Efficacy and quality of life assessment in the use of subcutaneous immunoglobulin treatment for children with primary immunodeficiency disorder.

Summary: Introduction. Most patients with primary and secondary immunodeficiencies need regular Intravenous Immunoglobulin (IVIG) or Subcutaneous Immunoglobulin (SCIG) treatment. This study aimed to evaluate the serum IgG trough levels, frequency of mild and severe infections, frequency and duration of hospitalization, duration of absence of school, and quality of life in patients switching their IVIG therapy to SCIG administration. Materials. Twenty-nine patients with immunodeficiency on regular IVIG treatment and who agreed to receive SCIG treatment were included. Seven patients discontinued treatment after the first SCIG administration. We collected data regarding serum IgG levels, annual numbers of infections, hospital admissions, and adverse events prior to and following SCIG initiation. PedsQL tests such as Scale Total Score (STS), Physical Health Total Score (PHTS), Psychosocial Health Total Score (PsyHTS), emotional functionality, social functionality, school/work problems score were calculated separately for all patients and their parents. Results. In twenty-two cases who were diagnosed as primary immunodeficiency, the most common indication for initiation of SCIG treatment was the long transfusion period of IVIG treatments and the difficulty of access to the hospital. No systemic side effects were noted except local redness, pain, and swelling on the injection site. The median IgG value was 588.9 mg/dl during IVIG treatment and 872 mg/dl one year after SCIG treatment. Annual frequency of infections and absence to school/work decreased significantly in the SCIG group while the annual number of hospitalizations and hospital stay time did not change significantly. There was a significant increase in the "quality of life" scores of the patients and their families. Conclusions. SCIG treatment provides ideal and protective immunoglobulin levels and offers the comfort of treatment in their home environment, thus increasing the patient's satisfaction and quality of life.

Do elevated serum IgM levels have to be included in probable diagnosis criteria of patients with ataxia-telangiectasia?

Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder that is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency. Delay in diagnosis or misdiagnosis is probable due to its wide clinical heterogeneity in infancy. Recurrent sinopulmonary infections are often the only presenting symptom and usually patients have decreased immunoglobulins. A total 10% of patients who present with decreased serum immunoglobulin G and A and with normal or elevated immunoglobulin M levels are often misdiagnosed as hyperimmunoglobulin M syndrome. Definitive diagnosis is made if a patient with progressive cerebellar ataxia has a disease causing mutation on the ATM gene. Ataxia-telangiectasia guideline of the European Society for Immunodeficiencies defines the probable diagnosis criteria. We evaluated twenty ataxia-telangiectasia patients (mean age 13.8±4.1 years) retrospectively who were followed-up for a mean of 38.6±27.0 months. Twelve patients had a family history of consanguinity. A total of 80% patients suffered from various infections. Neoplasms occurred in three of them. Patients showed immunological abnormalities as low IgG (45%), low IgA (65%) and elevated IgM (60%) levels. CD3+CD4+ T lymphocyte frequency was low in 45% patients. The mean AFP concentration at the diagnosis was 191.9±140.1 ng/mL and the raised IgM values did not show any statistically significant relationship with high AFP concentrations. Frequency of the elevated IgM concentrations in (60%) patients raises the concerns about thinking this finding has to be accepted as a probable diagnosis criterium.

Hyper-immunoglobulin M syndrome type 3 with normal CD40 cell surface expression.

Mutations of the CD40 gene have been found in patients with autosomal recessive hyper-immunoglobulin M (HIGM) syndrome type 3. Five patients from four unrelated families with CD40 mutation have been reported so far. Clinical manifestations include recurrent sinopulmonary infections, Pneumocystis carinii pneumonia and Cryptosporidium parvum infection. Affected patients typically have very low levels of IgG and IgA and normal or high levels of IgM. Flow cytometry analysis of these five patients demonstrated that peripheral blood B lymphocytes lacked expression of surface CD40. Herein, we present two siblings from second-degree consanguineous Turkish parents with homozygous CD40 deletion of four nucleotides including the stop codon resulting presumably to a longer protein. Clinical and immunological profile of these patients is similar to the already reported HIGM3 patients except normal CD40 expression on B lymphocytes. This observation emphasizes the requirement of CD40 mutation analysis for definite diagnosis of HIGM3 despite normal flow cytometric expression of CD40, particularly if the immunological and clinical profile is suggestive for HIGM3.

