Primary Diagnosis Of Patients Research Articles

Chronic Disseminated Candidiasis among Pediatric Cancer Patients: The Hidden Threat

Abstract Background Chronic disseminated Candidiasis (CDC) is a severe invasive fungal infection observed during neutrophil recovery in patients with acute leukemia treated with intensive chemotherapy. Clinical manifestations include persistent fever under broad-spectrum antibiotics and abdominal discomfort. HSC is characterized by the presence of nodular lesions in the liver, spleen, and other organs (lungs, kidneys, and skin) on radiological imaging. Methods The retrospective study was conducted from 2013 - 2022 including all pediatric hematological patients diagnosed with chronic disseminated candidiasis admitted and treated in Children’s Cancer Hospital Egypt (CCHE). Data included primary diagnosis, clinical presentation, microbiological, radiological, and treatment data. Results Three hundred fifty (350) pediatric cancer patients were diagnosed with candidemia. The median age was four years (4 months- 18 years). Chronic dissemination candidiasis (CDC) was reported in 30(9%) of our patients. The most affected organs were Liver (19 patients), spleen (13), renal (13), cautelous (13), brain (2) and retina (2). Candida tropicalis was the most common isolated spp. from blood/tissue culture (24 patients) followed by C. parapsilosis (3 patients). The primary diagnosis in patients with CDC was ALL (24 Patients) while (4 patients) has AML. CDC was developed on top of antifungal prophylaxis in 7 patients (24%): liposomal-amho B (3 patients), Micafungin (3 patients) and voriconazole (1 patient). Candida tropicalis was the most common isolated spp. from blood/tissue culture (80%). Steroid as treatment for CDC immune reconstitution syndrome done in around 50% of patients (Persistent fever with neutrophil recovery, absent progressive clinical/radiological findings). PET-CT was done in 10 patients with positive uptake in all cases, was helpful in resuming intensive chemotherapy in six patients despite persistent lesions in CT and was used to stop antifungal treatment despite positive radiological lesions in CT in three patients. The first line of treatment was echinocandin (53%) and liposomal ampho-B (46%) with overall mortality among CDC patients were 30%. Conclusion CDC is still a hidden threat among pediatric patients with still high mortality rate. Antifungal stewardship through screening and Rapid diagnosis using non-culture diagnostics are needed. PET scan is a helpful tool for diagnosis and response assessment and can add to treatment decision. Figure 1. Chronic Disseminated Candidiasis among Pediatric Cancer patients.

Secondary findings in genes related to cancer phenotypes in Turkish exome sequencing data from 2020 individuals.

Big data generated from exome sequencing (ES) and genome sequencing (GS) analyses can be used to detect actionable and high-penetrance variants that are not directly associated with the primary diagnosis of patients but can guide their clinical follow-up and treatment. Variants that are classified as pathogenic/likely pathogenic and are clinically significant but not directly associated with the primary diagnosis of patients are defined as secondary findings (SF). The aim of this study was to examine the frequency and variant spectrum of cancer-related SF in 2020 Turkish ES data and to discuss the importance of the presence of cancer-related SF in at-risk family members in terms of genetic counseling and follow-up. A total of 2020 patients from 2020 different families were evaluated by ES. SF were detected in 28 unrelated cases (1.38%), and variants in BRCA2 (11 patients) and MLH1 (4 patients) genes were observed most frequently. A total of 21 different variants were identified, with 4 of them (c.9919_9932del and c.3653del in the BRCA2 gene, c.2002A>G in the MSH2 gene, c.26_29del in the TMEM127 gene) being novel variations. In three different families, c.1189C>T (p.Gln397*) variation in BRCA2 gene was detected, suggesting that this may be a common variant in the Turkish population. This study represents the largest cohort conducted in the Turkish population, examining the frequency and variant spectrum of cancer-related SF. With the identification of frequent variations and the detection of novel variations, the findings of this study have contributed to the variant spectrum. Genetic testing conducted in family members is presented as real-life data, showcasing the implications in terms of counseling, monitoring, and treatment through case examples.

