Statistical challenges in preprocessing in microarray experiments in cancer

Many clinical studies incorporate genomic experiments to investigate the potential associations between high-dimensional molecular data and clinical outcome. A critical first step in the statistical analyses of these experiments is that the molecular data are preprocessed. This article provides an overview of preprocessing methods, including summary algorithms and quality control metrics for microarrays. Some of the ramifications and effects that preprocessing methods have on the statistical results are illustrated. The discussions are centered around a microarray experiment based on lung cancer tumor samples with survival as the clinical outcome of interest. The procedures that are presented focus on the array platform used in this study. However, many of these issues are more general and are applicable to other instruments for genome-wide investigation. The discussions here will provide insight into the statistical challenges in preprocessing microarrays used in clinical studies of cancer. These challenges should not be viewed as inconsequential nuisances but rather as important issues that need to be addressed so that informed conclusions can be drawn.     

Immunologic prognosis in hemoblastoses in children

The diagnostic value of monoclonal antibodies is discussed. The expression of ICO-GM1 and ICO-G2 myeloid antigens in pediatric patients with nonlymphoblastic leukemia was associated with poor prognosis whereas patients with the expression of T-cell markers fared better. The prognostic value of the antigens was not altered by brief cytotoxic treatment. The prognosis for non-T-cell ICO-II+ type childhood lymphosarcoma was worse as compared to Ia+ICO-II- lymphoma subset. It was concluded that the biology of malignant cells and degree of cell differentiation (as assessed immunologically) affects treatment outcome significantly and should be considered in individualizing therapy for childhood lymphosarcoma and leukemia.     

Hodgkin's disease in children in Kuwait

Between 1968 and 1981, 78 children younger than age 15 years were diagnosed, staged, treated, and followed up for a minimum period of 2 years. Most cases (64%) were in their first decade and the male-to-female ratio was 1.9:1. Mixed cellularity type occurred in 49% and nodular sclerosis in 32%. Lymphocytic depletion type was rare and occurred in only 4% of the cases. More than one half (53%) had Stages III and IV at presentation. The mediastinum was involved in 38%. The treatment of Stages I and II was mainly by radiotherapy, and Stages III and IV by combination of radiotherapy and chemotherapy. The total survival was 75% and relapse-free survival was 53%. Since 1975, lymphography became a routine investigation and staging laparotomy was performed in selected case. The mantle field was extended to include the para-aortic bar and spleen in Stage II with enlarged mediastinum, Stage IIIs after laparotomy, and cases in which laparotomy was thought to be indicated but was not performed. The new policy resulted in marked improvement in survival (from 56% to 87%) and relapse-free survival (from 32% to 70%). The stage at presentation was the main prognostic factor, although in the second period of the study, the difference between Stage I and II disappeared.     

Education in radiation oncology in Europe.

The outcome of an inventory among 22 European countries with respect to the radiotherapy facilities and the training of new radiation oncologists in each country is described. The radiotherapeutic profession, which mostly prescribes also cytostatics or hormones, has become well-regulated in the last 20 years. Most radiation oncologists are also involved in the diagnostic work-up and follow-up of the cancer patient. The numbers of radiotherapists and other staff, treatment capacities, and patients are given. The training for radiation oncologists is mostly taken at the university centers, but the curricula are rather diverse.     

Radiotherapy techniques in current use in Sweden

A systematic assessment of radiotherapy for cancer was conducted by The Swedish Council on Technology Assessment in Health Care (SBU) in 2001. The assessment included a review of radiotherapy techniques in current use in Sweden. The following conclusions were drawn: Radiotherapy demands adequate knowledge of diagnostic methods, anatomy, cancer biology and of the physical and biological properties of ionizing radiation. Well-functioning teamwork on the part of the oncologist, medical physicist and oncology nurse is important. Radiotherapy has a high degree of technical sophistication, including the use of computers, which necessitates expert technical support. Technical development is rapid, and since the previous report, multileaf collimators and electronic portal imaging have been introduced in the clinical routine. The use of brachytherapy for treatment of non-gynaecological malignancies is rapidly increasing. The need for quality assurance in all steps of the radiotherapy procedure is stressed. A critical review of the literature on intraoperative radiotherapy is also included as an Appendix.     