IgG-anti-IgA antibodies: an autoimmune finding in patients with psoriasis vulgaris.

AIM: Psoriasis is thought to be an autoimmune disease caused by inappropriate activation of the cellular immune system. In this study, we aimed to search out IgG-anti-IgA antibody levels, serum immunoglobulins and antinuclear antibodies (ANA). METHODS: The study enrolled 38 psoriasis vulgaris patients and 40 healthy controls. RESULTS: Mean IgG-anti-IgA levels were significantly higher in psoriasis patients. The frequency of positive ANA testing was 21.1%; however, there was no correlation between IgG-anti-IgA antibody levels and ANA positivity. Only one patient had low IgA levels without high IgG-anti-IgA concentrations. CONCLUSION: The data about high IgG-anti-IgA antibody levels are noteworthy for a new evidence of autoimmune mechanism.

Spontaneous pneumothorax in children with osteosarcoma: report of three cases and review of the literature.

Spontaneous pneumothorax is a rare manifestation of primary lung cancer or metastasis. It is estimated that < 1% of all cases of spontaneous pneumothorax are tumor-associated and metastatic osteogenic or soft-tissue sarcomas are associated most commonly with pneumothorax especially in the setting of cytotoxic chemotherapy or radiotherapy. In this article, we report three pediatric cases with osteosarcoma that developed spontaneous pneumothorax during chemotherapy with a review of the literature. Two of them had lung metastasis at the time of the detection of pneumothorax and the remaining patient was found to have a bronchopleural fistula. SPx is an emergency situation and early diagnosis and management can improve prognosis and quality of life of the patient however the optimal management has yet to be determined.

Correlation between c-erbB2 expression, lymphovascular invasion and other biological and clinical prognostic factors and preoperative tumor markers in patients with early-stage and locally advanced breast cancer.

PURPOSE: To evaluate the correlation between c-erbB2 expression, lymphovascular invasion and other biological and clinical prognostic variables and preoperative CA 15-3 and CEA levels in patients with early-stage and locally advanced breast cancer. METHODS: Preoperative serum concentrations of CA 15- 3 and CEA were measured in 123 patients undergoing surgical treatment for stage I-III breast cancer and the association between these markers and clinical and biological variables were evaluated. RESULTS: With cut-off values of 45 U/ml (CA 15-3) and 2.5 ng/ml (CEA), the sensitivity for CA 15-3 and CEA was 10% and 24% and their mean values were 23 U/ml and 2.32 ng/ml, respectively. A significant correlation between preoperative levels of CA 15-3 and CEA was noticed (p=0.023). Preoperative CA 15-3 levels were significantly higher in patients with tumors > 5 cm (p<0.0001), with positive axillary lymph nodes (p=0.04), with increasing nodal burden (p= 0.025) and in patients with stage III disease (p=0.003). Tumor size >5 cm (p=0.002), increasing axillary nodal burden (p=0.02) and stage III disease (p<0.0001) were also significantly correlated with CEA values above the cut-off level. There were no correlations between CA 15-3 and CEA levels and other variables including c-erbB2 expression, age, grade, hormone receptor status, and lymphovascular invasion. CONCLUSION: Preoperative CA 15-3 and CEA levels are significantly correlated with tumor size, axillary nodal status and stage in patients with non-metastatic breast carcinoma. No correlation between preoperative values of CA15-3/CEA and c-erbB2 status, lymphovascular invasion and other prognostic factors was detected.

A novel Y331X nonsense mutation in TNFRSF1A gene in two unrelated Turkish families with periodic fever syndrome.