Yoğun Bakım Ünitesinde Fiberoptik Bronkoskopi Kılavuzluğunda Perkütan Dilatasyonel Trakeostomiye Karşı Klasik Kör Perkütan Dilatasyonel Trakeostomi: Komplikasyonlar, Mortalite ve Sonuçlar

Aim: This study aimed to compare percutaneous dilatational tracheostomy (PDT) procedures performed with fiberoptic bronchoscopy (FOB) guidance and classical blind technique regarding complications, mortality, and patient outcomes. Material and Methods: This study included 62 patients receiving mechanical ventilator support in the intensive care unit (ICU) between October 2022 and June 2023. Patients were randomized into two groups: those who underwent FOB-guided PDT (group FOB, n=31) and those who underwent PDT with the classical blind technique (group C, n=31). Demographic data, clinical characteristics, PDT procedure times, complications, and mortalities were analyzed. Results: The median age was 64 (range, 19-94) years, and 67.7% (n=42) of the patients were male. Demographic data were found similar between groups. The most common primary diagnosis in patients who underwent PDT was intracranial hemorrhages (32.3%, n=20). While the median tracheostomy opening time in the entire study group was 13 (range, 3-31) days, there was no significant difference between the groups (p=0.637). The mean PDT procedure time (9.6±3.8 vs 12.6±5.4 min, p=0.015), median ICU stay (26 vs 37 days, p=0.004), and complication rate (6.4% vs 25.8%, p=0.038) were found to be significantly lower in group FOB. While the 28-day mortality in the entire study group was 17.7% (n=11), there was no significant difference between the groups (p=0.740). Conclusion: In PDT procedures performed under FOB guidance, procedure time, length of stay in the ICU, and procedure-related complication rates were significantly lower, while no significant difference was observed in terms of mortality.

UNOS Decisions Impact Data Integrity of the OPTN Data Registry.

The Organ Procurement Transplant Network (OPTN)/United Network for Organ Sharing (UNOS) registry is an important national registry in the field of solid organ transplantation. Data collected are mission critical, given its role in organ allocation prioritization, program performance monitoring by both the OPTN and the Centers for Medicare & Medicaid Services, and countless observational analyses that helped to move the field forward. Despite the multifaceted importance of the OPTN/UNOS database, there are clear indications that investments in the database to ensure the quality and reliability of the data have been lacking. This analysis outlines 2 examples: (1) primary diagnosis for patients who are receiving a second transplant and (2) reporting peripheral vascular disease in kidney transplantation to illustrate the extensive challenges facing the veracity and integrity of the OPTN/UNOS database today. Despite guidance that repeat kidney transplant patients should be coded as "retransplant/graft failure" rather than their native kidney disease, only 59% of new incident patients are coded in this manner. Peripheral vascular disease prevalence more than doubled in a 20-y span when the variable became associated with risk adjustment. This article summarizes critical gaps in the OPTN/UNOS database, and we bring forward ideas and proposals for consideration as a path toward improvement.

Significance of bone marrow immunohistochemical analysis in patients with plasma cell neoplasms

Background. The group of plasma cell neoplasms includes benign and malignant diseases. Sometimes there are difficulties in making a diagnosis. The study of the diagnostic and prognostic significance of immunohistochemical (IHC) markers is of current interest.Aim. To study the significance of IHC markers and histological features of the bone marrow in primary diagnosis in patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).Materials and methods. The study included 287 patients with plasma cell neoplasms: MGUS (n = 148), MM (n = 139). The observation period was 50 months. All patients have performed an aspiration biopsy and histological examination of the bone marrow with IHC analysis of CD138+, CD56+, CD34+, κ- and λ-chains expression.Results. During the observation period the progression of MGUS to MM was recorded in 8.8 % (n = 13) of cases, the progression of MM was determined in 38.1 % (n = 53) of cases.In patients with MGUS and MM the determined percentage of plasma cells at aspiration biopsy was somewhat lower than at histological examination (p >0.001). Statistically significant differences were determined between the groups MGUS and MM by the type of infiltration (р <0.001). With an increase in the percentage of bone marrow lesions by IHC (<20 % vs. 20–50 % and 20–50 % vs. >50 %), in our study interstitial and diffuse type of lesion with large accumulations was more common compared to the nodular type (p = 0.001).The CD138+ expression (IHC) more than 10 % was associated with a decrease of progression-free survival in patients with MGUS.In MM patients with an interstitial type of bone marrow infiltration and CD138+ over 10 % osteodestructive syndrome was detected by X-ray methods in 82.9 % of cases.Determination of CD56+ and immunoglobulin light chains expression in patients with MM and MGUS indicated an unfavorable prognosis.Resistance to chemotherapy or disease progression in MM patients most often occurred with a combination of IgG and immunoglobulin light chains secretion, with CD138+ plasma cells more than 50 % according to IHC, with a diffuse type of bone marrow lesion with accumulations of plasma cells. MGUS patients progressed more frequently with more than 20 % CD138+ plasma cells according to IHC, interstitial type and diffuse plasma cells accumulation type of bone marrow lesion, secretion of IgG or two immunoglobulins.Conclusion. The significance of the IHC study in the diagnosis of plasma cell neoplasms was confirmed. Markers associated with the disease progression and chemotherapy resistance in patients with MGUS and MM were identified.

