentorial primitive neuroectodermal tumours (PNET), and 2 partial responses (PR) in high-grade glioma, respectively. Overall cumulative exposure was at least 1.5 times higher than in the 5-d administration schedule. In conclusion, the recommended dose of temozolomide is 85 mg/m2 x 42 d. Dose-limiting toxicities are thrombocytopenia and lymphopenia. The observed response rate warrants phase II studies.

Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995).

The Dana-Farber Cancer Institute (DFCI) ALL consortium has been conducting clinical trials in childhood acute lymphoblastic leukemia (ALL) since 1981. The treatment backbone has included intensive, multi-agent remission induction, early intensification with weekly, high-dose asparaginase, cranial radiation for the majority of patients, frequent vincristine/ corticosteroid pulses during post-remission therapy, and for high-risk patients, doxorubicin during intensification. Between 1981 and 1995, 1,255 children with newly diagnosed ALL were evaluated on four consecutive protocols: 81-01 (1981-1985), 85-01 (1985-1987), 87-01 (1987-1991) and 91-01 (1991-1995). The 5-year event-free survival (EFS) rates (+/- standard error) for all patients by protocol were as follows: 74 +/- 3% (81-01), 78 +/- 3% (85-01), 77 +/- 2% (87-01) and 83 +/- 2% (91-01). The 5-year EFS rates ranged from 78 to 85% for patients with B-progenitor phenotype retrospectively classified as NCI standard-risk, 63-82% for NCI high-risk B-progenitor patients, and 70-79% for patients with T cell phenotype. Results of randomized studies revealed that neither high-dose methotrexate during induction (protocol 87-01) nor high-dose 6-mercaptopurine during intensification (protocol 91-01) were associated with improvement in EFS compared with standard doses. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.

Development of new jet injector for insulin therapy.

To improve diabetic patients' compliance to multiple injection protocols, we developed and tested a new insulin jet injector, the Preci-Jet 50. The prototype has the following features: small size (14 X 2 cm) and weight (160 g), capability of mixing two types of insulin, accuracy and reliability of the ejected volume (dose), ease of use and sterilization, simplicity of design, and capacity of adjusting jet pressure to individual skin resistance. The ejected volume, evaluated by gravimetry, was more accurate and more reliable with the injectors (N = 18) than with 0.5-cc disposable plastic syringes (N = 18). The dead space of the injectors (N = 16), as evaluated by isotopic recuperation of radioactive insulin, was minimal, allowing mixed insulin injections. The human-device interface evaluation demonstrated that diabetic patients (N = 13) learned easily to manipulate the injector and that their ability to use it properly improved after 1 mo of use. We conclude that this injector may be a practical tool for insulin-dependent diabetic patients.

Twice-daily mixed regular and NPH insulin injections with new jet injector versus conventional syringes: pharmacokinetics of insulin absorption.

The purpose of the present study was to evaluate the feasibility of using a jet injector in a split and mixed regular and NPH insulin regimen and to compare serum glucose and free-insulin profiles obtained with the injector and the conventional syringe and needle. Twelve insulin-dependent diabetic patients were hospitalized for 5 days. After a stabilization day, six patients received their insulin injection with the injector for 2 days and with the syringe and needle for the following 2 days; the regimen was reversed for the other six patients. Diet, exercise, and insulin dosage remained constant. The serum glucose levels with the injector were consistently lower than those obtained with the syringe at all times of the day except at 5:00 a.m. and 7:30 a.m., when mean values were similar for both treatments. Free-insulin levels were higher with the injector from 10:30 a.m. to 4:30 p.m. These findings suggest that insulin absorption is faster and possibly greater with the injector than with the syringe. When switching from a syringe to an injector insulin program, insulin dose adjustment may be necessary.

Results of an unrelated transplant search strategy using partially HLA-mismatched cord blood as an immediate alternative to HLA-matched bone marrow.