The autoinflammatory disorders differ in severity, as well as age of onset, duration, and manifestations, but they all share some common features: recurring fever peaks, inflammation of serosal membranes, musculoskeletal involvement, varying types of skin rash, amyloidosis as a sequel of the disease. TRAPS is very rare in Turkish population and we present two unrelated Turkish children with similar clinical phenotypes and laboratory findings related with autoinflammatory disorders and with novel p. Y331X mutation in TNFRSF1A gene. Both of the patients were male and they had recurrent fever without abdominal pain and arthralgia. Full cDNA and exon-intron binding regions of TNFRSF1A, MEFV, MVK, CIAS1 genes were analysed by direct DNA sequencing methods in order to differentiate TRAPS, FMF, HIDS, CINCA/MWS/FCAS respectively. We screened ten exons of TNFRSF1A gene, and detected a heterozygous c.1080C>G nucleotide substitution in exon 10 in both of the unrelated patients, resulting p.Y360X nonsense (protein truncated) mutation. According to classical TNFRSF1A gene nomenclature and the agreement of 30th amino acid as the first one, it is accepted as p.Y331X. It was interesting to determine same mutations in fathers of two patients. In one of the cases, E148Q heterozygous mutation, which is one of the disease-causing mutations of MEFV gene, was detected. No nucleotide substitution was identified in exon and exon-intron splicing regions encoding 396 amino acid of MVK gene in both of the patients. In CIAS1 gene, two different nucleotide substitutions resulting synonymous amino acid mutation were detected in exon 3: c.[732G>A] and c.[786A>G] nucleotide substitutions and compatible p.A242A (according to c.DNA p.A244A) and p.R260R (according to c.DNA p.R262R) synonymous amino acid mutations. These nucleotide substitutions were also detected in parents and were reported to be normal variations in Turkish population. In conclusion, in Turkish patients, with dominantly inherited recurrent fever, TRAPS is a diagnosis worthy of attention and novel mutations have to be reported with phenotype associations.

Determination of cut-off titers and agreement between immunofluorescence and immunoblotting methods for detecting antinuclear antibodies in children.

Detection of antinuclear antibodies (ANA) is a diagnostic adjunct in patients with suspected autoimmune connective tissue diseases, and various detection methods are in use. The aim of this study was to analyze the agreement between the ANA immunoflourescence (IF) and immunoblotting (IB) methods and determine cut-off for children subjects in a laboratory setting. We evaluated 729 serum samples that were analyzed by both ANA IF and IB. The results were evaluated by chi(2) test and, for agreement, kappa index was used. Frequencies determined for both 1:40-1:100 cut-off titers of ANA IF in relation to IB testing supported the idea that 1:100 starting dilution should be recommended in children subjects for ANA IF method and antigen specific immunoblot testing was needed, especially for some of the ANA IF negative samples. Agreement between the two methods, especially with homogenous, granular, and nucleolar ANA IF patterns, was statistically significant.

Leiomyoma of the seminal vesicle mimicking tumoral extension of prostatic carcinoma.

Leiomyoma of the seminal vesicle is an extremely rare tumour. The diagnosis of this entity is important when it co-exists with prostatic carcinoma, since it can simulate tumour extension from prostate or bladder cancer on MR imaging and lead to overstaging. In this report, we describe a 74-year-old man with a leiomyoma of the seminal vesicle that mimics tumour extension from co-existent prostatic cancer on T2-weighted MR imaging. To our knowledge, this is the first description of imaging findings of concurrent leiomyoma of the seminal vesicle and prostatic carcinoma.

Renal involvement as a rare complication of Dorfman-Chanarin syndrome: a case report.

Dorfman-Chanarin syndrome is a rare, autosomal recessive inherited lipid storage disease with congenital ichthyotic erythroderma due to an acylglycerol recycling defect. It is characterized by accumulation of neutral lipids in different tissues. Liver, muscle, ear, eye, and central nervous system are generally involved, so we presented a patient with severe ichthyosis, lipid vacuoles in neutrophils, and multiorgan involvement including a very rare complication, renal involvement. A 7-month-old girl was presented with frequent respiratory infection, congenital ichthyotic erithroderma and suspicion for immune deficiency. On her physical examination hepatomegaly, developmental delay, palmar and plantar hyperkeratosis and increased deep tendon reflexes with clonus and high tonus were found. Laboratory investigations revealed elevation at transaminases levels, hypoalbuminemia, hypergammaglobulinemia, presence of autoantibodies and eosinophilia. Vacuolization in leukocytes confirmed Dorfman-Chanarin syndrome, whereas no mutation at RAG1-2 and ARTEMIS genes ruled-out immune deficient status of the patient. At the age of eight months the patient died from severe renal failure. Her necropsies demonstrated microvesicular lipid accumulation not only at the liver but also at the renal species. The variability of involvement of different systems in Dorfman-Chanarin syndrome is well described, however the renal findings has not been reported previously at the literature.