The BRCA Gene in Epithelial Ovarian Cancer.

Simple SummaryEpithelial ovarian cancer (EOC) is still the most lethal gynecological cancer. In the recent years, the germline alterations in breast cancer 1 (gBRCA1) and breast cancer 2 (gBRCA2) genes are of key importance not only for genetic counseling purposes, but for its therapeutic implications, as well as somatic mutations, for the latter. The integration of poly-(ADP ribose) polymerase inhibitors (PARPis) as part of the therapeutic options has changed EOC natural history.Epithelial ovarian cancer (EOC) is still the most lethal gynecological cancer. Germline alterations in breast cancer 1 (gBRCA1) and breast cancer 2 (gBRCA2) genes have been identified in up to 18% of women diagnosed with EOC, and somatic mutations are found in an additional 7%. Testing of BRCA at the primary diagnosis of patients with EOC is recommended due to the implications in the genomic counseling of the patients and their families, as well as for the therapeutic implications. Indeed, the introduction of poly-(ADP ribose) polymerase inhibitors (PARPis) has changed the natural history of patients harboring a mutation in BRCA, and has resulted in a new era in the treatment of patients with ovarian cancer harboring a BRCA mutation.

P-EGS10 Clinicopathology of Critically Ill Patient With Coffee Ground Vomitus Undergo Oesophagogastroduodenoscopy

Abstract Background The incidence of acute gastrointestinal bleed in Malaysia is approximately 72 per 100000, as the incidence in patients who had mechanical ventilation is 2.6%. Coffee ground vomitus is one of the presentations of upper gastrointestinal bleed, and the decision for upper gastrointestinal endoscopy in a critically ill patient with such presentation would be a dilemma as endoscopy might lead to several complications such as endotracheal tube dislodgement, transient bacteremia, cardiopulmonary event, and perforation. We studied the clinicopathology of patients who were referred to our unit with coffee ground vomitus in a critically ill condition, as it would help us further in determining the severity and outcome of the patients. Methods This was a retrospective cross-sectional study from 59 patients in the critical unit in Hospital Melaka who were referred to the surgical department for coffee ground vomitus and underwent esophagogastroduodenoscopy. The study was conducted from November 2020 till July 2021. Results The median age of the patient was 73 years old and the mean body mass index was 25.6.. The primary diagnosis of patients in the critical care was Acute Coronary Syndrome 18%, Sepsis 17%, and cerebrovascular accidents 10%. The mean systolic blood pressure was 126 and the mean pulse rate was 94. The mean hemoglobin level upon admission was 10.7 and 9.07 upon referral. Other laboratory parameters that were analyzed were urea, INR, platelet, and lactate. 51% had history of taking antiplatelet or anticoagulants. 92% of patients underwent urgent OGDS (within 24 hours of referral), and 30% of them had findings of high-risk ulcers (Forrest 1b, 2a, and 2b) which need urgent intervention. Conclusions The data from the study would be beneficial in providing evidence for further clinical research in our center on identifying the factors that will predict the outcome of OGDS towards the patient either for endoscopic intervention or diagnostic endoscopy only.

Efficacy of spirometry in COPD patients with pulmonary hypertension: A study in a tertiary care unit

Therapy for COPD patients, in particular those with advanced stage, is generally disappointing and frustrating for both the doctors and patient. Of the symptoms, dyspnea is an important and debilitating symptom for which most patient with COPD seek medical attention. For the evaluation of lung function test for pulmonary hypertension, arterial PO2 and FEV1 seem to be most reliable.COPD was diagnosed as per GOLD criteria. Baseline FEV was measured by spirometer. The patient then received two puffs of salbutamol. 15 minutes later 3-5 forced expiratory maneuver was repeated and the best FEV was recorded. Symptoms Score, and dyspnea grade were correlated with FEV both pre and post bronchodilator. The mean age of the 52 patients was 60±10.6 Years. The mean symptom score was 4.07 with SD : ± 0.81. 7.69% patients were in MRC dyspnea scale grade 1, 21.15% patients had grade 2 dyspnea, 25% patients had grade 3 dyspnea, 40.38% patients had grade 4 dyspnea and 5.76% patients had dyspnea of grade 5. There was a strong significance in the correlation of Symptom scale with Pre bronchodilator % predicted FEVand with post bronchodilator % predicted FEVThere was a high correlation between dyspnea and pulmonary hypertension measured by percentage predictive value. Spirometry was found to be very useful for the diagnosis and staging of COPD. This could be used in primary diagnosis of patients with COPD.