Radiotherapy Techniques in Current Use in Sweden

A systematic assessment of radiotherapy for cancer was conducted by The Swedish Council on Technology Assessment in Health Care (SBU) in 2001. The assessment included a review of radiotherapy techniques in current use in Sweden. The following conclusions were drawn: Radiotherapy demands adequate knowledge of diagnostic methods, anatomy, cancer biology and of the physical and biological properties of ionizing radiation. Well-functioning teamwork on the part of the oncologist, medical physicist and oncology nurse is important.Radiotherapy has a high degree of technical sophistication, including the use of computers, which necessitates expert technical support.Technical development is rapid, and since the previous report, multileaf collimators and electronic portal imaging have been introduced in the clinical routine.The use of brachytherapy for treatment of non-gynaecological malignancies is rapidly increasing.The need for quality assurance in all steps of the radiotherapy procedure is stressed. A critical review of the literature on intraoperative radiotherapy is also included as an Appendix.     

Training in radiotherapy in The Netherlands.

The training in radiotherapy in The Netherlands is an example of a master apprentice system. In this overview we will discuss the organization and describe the official bodies involved in the Dutch training programs. Also the contents and the system of accreditation are presented.     

Evaluation of depression in newly diagnosed breast cancer cases in Hatay province of Turkey in 2011

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females in Turkey. The main problems experienced by women with breast cancer are physical losses, emotional distress and degradation in family, work and social roles. The purpose of this cross-sectional retrospective study was to investigate the socio-demographical characteristics and depressive symptoms of 125 newly diagnosed cases with breast cancer reported to cancer control department of Hatay provincial health directorate in 2011. To evaluate the depressive symptoms the Beck Depression Inventory (BDI) was used. All 125 cases who participated in the study were female. The mean age was 49.2 ± 11.9. The mean BDI score of the cases was 17.5 ± 10.6. The number of cases whose BDI scores were 17 and above was 65 (52.0%), and the number of cases whose BDI scores were under 17 was 60 (48.0%). The most striking finding in our study was that only 4 of the cases were receiving psychological help and support. The rate of depression was found high in our study and psychological support is a must for patients with a life threatening disease such as cancer.     

Time-trends in cancer incidence and mortality in Japan

The cancer incidence and mortality in Japan are described herein. The total number of deaths from all malignant neoplasms in 1998 was 284,000, corresponding to 30.3% of the total number of deaths among Japanese. Lung was the leading site of cancer deaths (17.9%), followed by the stomach (17.9%), large bowel (12.1%), liver (11.8%), pancreas (6.2%), gallbladder and extrahepatic biliary tract (5.2%), lymphatic tissue (3.7%), esophagus (3.4%), breast (3.1%), prostate (2.4%), leukemia (2.3%) and uterus (1.8%). The stomach was the leading site of cancer deaths until 1997, but was replaced by the lungs in 1998. The age-standardized mortality rates (1975-1998) have increased gradually for males, but decreased slightly for females. The rates have decreased remarkably for the stomach and uterus, while increasing for the lungs, large bowel, female breast, gallbladder and extrahepatic biliary tract, pancreas, and others. The total incidence for all cancers in Japan was estimated to be 454,000 in 1995. The stomach was the leading cancer site (22.2%), followed by the large bowel (17.7%), lung (11.6%), liver (7.8%), breast (6.6%), pancreas (3.7%), gallbladder and extrahepatic biliary tract (3.4%), lymphatic tissue (3.1%) and uterus (2.9%). The age-standardized incidence rates for all sites (1975-1995) have increased gradually for males, while remaining constant for females after a slight increase in the late 1970s. The incidence rates have decreased for the stomach and uterus, but increased for the large bowel, female breast, lung, liver, gallbladder and extrahepatic biliary tract, pancreas, prostate and others. The increase in the incidence rate was prominent for the large bowel, female breast and prostate.     