Cord blood (CB) is an alternative to other sources of stem cells for transplantation. However, the impact of including CB in the initial strategy of unrelated graft search in a cohort of patients has been the object of limited analysis. Here, we report the results of such a strategy in 91 consecutive children. Absence of mismatch was required for adult donors, and up to two mismatches were allowed for CB grafts, with a nucleated cell dose over 2.5 x 10(7) cells/kg. A graft was found for 84 of the 85 children who remained available for a 3-month search. In all, 64 patients were transplanted, 36 with CB and 28 with bone marrow (BM). Primary graft failure, acute grade II-IV and extensive chronic graft-versus-host disease occurred in five, five and zero CB, and in three, one and two BM patients, respectively. The 3-year survival was 59% in CB and 57% in BM patients. Accepting CB as a source of stem cells offers a graft to almost every child in need of an unrelated transplantation, with a probability of survival similar to that of unrelated BM transplantation.

Carboplatin treatment of progressive optic pathway gliomas to delay radiotherapy.

Six patients with optic pathway gliomas who were previously managed with surgery and/or chemotherapy were treated with carboplatin (560 mg/sq m) after radiographic evidence of disease progression. The median age at diagnosis was 2 years (range 4 months to 7 years), and the interval between diagnosis and carboplatin therapy ranged between 7 months and 6.5 years (median 1.8 years). Treatment was given at 4-week intervals and continued until unacceptable toxicity supervened, the disease progressed, or the disease was stable for 12 months. All patients demonstrated disease stability at the outset of the third cycle and continued to do so at the time of this writing. Two patients are 16 and 32 months from initial carboplatin therapy and have been off treatment for 5 and 14 months, respectively; two patients are still receiving therapy at 7 and 11 months after their initial treatment. During the study, two patients developed hypersensitivity to the drug, requiring its discontinuation. Toxicity was minimal, consisting mainly of thrombocytopenia, requiring a one-dose reduction in four of the six treated patients. No platelet transfusions were needed. These results suggest that carboplatin can arrest growth of progressive optic pathway gliomas in children and can allow delay of radiotherapy. A larger trial will be required to define the optimal use of carboplatin in the treatment of low-grade gliomas in children.

Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas.

In this study, the authors sought to investigate the response rate and toxicity of carboplatin in patients with progressive low-grade glioma (LGG). Thirty-two patients with progressive LGG were treated with carboplatin at a dosage of 560 mg/m(2). Treatment was given at 4-week intervals and continued until the disease progressed, unacceptable toxicity supervened, or for 12 additional courses after achieving maximal response. Patients with stable disease were treated with a total of 12 cycles. All patients were treated as outpatients. Patients were evaluated for response to treatment and toxicity. All patients received a minimum of two cycles of carboplatin, and were examined for response. A partial response was achieved in nine patients (28%) and a minimal response in two (6%), for an overall response rate of 34% (11 of 32 patients). Eighteen patients (56%) had stable disease. A partial response was achieved in the nine patients after a median of six cycles (range 4-11 cycles), a minimal response was achieved in the two patients after five cycles. Glioma progression was noted in three patients after three, five, and five cycles, respectively. The 11 patients in whom some response was achieved had either an optic pathway tumor or a juvenile pilocytic astrocytoma. Twenty-six of the 32 patients had those characteristics, making the response rate in that group 42% (11 of 26 patients). Thirty-two patients received a total of 387 cycles of chemotherapy. Hematological toxicity was moderate. Twenty-one patients developed thrombocytopenia (platelet count < 50,000/microl); three patients required one platelet transfusion each. Nine patients developed neutropenia (absolute neutrophil count < 500/microl); one developed fever and required administration of antibiotic agents. One dose adjustment in each of the patients prevented further thrombocytopenia and neutropenia. Two patients with stable disease died of respiratory complications. One patient developed Grade III ototoxicity after receiving five cycles, one patient developed hypersensitivity to carboplatin, and none developed nephrotoxicity. Carboplatin given at a dosage of 560 mg/m(2) every 4 weeks has activity in patients with progressive LGG. This drug regimen is relatively simple and well tolerated. Further investigation and longer follow-up study are warranted.

[T4 and T8 lymphocytic populations after total hip replacement]. / Etude des populations lymphocytaires CD 4 et CD 8 après chirurgie pour prothèse de hanche.