The Impact of the COVID-19 Pandemic on Pediatric Clinical Practice in Wenzhou, China: A Retrospective Study.

Introduction: The COVID-19 pandemic has affected all aspects of life worldwide. The aim of the present study was to review and describe and acknowledge the impact of COVID-19 on the pediatric health care system at a pediatric tertiary hospital in Wenzhou.Methods: A retrospective study was conducted at Yuying Children's Hospital of Wenzhou Medical University, a public pediatric tertiary hospital in Southern Zhejiang Province that specializes in pediatrics. The data regarding the primary diagnosis of patients were extracted from the electronic medical records system of the hospital. Data for outpatients and inpatients treated at the pediatric department were analyzed in the time frame of 22 weeks since the beginning of the pandemic (from December 30, 2019 to June 2, 2020) and compared with data from the same period in 2019.Results: The total number of outpatient cases in the previous 22 weeks of the year declined from 560,620 in 2019 to 247,030 in 2020, and inpatient cases decreased from 14,177 to 7,555. This negative trend settled by week 6 and 7 and subsequently approached the 2019 numbers. The most noticeable decrease in the number of cases was observed in children of preschool age. Moreover, the number of weekly visits decreased at the beginning of the epidemic, reached the lowest value during the lockdown period, and recovered after the lockdown.Conclusion: Based on the results of this study, clinical practice in a pediatric department in Wenzhou was substantially affected by the epidemic and measures such as physical distancing and increased personal hygiene, particularly in preschool-age children. An understanding of the trends and impacts of the pandemic on pediatric patients and health systems will facilitate better preparation of pediatricians in the future.

Inpatient outcomes and predictors of mortality in patients with gastrointestinal malignancies presenting with sepsis: A nationwide analysis.

4045 Background: Sepsis is a frequent cause of morbidity and mortality in patients with malignancy. However, there is paucity of literature on mortality, hospital charges and overall healthcare utilization among patients with GI malignancy, which we hope to characterize in this study. Methods: We queried retrospective data from the Nationwide Inpatient Sample (NIS) database for the year 2016. Sepsis (Dx1) was identified using ICD-10 code as primary diagnosis in patients with known GI malignancies (Dx2). Univariate and multivariate Poisson regression analysis was done to study outcomes. Propensity score matching was done to minimize confounding factors. Primary outcome was inpatient mortality. Secondary outcomes were Length of Stay (LOS), Total Charge (TOTCHG) and ICU admission. Results: A total of 43,240 patients with GI malignancy were admitted in 2016 with sepsis. Two most common GI malignancies admitted with sepsis were colorectal (35%) and hepato-cellular cancer (HCC) (28.2%). Overall mortality in GI cancer was 19.8% vs 10.2% in all cancers (p<0.01). There was male (59%) and Caucasian (63%) preponderance. Out of all hospital admissions for GI malignancy, 41.4% were secondary to sepsis. E. coli (31%) infection and gram-negative bacteremia (15%) were the most common causes of sepsis. Sepsis with GI malignancy was associated with length of stay of 7.4 days vs 5.4 days (coef 2.44, 95% CI 2.3-6.7 p=0.04) and a mean hospital charge of $88,728 vs $ 54, 668 (coef 34,140, 95% CI 44,264-90,646, p<0.01) as compared to without sepsis. After adjusting for demographic and patient related variables, independent predictors of mortality were old age, uninsured, African Americans, septic shock requiring pressor support, AKI, inpatient hemodialysis, metabolic encephalopathy and acute respiratory failure. Conclusions: Sepsis poses a substantial healthcare burden in patients with GI malignancy and is a major cause of mortality. Early antibiotic treatment is necessary for sepsis control in patients with GI malignancy. [Table: see text]

Extracorporeal Life Support in Pediatric Patients with Bronchopulmonary Dysplasia and Associated Pulmonary Hypertension.

