Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

An epistatic interaction between pre-natal smoke exposure and socioeconomic status has a significant impact on bronchodilator drug response in African American youth with asthma.

BACKGROUND: Asthma is one of the leading chronic illnesses among children in the United States. Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Bronchodilator medications are part of the first-line therapy, and the rescue medication, for acute asthma symptoms. Bronchodilator drug response (BDR) varies substantially among different racial/ethnic groups. Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, however, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. To improve our understanding of disparate health outcomes in complex phenotypes such as BDR, it is important to consider interactions between environmental and biological variables. RESULTS: We evaluated the impact of pairwise and three-variable interactions between environmental, social, and biological variables on BDR in 233 African American youth with asthma using Visualization of Statistical Epistasis Networks (ViSEN). ViSEN is a non-parametric entropy-based approach able to quantify interaction effects using an information-theory metric known as Information Gain (IG). We performed analyses in the full dataset and in sex-stratified subsets. Our analyses identified several interaction models significantly, and suggestively, associated with BDR. The strongest interaction significantly associated with BDR was a pairwise interaction between pre-natal smoke exposure and socioeconomic status (full dataset IG: 2.78%, p = 0.001; female IG: 7.27%, p = 0.004)). Sex-stratified analyses yielded divergent results for females and males, indicating the presence of sex-specific effects. CONCLUSIONS: Our study identified novel interaction effects significantly, and suggestively, associated with BDR in African American children with asthma. Notably, we found that all of the interactions identified by ViSEN were "pure" interaction effects, in that they were not the result of strong main effects on BDR, highlighting the complexity of the network of biological and environmental factors impacting this phenotype. Several associations uncovered by ViSEN would not have been detected using regression-based methods, thus emphasizing the importance of employing statistical methods optimized to detect both additive and non-additive interaction effects when studying complex phenotypes such as BDR. The information gained in this study increases our understanding and appreciation of the complex nature of the interactions between environmental and health-related factors that influence BDR and will be invaluable to biomedical researchers designing future studies.

Implications of lung corrections for dose specification in radiotherapy.

The influence of taking into account the lung density in the calculation of the dose distributions was examined for a group of 23 patients with bronchus carcinoma. Anatomical information and electron densities were available by means of CT scans. All calculations were made for cobalt-60 gamma rays using a patient specific multiple field irradiation technique. The effect of lung tissues for the dose distributions was calculated using a generalization of Batho's method. All patients entered into this study were planned to receive a minimum tumor dose of 60 Gy, calculated without correction for lung density. The actual dose in each patient was recalculated with lung correction. In the group of patients the corrected minimum tumor dose varied between 63 Gy and 77 Gy (105-128%). The calculated homogeneity of the dose in the target area and the dose to surrounding normal tissues are also affected by lung correction. For different radiation techniques and different methods of dose specification, the interrelation between corrected and uncorrected dose is presented in tables. The impact of lung correction on the uncorrected dose schedules that are commonly used in the treatment of patients with lung cancer is discussed.

Late complications of postoperative radiation therapy for cancer of the rectum and rectosigmoid.