Immunosuppression is involved in the occurrence of sepsis after surgical trauma. A postoperative lymphocytopenia is a recognised fact. In the opposite, studies on T-lymphocytes helpers (CD 4) and suppressors (CD 8) resulted in conflicting results. The aim of this study was to assess the variations in these two T-lymphocyte sub-populations using strongly standardized conditions in order to minimize the risk of non specific variations: same surgeon, same surgical technique, blood samples collected just before induction, immediately and 24 hours after surgery, automatized measures (Technicon H1). The results confirmed the lymphocytopenia, 24 hours after surgery, but no differences on CD 4 and CD 8 percentages were noted. It is concluded that during the first 24 postoperative hours surgery does not change the relative proportions of T-helpers and T-suppressors. Their measurement is not more useful than total lymphocyte count for assessment of postoperative immunosuppression.

[Monitoring after total hip prosthesis. Value of semi-quantitative D-dimer assay]. / Surveillance après prothèse totale de hanche. Intérêt du dosage semi-quantitatif du D-dimère.

Criteria for positive assay of the D-dimer were defined in order to establish its diagnostic value for phlebitis in the post-operative period. A retrospective study was carried out on the files of 94 patients who had received a total hip prosthesis in 1990. A semi-quantitative assay technique was used to measure the D-dimer because it is the only method giving immediate results. Three criteria were used to classify the results: criterium A: D-dimer greater than or equal to 2 micrograms/ml; criterium B: D-dimer greater than or equal to 4 times the preceding test; absence of both of these criteria. The results were compared to echo-doppler results and confirmed by phlebography when necessary. The incidence of proximal phlebitis was low (2 percent); criterium B showed a 100 percent negative predictability and a 29 percent positive predictability. None of the cases of phlebitis diagnosed with this test had been suspected clinically. This test provides a means of patient screening and spares the need for other explorations.

The return of research results to participants: pilot questionnaire of adolescents and parents of children with cancer.

PURPOSE: The offer to return research results to participants is increasingly recognized as an ethical obligation, although few researchers routinely return results. We examined the needs and attitudes of parents of children with cancer and of adolescents with cancer to the return of research results. METHODS: Seven experts in research ethics scored content validity on parent and adolescent questionnaires previously developed through focus group and phone interviews. The questionnaires were revised and provided to 30 parents and 10 adolescents in a tertiary care oncology setting. RESULTS: The content validity index for individual questions and the overall questionnaires scored as 0.86 for both questionnaires. All 30 parents and 10 adolescents who agreed to participate returned questionnaires. The majority (>95%) indicated that they had a strong or very strong right to receive results. Letter or e-mail was a satisfactory means to return results described as good or neutral (66% parents, 100% adolescents) but more participants wished face-to-face disclosure of results with negative implications (50% parents, 60% adolescents). Very few wanted results disseminated through a Web site. The majority acknowledged the need for peer-review before disclosure (60% of adolescents and parents) but did not want "to be the last to know." CONCLUSIONS: Our data suggest that pediatric oncology patients and parents of children with cancer strongly feel that they have a right to research results, and that they wish to receive these in a timely manner.

Epidemiological survey of central nervous system germ cell tumors in Canadian children.

OBJECTIVES: To determine the incidence and characteristics of pediatric patients with central nervous system (CNS) germ cell tumors (GCT) in Canada. METHOD: A national retrospective review of hospital charts was done on all patients with CNS GCT diagnosed between 1990 and 2004. Patients had to be under age 18 years at the time of diagnosis of a CNS germ cell tumor and be a resident of Canada. Information extracted included age and year of diagnosis, pathological diagnosis, location of tumor, evidence of disseminated disease at time of diagnosis and biological markers. RESULTS: One hundred and twenty-one cases were identified (83 germinoma; 38 non-germinoma germ cell tumor). The mean annual incidence of CNS GCT was 1.06 per million children (0.7 per million for germinoma; 0.3 per million for NGGCT). Though yearly incidences varied, there was no clear trend to increased incidence. Male predominance was noted (2.4:1 for germinoma; 11:1 for NGGCT). The primary locations were the pineal and suprasellar regions. At the time of diagnosis, disseminated disease was not uncommon (22% germinoma; 32% NGGCT). Beta human gonadotrophin was elevated in the serum, cerebrospinal fluid (CSF) or both in 7% of patients with germinoma and 36% of patients with NGGCT. Elevation of alpha-fetoprotein in serum, CSF or both was seen in 34% of patients with NGGCT. CONCLUSION: The incidence of CNS germ cell tumors in Canadian children is similar to that observed in other Western countries.

Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis.

Thymidylate synthase (TS) is an essential enzyme in proliferating cells and an important target for several chemotherapeutics. Several TS gene polymorphisms correlate with variable TS expression: a double (2R) and triple (3R) 28-bp repeat element, a G to C substitution of the 3R allele and a 6 bp variation in 3'UTR. We have previously shown that childhood acute lymphoblastic leukemia (ALL) patients who are homozygous for the 3R allele had reduced event-free survival (EFS) probabilities. Here, we analyzed all three polymorphisms in an extended group of ALL patients (n=259). The effect of the 3R homozygosity on ALL outcome was confirmed (P=0.006), whereas 6 bp polymorphism did not influence EFS when analyzed separately. No significant difference among 3R3R genotype subgroups, as defined by a G to C substitution, was observed. The haplotype analysis revealed the higher frequency of the 3RC/6 bp+ haplotype (P=0.04) and the protective role of the 2R/6b p- (P=0.04). Consequently, homozygosity for the 6 bp- allele appeared to reduce an event-predisposing effect of 3R variant. Although of importance for translation into the clinical practice, these findings need confirmation in larger studies.

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia.

The central role of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia (ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability of event-free survival (EFS) in univariate analysis (hazard ratio (HR)=2.2, 95% confidence interval (CI), 1.0-4.7 and 2.8, 95% CI, 1.1-7.3, respectively). Multivariate analysis supported only the role of the MTHFR variant (HR=2.2, 95% CI, 0.9-5.6). However, the association of both genes with ALL outcome appears to be more obvious in the presence of another event-predisposing variant belonging to the same path of drug action. The combined effect of a thymidylate synthase (TS) triple repeat associated with increased TS levels, with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 allele, resulted in a highly significant reduction of EFS (multivariate HR=9.0, 95% CI, 1.9-42.8 and 8.9, 95% CI, 1.8-44.6, respectively). These results reveal the role of gene-gene interactions within a folate pathway, and how they can correlate with relapse probabilities in ALL patients.

False positive images in the follow-up of patients with brain tumors.

In recent years, major advances in the diagnosis and treatment of patients with brain tumors have been seen. Today, evaluation of the central nervous system almost always includes magnetic resonance imaging (MRI). The appearance of a new lesion on the MRI scan of a patient previously treated for a central nervous system (CNS) tumor raises concern for recurrent disease with the need for selection of new, potentially toxic therapy. However, the sensitivity of MRI may allow demonstration of new lesions which are not due to tumor. We now report three patients with medulloblastoma who demonstrated new enhancing lesions on MRI following treatment of their tumors with surgery (3 patients), chemotherapy (2 patients), and radiotherapy (2 patients). Two patients underwent resection of the lesion revealing gliosis. One patient had serial imaging that showed disappearance of the lesions. This suggests that not all new enhancing lesions in previously treated brain tumor patients represent tumor. Histologic proof of a suspicious lesion should be demonstrated prior to initiation of new therapy.

Prognostic value of contrast-enhanced magnetic resonance imaging in brainstem gliomas.

Brainstem gliomas are an important oncologic problem in the pediatric age group, constituting between 10 and 15% of childhood central nervous system neoplasms. A new classification scheme based on magnetic resonance imaging (MRI) has recently been proposed leading to speculation that gadolinium-DTPA-enhanced MRI may prove useful in defining the prognosis of subsets of patients with these tumors. We retrospectively reviewed gadolinium-DTPA-enhanced MRIs in 26 consecutive newly diagnosed pediatric patients (11 males, 15 females) from our institution between June 1988 and June 1994 with the diagnosis of diffuse brainstem glioma. The site, extent of invasion, T1 and T2 signals, and the pattern and the degree of contrast enhancement of the tumors were evaluated. We correlated the image features, clinical symptoms, and survival period in each patient. Seventeen tumors demonstrated contrast enhancement and 9 did not. The survival in the whole group ranged between 3 months and > 5 years with a median of 9 months. There was no statistical difference in the median survival between patients with or without contrast enhancement (11 versus 8 months).