This retrospective study reviews outcomes of 281 pediatric patients with bronchopulmonary dysplasia (BPD) managed with extracorporeal life support (ECLS). Data from 1982 to 2018 from the Extracorporeal Life Support Organization (ELSO) registry were queried for children aged 60 days to 18 years with a prior diagnosis of BPD, and all patients with secondary pulmonary hypertension (PH) were identified. Overall survival of patients with and without PH was 86.7% and 68.0%, respectively (p = 0.23). There was no report of patients with PH before 2004. Patients with BPD + PH were more likely to have associated intraventricular hemorrhage (p = 0.002) and retinopathy of prematurity (p = 0.05), as well as a greater reported use of sildenafil (p = 0.0001) and milrinone (p = 0.008) before ECLS. The most common primary diagnosis in patients with BPD was viral respiratory infection (45.3%) and in patients with BPD + PH was respiratory failure without mention of infection (40.0%). Inotrope use was the most common complication reported (36.7%) with survival of 54.4%. We conclude that data from the ELSO registry demonstrate reasonable survival in both, patients with BPD and BPD + PH. Thus, patients with BPD and associated PH should be considered candidates for ECLS.

Clinical Profile and Prognostication in Patients Admitted at Medical Intensive Care Unit at B. P. Koirala Institute of Health Sciences

Introduction: Critical Care management is an important issue in developing countries where Medical Intensive Care Units (MICU) patients have comorbidity or complications of multisystem involvement.
 Objectives: The objective of study was to analyze clinical profiles of patients in Medical Intensive Care Unit and identify applicable factors that prognosticate outcomes.
 Methodology: Study conducted at Medical Intensive Care Unit of B. P. Koirala Institute of Health Sciences, Dharan, Nepal. Records from July 31, 2013 to August 1, 2014 were retrospectively studied. Clinical profiles were analyzed, outcomes defined as improved, referred, Leave Against Medical Advice (LAMA) or death. An online calculator (MD+Calc) was used to calculate Sequential Organ Failure Assessment Score (SOFA). Descriptive statistics were used, values <0.05 were statistically significant.
 Results: Of 70 patients 36 (51.4%) were female, 30 (42.9%) had sepsis of which 12 (40%) had Community-Acquired Pneumonia. 8 (11.43%) had Acute Respiratory Distress Syndrome, 7 (10%) had congestive cardiac failure. 43 (61.43%) improved, 17 (24.3%) expired, 9 (12.86%) LAMA, one patient was referred. Sequential Organ Failure Assessment Score was >9 in 23 (41.07%) cases. Of 17 expired cases, 14 (82.35%) had SOFA score >9.
 Conclusion: Sepsis with pulmonary involvement is primary diagnosis in patients requiring Medical Intensive Unit Care. Sequential Organ Failure Assessment Score was useful for prognostication and can be used for better clinical decision-making.

The use of narrow band imaging for the detection of benign lesions of the larynx.

In the cases of uncertainty, even if the patient has no complaints about his voice quality, sometimes, benign vocal fold mass lesions are removed to exclude malignancy with the risk of resultant dysphonia. Narrow Band Imaging (NBI) enables a specific visualization of vessel structures in the superficial tissue. Benign lesions of the larynx are frequently characterized by abnormal vessel configuration or an absence of vessels in the area of the lesion. It was hypothesized that, in the primary diagnosis of patients with these benign lesions, the combination of white light and NBI endoscopy enables a better detection compared with white light endoscopy alone. Twenty-nine patients (eight patients with a cyst on a vocal fold, eight with a polyp, seven with a Reinke´s edema, two with a leukoplakia, one with a carcinoma, one with a granuloma, and two without any pathologic finding) were examined with normal white light and NBI endoscopy. 87 video sequences (29 white, 29 NBI, and 29 white/NBI) were generated and randomized and presented to 20 otolaryngologists who rated the videos in terms of the suspected diagnosis. Results were compared with the histopathologic findings of microlaryngoscopy. The probability of detecting benign lesions of the vocal folds was higher using NBI in combination with white light endoscopy compared with white light endoscopy alone. For vocal fold cysts, this difference was statistically significant. NBI endoscopy in combination with normal white light endoscopy improves the detection rate of benign lesions of the larynx, especially of vocal fold cysts.

Risk-Factor Profile and Comorbidities in 2398 Patients With Newly Diagnosed Hypertension From the Abuja Heart Study.