The role of postoperative radiotherapy in node negative breast cancer patients with pT3-T4 disease.

AIMS: To evaluate the role of postmastectomy radiotherapy (PMRT) in patients with pT3-T4N0M0 breast cancer. METHODS: 156 patients with T3-T4N0M0 breast cancer were retrospectively analyzed. RESULTS: Locoregional recurrences were seen in 17 of 156 patients with a median time for development of 27 months (5.7-248.7 months). Two of 9 patients who were not treated with post-operative radiation therapy had locoregional recurrence as compared with 16 of 147 patients receiving radiotherapy. In multivariate analysis, presence of locoregional recurrence was the only significant prognostic factor for overall survival (18% vs. 86%, p<0.001, RR=9.05). The patients with a median number of dissected lymph nodes >or=10 had a significantly better locoregional disease free survival rate as compared with patients with dissected lymph nodes <10 (90% vs. 78%, p=0.04). Chest wall recurrences were clearly higher in patients without chest wall RT since 5 of 49 patients without RT had recurrences in the chest wall region while only 4 of 107 who received chest wall RT had recurrence. However receiving RT to peripherical lymphatic regions had no additional effect on reducing recurrences in these regions (5% vs. 4%). CONCLUSIONS: Due to the lack of phase III randomized trials directly addressing the role of postmastectomy radiotherapy in these stages, our series suggest that postmastectomy radiotherapy to the ipsilateral chest wall is recommended for patients with PT3N0 and T4N0 breast cancer. The need for irradiating axillary or supraclavicular region shall be neglected in patients who undergo sufficient axillary sampling.

Fc gamma RIIa, IIIa and IIIb polymorphisms in Turkish children susceptible to recurrent infectious diseases.

The efficacy of IgG-induced Fc gamma receptor (FcgammaR) function displays interindividual heterogeneity due to genetic polymorphisms of three FcgammaR subclasses: FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb. FcgammaR polymorphisms may contribute to disease susceptibility or may alter disease course. The aim of this study is to examine FcgammaR gene polymorphisms in Turkish children with recurrent respiratory tract infections and without well known humoral immunodeficiencies. For the patients in the study group (n=52), recurrent infection was defined as the presence of at least six infection episodes a year. Seventy-one healthy children with a maximum of two infections in a year were enrolled as the control group. Subjects in both groups had no abnormalities in serum immunoglobulins, IgG subsets and specific antibody levels. For FcgammaRIIa: H131H, H131R, R131R genotypes and 131R, 131H alleles; for FcgammaRIIIa: F158F, F158V, V158V genotypes and 158F, 158V alleles; and for FcgammaRIIIb: -NA1/NA1, NA1/NA2, NA2/NA2 genotypes and NA1, NA2 alleles were determined by using amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Compared with the control group, the FcgammaRIIa-R131R genotype and 131R allele were found to be significantly elevated in the study group, and FcgammaRIIa-H131H genotype and 131H allele in the study group were significantly lower than in the control group. Genotypes and alleles related with FcgammaRIIIa and FcgammaRIIIb gene polymorphisms did not show any significant difference between the study and control groups. FcgammaRIIa gene polymorphism (R131R) may increase the risk and susceptibility for recurrent infectious diseases in children.

Treatment results and prognostic factors in oral tongue cancer: analysis of 80 patients.