Spatial variation in stage distribution in colorectal cancer in the Netherlands

BackgroundIn the Netherlands the incidence of colorectal cancer has increased, mainly in the eastern part of the country. Patient delay due to unawareness or ignorance of symptoms and differences in use of diagnostic tools could have influence on the stage distribution. The aim of this study was to evaluate geographical differences in stage-specific incidence rates of colon and rectal cancer in the Netherlands.MethodsAge-adjusted incidence rates for cancers of the colon and rectum diagnosed in 2001–2005 and registered in the Netherlands Cancer Registry were calculated for each municipality and stage. The incidence for each 500 m by 500 m grid was estimated as a weighted average of the incidence rates of the neighbouring municipalities. The incidence rates and the stage distribution are both presented as maps. Geographic variation in stage-specific incidence was evaluated using spatial scan statistic.ResultsIn both colon and rectal cancer, significant spatial variation in stage-specific incidences was found, except for colon cancer of stages III and IV. The regions with a higher stage-specific incidence were almost all in the south eastern part of the Netherlands, however, these differences were not seen in the stage distribution. There were no differences in stage distribution between large cities and the rest of the country.ConclusionsThese maps give insight into differences in stage-specific incidences of colon and rectal cancer in the Netherlands. Educational interventions to increase the awareness of symptoms of colorectal cancer may be especially useful for the population in regions with high incidence of advanced stages.     

Parenteral opioids in end-of-life care in cancer patients

The ethical obligation to relieve pain and other distressing symptoms in patients with cancer is now receiving increasing attention and concern in palliative and end-of-life care. The vast majority of patients with cancer pain are prescribed opioids in oral formulation. However, a patient at the end of his or her life often needs parenteral administration of opioids as the medical condition deteriorates, irrespective of using sedatives. Controlled release opioid preparations currently available in Japan are CR morphine sulphate, CR oxycodone and transdermal fentanyl patch. The opioids available in injectable preparations are morphine HCL and fentanyl citrate. Accordingly, not only the guideline for switching opioids, so-called "opioid rotation," but the guideline for changing the opioid administration route is also necessary in end-of-life care. The authors specifically indicate when and how to convert opioid administration from the oral to the parental route.     

Original experience in plastic surgery of pelviureteral segment in hydronephrosis in children

The study of postoperative urodynamics of the upper urinary tract was made in 339 patients with obstruction of the pyeloureteral segment and on experimental animals (morphological tests). This study revealed factors deteriorating functional capacity of anastomosis in early postoperative period. The findings allow the surgeons to update the technique of the pyeloureteral segment resection and uretero-pyeloanastomosis, to determine indications for applying nonsteroid anti-inflammatory drugs in the postoperative period, to reveal advantages and establish indications for drainage-free pyeloplasty. Thus, use of drainage-free modified technique of pyeloplasty in certain indications is a safe and less traumatic method of the patients' management which increases efficacy of Anderson-Hines operation.     

Current opinion in the management in acute otitis media

The management of Acute otitis media has been a subject of controversy. This paper discusses the the current opinion on the subject including a review of recent literature. The use and choice of antibiotics reflects the wide variation in opinion for both first line and second-line therapy. The role of tympanocentesis and prophylactic treatment is discussed. The introduction of vaccines holds new promise on the prevention of Acute otitis media. Factors affecting outcome influence the management plan especially in recurrent cases, high risk groups and treatment failures.     