Risk factors, comorbidities, and end-organ damage in newly diagnosed hypertension (HT) are poorly described in larger cohorts of urban African patients undergoing epidemiological transition. We therefore decided to characterize a large cohort of hypertensive subjects presenting to a tertiary health center in sub-Saharan Africa.It is an observational cross-sectional study. We prospectively collected detailed clinical, biochemical, electrocardiography, and echocardiography data of all subjects with HT as the primary diagnosis in patients presenting at the Cardiology Unit of the University of Abuja Teaching Hospital over an 8-year period.Of 2398 subjects, 1187 patients (49.4%) were female with a mean age of 51 ± 12.8 years. Presenting symptoms and signs were most commonly palpitation in 691 (28.8%) followed by dyspnoea on exertion in 541 (22.6%), orthopnea in 532 (22.2%), pedal oedema in 468 (19.5%), paroxysmal nocturnal dyspnoea in 332 (13.8%), whereas only 31 (1.3%) presented with chest pain. Risk factors were obesity in 671 (28%); 523 (21.8%) had total cholesterol >5.2 mmol/L, diabetes mellitus was present in 201 (8.4%) and 187 (7.8%) were smokers.End-organ damage was present in form of echocardiographic left ventricular hypertrophy in 1336 (55.7%) followed by heart failure in 542 (22.6%). Arrhythmias occurred in 110 (4.6%) of cases, cerebrovascular accident in 103 (4.3%), chronic kidney disease in 26 (1.1%), hypertensive encephalopathy in 10 (0.4%), and coronary artery disease in 6 (0.26%). There were marked differences in sex as women were more obese and men presented with more advanced disease.The burden of HT and its complications in this carefully characterized African cohort is quite enormous with more than three-fourth having one form of complication. The need of effective primary and secondary preventive measures to be mapped out to tackle this problem cannot be overemphasized.

Chronic thromboembolic pulmonary hypertension: Time delay from onset of symtoms to diagnosis and clinical condition at diagnosis

Chronic-thromboembolic pulmonary hypertension (CTEPH) is a serious complication of acute pulmonary embolism (PE). In untreated patients prognosis is poor. It depends on WHO-functional class. A delay from onset of symptoms and diagnosis can lead to a further worsening of prognosis. A pulmonary endarterectomy is the treatment of choice. We aimed to evaluate the time delay from onset of symptoms to diagnosis and the WHO-functional class at primary diagnosis in patients with CTEPH. Retrospective analysis of data from 70 monocentrically registered patients (48 women, 22 men, mean age 66,2 years ± 13,8 years) with confirmed CTEPH from the pulmonary hypertension expert center Missionsärztliche Klinik. Diagnostic work-up was performed according to the current guidelines. Mean delay from onset of symptoms to diagnosis of CTEPH was 18 ± 26 months. Time delay was only slightly shorter in patients with a history of PE (n = 56; 81 %) than in patients without a history of PE (n = 13; 19 %): 16,9 ± 23,8 vs. 23,5 ± 36,9 months. Time delay was higher in patients who received vasoactive medication before the first contact with a PH expert center and in patients who were classified as technically not suitable for a thrombendarterectomy. 38 patients with a history of acute PE did not have a period without symptoms. In 18 patients symptoms had transiently gone after PE. More than 70 % presented in WHO functional class III or IV. Time delay between onset of symptoms and diagnosis of CTEPH and referral to a PH expert center is long and the majority of patients presented in WHO-functional class III or IV. Prognosis is poor in untreated patients and getting worse with a higher WHO-functional class. For this reason, and because CTEPH can be cured by a pulmonary endarterectomy, each patient with suspected PH should be referred to a PH expert center to exclude CTEPH.

Functional Validation and Clinical Significance Of a Newly Established Non-Transferrin-Bound Iron (NTBI) Assay System Utilizing Conventional Automated Analyzer