Treatment results and prognostic factors for 80 patients with oral tongue cancer admitted to Istanbul University Oncology Institute between 1987 and 2000 were retrospectively analysed. The patients were treated by surgery and postoperative or curative radiotherapy. Median age was 55 (22-93) out of which 41 patients (51%) were male and 39 (49%) were female. One patient (1%) had stage I disease, 28 patients (36%) stage II, 18 patients (23%) stage III and 32 patients (40%) stage IVA disease. Nineteen patients (24%) were medically inoperable or refused surgical treatment, so were treated with curative radiotherapy to a total dose of 70Gy (group A). The remaining 61 patients (76%) were treated with surgery and postoperative external beam radiotherapy (group B). The median follow-up time was 44 months. The 5-year overall and loco-regional disease-free survival rates were 42% and 46%, respectively. The 5-year overall survival rates were 16% in group A and 49% in group B (P=0.0002). The 5-year disease-specific survival rate was 23% in group A while in group B it was 49%; the difference was statistically significant (P=0.02). Combined treatment improves overall and disease-free survival in patients with stage II, III and IVA oral tongue cancer. In patients who are not candidates for surgery, the effect of radiotherapy may be increased with the use of brachytherapy.

Postoperative hypofractionated radiotherapy in glioblastoma multiforme.

PURPOSE: To evaluate the safety and efficacy of hypofractionated radiotherapy (HRT) in glioblastoma multiforme (GM) patients in terms of overall and progression-free survival. PATIENTS AND METHODS: Adult patients with GM were prospectively treated with HRT after total, subtotal or partial tumor excision. HRT was applied 3 days a week with a tumor dose of 3.33 Gy per fraction. At the first phase of treatment 12 fractions and at the second phase 3 fractions with smaller fields were delivered. The total dose was 50 Gy/15 fractions/5 weeks. The results were compared with a historical control group of GM patients treated with conventional RT. RESULTS: 20 patients with GM were treated between 1997-2000 at our department. The tumor was multifocal in one (5%) case. The types of operations used were total tumor excision 10(50%) cases, subtotal excision 5 (25%) cases and partial excision 5 (25%) cases. For the historical control group the corresponding operations were 19 (56%), 6 (18%) and 9 (26%). In the study group one-year survival was 50% and median survival 12 months. Mean overall survival was 13.5 (11.3 months for the historical control group, p=0.16) and progression-free survival 6.8 months (5.6 for the historical control group, p=0.36). Treatment was well tolerated. Acute toxicity was minimal and only one HRT patient had late toxicity (brain necrosis). CONCLUSION: The mean overall survival with HRT was better but statistically non significant compared with the historical control group. Our study supports that HRT can be used instead of conventional and hyperfractionated radiotherapy and studies of HRT with higher doses may be meaningful.

Cerebellar and multiple spinal hemangioblastomas and intraventricular meningioma managed with subtotal resection and external beam radiotherapy; report of a case with literature review.

Hemangioblastomas are cystic, highly vascular benign neoplasms that constitute 1.5-2.5% of all intracranial tumors and 7-10% of primary posterior fossa tumors. They occur sporadically (80%) or in association with von Hippel-Lindau (VHL) disease (20%). This disease consists of multiple intracranial, retinal and spinal hemangioblastomas, pheochromocytoma, retinal angiomas, pancreatic cysts, renal cell carcinomas and adrenal tumors. Our patient was a 21-year-old male who presented with cerebellar and multiple spinal hemangioblastomas, and intraventricular meningioma. There was a positive family history (mother and brother) of VHL disease. Intracranial and spinal lesions were treated with external beam radiotherapy following subtotal excision of the cerebellar lesion. Three-year follow-up revealed radiologically stable lesions. Microsurgical resection remains the treatment of choice for the vast majority of symptomatic and sporadic cystic hemangioblastomas. However, since hemangioblastoma is a highly vascular tumor and local invasion of critical structures is frequent and multifocality is often a characteristic of the hemangioblastomas that are associated with VHL disease, subtotal excision is frequent and adjuvant therapies such as external beam radiotherapy or stereotactic radiosurgery represent a reasonable treatment in such cases.

The results of concomitant and sequential chemoradiotherapy with cisplatin and etoposide in patients with locally advanced non-small cell lung cancer.