Acidic extracellular environment affects miRNA expression in tumors in vitro and in vivo

Hypoxia can control the expression of miRNAs in tumors which play an important role for the control of the malignant behavior. The aim of the study was to analyze whether extracellular acidosis, a common feature of tumors, also has an impact on the miRNA expression in isolated cells as well as in solid tumors. MiRNA expression was analyzed in two rat tumor cell lines (AT1 prostate and Walker-256 mammary carcinomas) by NGS and qPCR. In vivo the same cell lines were implanted subcutaneously and the tumor pH was modulated by inspiratory hypoxia and inhibition of the respiratory chain. In addition, the expression of five genes (Brip1, Ercc6l, Ikbke, Per3, Tlr5) which are potential targets of the miRNAs were analyzed on mRNA level. Screening showed that 38 (AT1) resp. 41 (Walker-256) miRNAs were pH-dependent. Validation by qPCR revealed that only 4 miRNAs were consistently regulated in both cell lines: miR-183, miR-203a, miR-215 and miR-7a. The expression of miR-7a was increased by low pH whereas all others were decreased. In the tumors in vivo all 4 miRNAs were down-regulated. The potential targets showed pH dependency in both cell lines. In conclusion, extracellular acidosis regulates the expression of miRNAs in vitro and in vivo. The expression of targets of these miRNAs were also pH-dependent. The pH may therefore affect the biological behavior of tumors via miRNAs.     

Surgical results in lung cancer in women

The paper deals with the immediate and long-term results of treatment of 173 female and 1,330 male patients with lung cancer operated on at the Department of Lung and Mediastinal Tumors of the Institute in 1960-1979. The results of radical surgery were better in females: 5-year survival rate was 1.5 times that in males (44.4% vs 31.4%) whereas at 10 years it was twice as high (35.5 vs 17.2%).     

Chromosomal alterations in ductal carcinomas in situ and their in situ recurrences

BACKGROUND: Ductal carcinoma in situ (DCIS) recurs in the same breast following breast-conserving surgery in 5%-25% of patients, with the rate influenced by the presence or absence of involved surgical margins, tumor size and nuclear grade, and whether or not radiation therapy was performed. A recurrent lesion arising soon after excision of an initial DCIS may reflect residual disease, whereas in situ tumors arising after longer periods are sometimes considered to be second independent events. The purpose of this study was to determine the clonal relationship between initial DCIS lesions and their recurrences. METHODS: Comparative genomic hybridization (CGH) was used to compare chromosomal alterations in 18 initial DCIS lesions (presenting in the absence of invasive disease) and in their subsequent ipsilateral DCIS recurrences (detected from 16 months to 9.3 years later). RESULTS: Of the 18 tumor pairs, 17 showed a high concordance in their chromosomal alterations (median = 81%; range = 65%-100%), while one case showed no agreement between the paired samples (having two and 20 alterations, respectively). Morphologic characterization of the DCIS pairs showed clear similarities. The mean number of CGH changes was greater in the recurrent tumors than in the initial lesions (10.7 versus 8.8; P =.019). The most common changes in both the initial and the recurrent in situ lesions were gains involving chromosome 17q and losses involving chromosomes 8p and 17p. The degree of concordance was independent of the time interval before recurrence and of the presence of positive surgical margins. CONCLUSIONS: In this study, DCIS recurrences were clonally related to their primary lesions in most cases. This finding is consistent with treatment paradigms requiring wide surgical margins and/or postoperative radiation therapy.     

Spontaneous lymphosarcoma arising in a nude mouse: characterization in vivo and in vitro.

A lymphosarcoma spontaneously arising in a nude mouse and a continuous cell line (NML-1) derived from it are described and compared. The primary tumor and a transplantable tumor line from it were composed of lymphoid cells, with no C-type viral particles seen by electron microscopy. The culture line was composed of cells with morphologic and functional properties of macrophages; budding C-type particles were abundant. The cells in the tumors produced in nude mice by injection of the NML-1 cells also resembled macrophages morphologically rather than lymphocytes; however, by electron microscopy, no C-type particles were seen. The findings suggest some type of in vivo suppression of complete expression of the virus.     

Hemoglobin in lymphogranulomatosis in children

The peculiarities of hemoglobin content and properties in lymphogranulomatosis were studied in children by different methods. In most patients the content of fetal hemoglobin and methhemoglobin was found to increase and the rate of ferricyanide oxidation of hemoglobin also increases. Simultaneously, the rate of non-homogenicity of basic hemoglobin fractions was observed to increase on account of immunologically different components.