IntroductionIron is an essential metal in the body. However, iron overload is toxic, as excess ‘free' reactive iron produces damaging free radicals which can lead to cellular and organ damage. Iron homeostasis is therefore tightly regulated. However, when iron balance collapses (as in prolonged transfusion), transferrin (Tf) becomes fully saturated and non-Tf-bound iron (NTBI) appears in serum. NTBI levels are increased in various iron overload states, and decreased after treatment with iron chelators (example deferasirox) in thalassemia and hemochromatosis, and is therefore important in evaluating and monitoring iron toxicity risks. Although several NTBI measurement methods have been reported, they are extremely complicated and low in sensitivity, thus very few laboratories can quantify NTBI. Consequently, NTBI research has not progressed significantly to date. We previously established a novel assay system utilizing automated analyzers (used widely in clinical laboratories for diagnostic testing), which we presented at ASH 2012 poster session. Using this assay, we sought to measure NTBI in iron overloaded animals, healthy volunteers and patients' sera. MethodsData was analyzed using the HITACHI 7700 auto analyzer. Human serum was obtained from 41 healthy volunteers (16 males, 25 females) and 118 patients (61 males, 57 females) receiving treatment at the Asahikawa Medical University Hospital. Average age of healthy volunteers was 34.4 years and 60.6 years in patients. The primary diagnosis in patients included malignant lymphoma, acute myeloid leukemia, myelodysplastic syndromes, multiple myeloma and others. Patient data, including hemoglobin, biochemical markers including C-reactive protein (CRP), serum iron (sFe), unsaturated iron binding capacity (UIBC) and serum ferritin were obtained from the patients' records or determined for the healthy volunteers. Mice were administered intraperitoneal injections of physiological saline solution or iron-dextran (Fe 1 mg/day or Fe 10 mg/day) for 5 days, after which serum was collected. Rats received intravenous injections of physiological saline or iron sucrose. Serum was collected after 1, 3 and 6 hours iron injection. Informed consent was obtained from all study subjects, and study protocol and experimental procedures were approved by the Ethical and Animal Experiments Committee of Asahikawa Medical University and Hospital. Statistical analysis was done using Mann-Whitney U-test and Student paired t-test. Results and ConclusionMedian NTBI in healthy volunteers was 0.45 μM; no statistical difference was found between the sexes. Median NTBI in the patient group was 0.38 mM, a slight decrease to that of the healthy volunteers (statistical significance p=0.0144). In transferin saturation (TSAT) and NTBI measurement in the patients, NTBI increased markedly as TSAT reached over 80%. A slightly positive correlation was found between sFe and NTBI, but no significant correlation was observed between serum ferritin and NTBI. CRP>0.3 mg/dL is a positive indicator of inflammation, so median NTBI was compared with CRP-positive and -negative groups; NTBI decreased significantly in the CRP-positive group (p<0.05). On the other hand, median serum ferritin significantly increased in the CRP-positive group (p<0.05). This data shows NTBI is an unmistakably unique marker of iron metabolism unlike serum ferritin. This characteristic of NTBI may be helpful in overcoming problems with serum ferritin use as a marker of iron metabolism (serum ferritin is affected by inflammation), and provide additional information that directly reflects changes in iron metabolism, even in inflammatory states.Compared to the control group, a statistically significant increase in NTBI was observed in the Fe 10 mg/day mice group. After intravenous iron administration in the rats, NTBI was 0.16±0.04 μM at pre-treatment, and rapidly increased to 2.78±0.62 μM after 1 hour iron injection; this increase decreased over time, indicating that NTBI can be used not only as a marker to evaluate iron overload but also to precisely monitor dynamic changes in iron in serum. Our novel system revealed new findings and it indicates that this system must be useful for studying the physiological and clinical importance of NTBI. Disclosures:No relevant conflicts of interest to declare.

Abstract PD04-08: Circulating tumor cells (CTC) in peripheral blood of breast cancer patients two years after adjuvant chemotherapy depending on endocrine treatment — The German SUCCESS-Trial

Abstract Background: The prognostic significance of CTC in metastatic, as well as in primary breast cancer has been demonstrated (Rack et al., ASCO 2010). The optimal endocrine treatment strategy for postmenopausal patients (pts) with hormone sensitive breast cancer remains unclear.We analyzed the prevalence of CTC two years after primary diagnosis in patients with tamoxifen or anastrozole treatment. Methods: As part of the translational research project of the German SUCCESS-trial, we analyzed 23ml of peripheral blood from 307 N+ and high risk N-postmenopausal pts with hormone sensitive breast cancer two years after adjuvant taxane based chemotherapy and with tamoxifen or anastrozole treatment. The presence of CTCs was assessed with the CellSearchSystem (Veridex, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labelled with anti-cytokeratin (8,18,19) and anti-CD45 antibodies to distinguish between epithelial cells and leukocytes. Standard within the study was early switch treatment (tamoxifen for 2 years, followed by anastrozle), while pts with contraindications against tamoxifen were allowed to receive anastrozole up-front. Results: In 10.1% of pts (n=31) &amp;gt;1 CTC was detected after the completion of chemotherapy (range 2-33), while 7.8% (n=24) presented with &amp;gt;1 CTC (range 2-99) two years after completion of chemotherapy. The median age in the tamoxifen group was 59.9 years and 59.8 in the anastrozole group. In the tamoxifen group, 33.0% of the pts had a pT1 tumor, 5.3% G1 grading and 21.6% of the pts were node negative. In the anastrozole group, 30.0% of the pts had a pT1 tumor, 7.5% G1 grading and 22.5% of the pts were node negative, respectively. None of these differences were statistically significant. After the completion of chemotherapy, 9.7% of the pts were CTC positive in the tamoxifen group (range number of cells: 2-33) and 11.3% in the anastrozole group (range of cells: 2-24), p=0.69. Two years after primary diagnosis, 7.9% of the pts were CTC positive in the tamoxifen group (range number of cells:2-99) and 7.5% in the anastrozole group (range cells: 2-5), p=0.90. Actuarial disease free and overall survival will be presented at the meeting. Conclusions: The prognostic relevance of CTC in peripheral blood of early breast cancer patients both before and after chemotherapy has been demonstrated. The presented data will add information on the monitoring potential of CTC during adjuvant endocrine treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD04-08.