PURPOSE: To report on the treatment results and demographic characteristics of patients with locally advanced non small cell lung carcinoma (NSCLC) who were treated with concomitant or sequential chemoradiotherapy. PATIENTS AND METHODS: 132 patients with locally advanced NSCLC (stage IIIB) were evaluated. Their median age was 60 years (range 33-80). Histopathological diagnosis was epidermoid carcinoma in 96 (73%) patients, adenocarcinoma in 33 (25%) patients and large cell carcinoma in 3 (2%) patients. Karnofsky performance status (KPS) score was >/= 70 in 112 (85%) patients. Weight loss was greater than 5% in 34 (26%) patients at presentation. One hundred and six (80%) patients were treated with sequential chemoradiotherapy which consisted of 3 monthly cycles of cisplatin (100 mg/m(2), day 1) and etoposide (100 mg/m(2)/day, days 1-3) before radiotherapy. Radiotherapy consisted of a total dose of 60 Gy in 30 fractions (2 Gy / fraction), given to a volume including primary tumor and mediastinum. Two to 4 cycles of chemotherapy were administered after completion of radiotherapy to patients whose disease had not progressed after initial chemotherapy. Twenty-six patients were treated with concomitant chemoradiotherapy. The same radiotherapy regimen was started with the 2nd cycle of chemotherapy which consisted of cisplatin (80 mg/m(2), day 1) and etoposide (100 mg/m(2)/day, days 1-3). Chemotherapy was completed after 4 cycles in all patients. RESULTS: Overall survival (OS) was 14.5 months in 106 patients treated with sequential chemoradiotherapy and 14.6 months in 26 patients treated with concomitant chemoradiotherapy (p=0.99). Median time to progression was 9.77 months in the concomitant group and 11.6 months in the sequential group (p=0.47). However, progression-free survival was better in patients of both groups whose KPS was >70 (12.4 months versus 11.5 months, p= 0.02). While presence of anemia was found as an adverse prognostic factor only in univariate analysis, non-epidermoid histology, KPS less than 70 and presence of N2-N3 disease were found as adverse prognostic factors in both univariate and multivariate analysis. CONCLUSION: The addition of chemotherapy to radiation concomitantly or sequentially prolongs survival in locally advanced NSCLC patients with acceptable adverse event profiles in both arms compared with results of the trials in the literature in which radiotherapy is used as single treatment modality.

Mycobacterium fortuitum-chelonae complex infection in a child with complete interleukin-12 receptor beta 1 deficiency.

A 10-year-old boy had chronic diarrhea, abdominal pain, severe weight loss and hepatomegaly; multiple enlarged para-aortic and mesenteric lymph nodes. Mycobacterium fortuitum-chelonae complex was identified in the culture of the lymph nodes. Interleukin-12 receptor beta 1 expression could not be observed in phytohemagglutinin-driven T cell blasts. A homozygous missense interleukin-12 receptor beta 1 mutation was found (R173P).

Aerobic bacterial and fungal infections in peripheral blood stem cell transplants.

Allogeneic and autologous peripheral blood stem cell transplants are frequently complicated by infections. This study was performed to evaluate early and late infections in 74 patients who underwent peripheral blood stem cell transplantation (PBSCT). Fifty-eight patients received allogeneic and 16 autologous PBSCT. All patients received fluconazole, ciprofloxacin and acyclovir prophylaxis. 93.1% of alloPBSCT patients and 87.5% of autoPBSCT patients developed fever. Febrile episodes were commonly seen in the week of transplantation (66%). There was a median of 3 days with fever in alloPBSCT, and 2 days in autoPBSCT. Period of neutropenia was 15 days for AlloPBSCT and 12 days for AutoPBSCT. The microbiological identification rate was 47% (32/68). Gram-positive infections dominated the early period (50%) and Gram-negative bacterial infections dominated the late period (50%). All our patients had Hickman-type catheters and 26 infections involving catheters were seen. Sixteen occurred in the early, and 10 in the late period. Ten of 14 (71.4%) late bacterial infections were catheter-related. The dominance of Gram-positive infections and high rates of methicillin resistance warranted the use of vancomycin extensively. Surveillance cultures were found to be useful in selected patients. Although slime factor is an important virulence factor, there was no difference between slime factor positive and negative coagulase-negative staphylococci isolated during infections. In conclusion, febrile episodes are the most frequent complication of PBSCT and Gram-positive microorganisms remain the main pathogen in these patients because of catheter use, mucositis and ciprofloxacin prophylaxis. Methicillin resistance is increasing and glycopeptides remain the only choice for treating such infections. Although the infection rate is high, measures taken to prevent and treat infections result in very low rates of mortality from infection in PBSCT patients.