Randomized phase II study evaluating a carbon ion boost applied after combined radiochemotherapy with temozolomide versus a proton boost after radiochemotherapy with temozolomide in patients with primary glioblastoma: The CLEOPATRA Trial

BackgroundTreatment standard for patients with primary glioblastoma (GBM) is combined radiochemotherapy with temozolomide (TMZ). Radiation is delivered up to a total dose of 60 Gy using photons. Using this treatment regimen, overall survival could be extended significantly however, median overall survival is still only about 15 months.Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.First Japanese Data on the evaluation of carbon ion radiation therapy showed promising results in a small and heterogeneous patient collective.Methods/DesignIn the current Phase II-CLEOPATRA-Study a carbon ion boost will be compared to a proton boost applied to the macroscopic tumor after surgery at primary diagnosis in patients with GBM applied after standard radiochemotherapy with TMZ up to 50 Gy. In the experimental arm, a carbon ion boost will be applied to the macroscopic tumor up to a total dose of 18 Gy E in 6 fractions at a single dose of 3 Gy E. In the standard arm, a proton boost will be applied up to a total dose 10 Gy E in 5 single fractions of 2 Gy E.Primary endpoint is overall survival, secondary objectives are progression-free survival, toxicity and safety.DiscussionThe Cleopatra Trial is the first study to evaluate the effect of carbon ion radiotherapy within multimodality treatment of primary glioblastoma in a randomized trial comparing this innovative treatment of the treatment standard, consisitng of photon radiotherapy in combination with temozolomide.Trial RegistrationISRCTN37428883 and NCT01165671

Predictive value of CA 125 and CA 72-4 in ovarian borderline tumors

The aim of this study was to assess the prognostic value of cancer antigen (CA) 125 and CA 72-4 in patients with ovarian borderline tumor (BOT). All women diagnosed and treated for BOT at our institution between 1981 and 2008 were included into this retrospective study (n=101). Preoperatively collected serum samples were analyzed for CA 125 (Architect, Abbott and Elecsys, Roche) and CA 72-4 (Elecsys, Roche) with reference to clinical data and compared to healthy women (n=109) and ovarian cancer patients (n=130). With a median of 34.7 U/mL (range 18.1-385.0 U/mL) for CA 125 and 2.3 U/mL (range 0.2-277.0 U/mL) for CA 72-4, serum tumor markers in BOT patients were significantly elevated as compared to healthy women with a median CA 125 of 13.5 U/mL (range 4.0-49.7 U/mL) and median CA 72-4 of 0.8 U/mL (range 0.2-20.6 U/mL). In addition, there was a significant difference compared with ovarian cancer patients who showed a median CA 125 of 401.5 U/mL (range 12.5-35,813 U/mL), but no difference was observed for CA 72-4 (median 3.9 U/mL, range 0.3-10,068 U/mL). Patients with a pT1a tumor stage had significantly lower values of CA 125 but not of CA 72-4 compared with individuals with higher tumor stages (median CA 125 29.9 U/mL for pT1a vs. 50.9 U/mL for >pT1a; p=0.014). There was a trend for increased concentrations of CA 125 but not of CA 72-4 in the presence of ascites, endometriosis or peritoneal implants at primary diagnosis. With respect to the prognostic value of CA 125 or CA 72-4, CA 125 was significantly higher at primary diagnosis in patients who later developed recurrence (251.0 U/mL vs. 34.65 U/mL, p=0.012). Serum CA 125 and CA 72-4 concentrations in BOT patients differ from healthy controls and patients with ovarian cancer. CA 125, but not CA 72-4, at primary diagnosis correlates with tumor stage and tends to be increased in the presence of ascites, endometriosis or peritoneal implants. Moreover, CA 125 at primary diagnosis appears to have prognostic value for recurrence.

Socioeconomic Deprivation and Extended Hospitalization in Severe Mental Disorder: A Two-Year Follow-Up Study

Socioeconomic Deprivation and Extended Hospitalization in Severe Mental Disorder: A Two-Year Follow-Up Study