PURPOSE: We retrospectively examined the surgical, medical, radiotherapeutic and technical factors associated with late small bowel and nonsmall bowel morbidity. METHODS AND MATERIALS: The medical records of 224 patients with cancer of the rectum and rectosigmoid treated mainly with abdominoperineal resection or anterior resection and postoperative radiotherapy at the University of Texas M.D. Anderson Cancer Center from 1973 to 1990 were reviewed. The median dose was 54 Gy (range 34-66 Gy) at 1.8-2 Gy per fraction using various techniques (23 had extended fields to L1 or L2; pelvic fields were treated with anterior-posterior in 85, 83 had a 3-field plan and 33 had a 4-field "box"). A positioning technique that treats patients on an open table-top device was used in 78 patients to move the small intestine out of the pelvis. Bladder distension was used in eight. Forty-seven patients received concomitant 5-fluorouracil. Small bowel series were performed in 122 patients to assess the volume of small bowel inside the pelvis below the conjugate line. RESULTS: In 29 patients, the median time to the development of small bowel obstruction was 7 months (range 0-69 months); 18 patients required reoperations. The small bowel obstruction rate was 30% in patients treated with daily extended field radiotherapy, 21% in those with a single pelvic field and 9% with multiple pelvic fields. Small bowel obstruction was positively correlated with postsurgical adhesions prior to radiotherapy and absence of reperitonealization at the time of initial surgery (p < 0.05). There was no correlation of small bowel obstruction with a history of hypertension, diabetes, prior surgery, history of abdominal infections, postoperative infections, wound healing, pathologic tumor stage, types of surgical procedures, sites of primary tumor, age, or sex. Patients developing small bowel obstruction had larger amounts of small bowel assessed radiologically below the conjugate line than those without complications. With the open table-top device, the small bowel obstruction rate was 3%. In 47 patients treated with radiation and chemotherapy on the open table-top device, the small bowel obstruction rate was 15%, but these patients had more small bowel inside the pelvis than those without the complication. The median time to the development of nonsmall bowel obstruction in 29 patients was 8 months (range 0-85 months), and the nonsmall bowel obstruction complications were significantly correlated with postoperative infection. Most nonsmall bowel obstruction complications were in the genitourinary tract and occurred in patients who had abdominoperineal resection. CONCLUSION: The open table-top device, by moving the small bowel out of the treatment field, reduces small bowel obstruction in patients treated with radical surgery and postoperative radiotherapy for cancer of the rectum and rectosigmoid. This technique is facile, reproducible, and does not require patient compliance.

Base-of-tongue carcinoma: treatment results using concomitant boost radiotherapy.

PURPOSE: To evaluate the efficacy of accelerated fractionated radiotherapy using the concomitant boost schedule for patients with squamous cell carcinoma of the base of tongue. METHODS AND MATERIALS: Between September 1984 and July 1992, 54 patients with squamous carcinoma of the base of tongue were treated at The University of Texas M. D. Anderson Cancer Center using the concomitant boost schedule. The distribution of T and N stages was T1-4, T2-27, T3-22, and T4-1; N0-9, N1-11, N2-24, N3-7, and NX-3. American Joint Committee on Cancer (AJCC) stage groupings were II-6, III-14, and IV-34. Before radiation, nodal excision and neck dissection were done in 5 and 10 patients, respectively; 5 patients had neck dissections after radiotherapy. Standard on and off spinal cord fields were irradiated with 1.8 Gy fractions to 54 Gy given over 6 weeks. The boost was given concomitantly during the large field treatment as a second daily (1.5 Gy) fraction, with an interfraction interval of 4-6 h. The median dose to the primary tumor was 72 Gy (range, 66-74 Gy). The median treatment duration was 42 days (range, 39-48 days). Only three patients had treatment interrupted for more than one scheduled treatment day. RESULTS: The 5-year actuarial overall survival and disease-specific survival rates were 59 and 65%, respectively, with a median follow-up of 41 months. The 5-year actuarial locoregional control rate was 76%. The actuarial local control rates achieved with radiotherapy at 5 years for T1, T2, and T3 primary tumors were 100%, 96%, and 67%, respectively; including surgical salvage, the local control rate of T3 primary tumors was 70%. Six patients had regional failures, which in three patients occurred in conjunction with primary tumor recurrence. Twenty-six patients with regional adenopathy were treated with radiation alone to full dose and had a complete clinical response in the neck; no planned neck dissections were performed in these patients. Only 2 of these 26 patients had subsequent regional failures. The 5-year actuarial risk of distant metastases in patients whose disease was controlled locoregionally was 21%. Grade 3 or 4 confluent acute mucositis occurred in 94% of patients. However, late complications were limited to two cases of transient mandibular exposure and three cases of self-limited mucosal ulcerations. CONCLUSION: The concomitant boost fractionation schedule is a very effective regimen for this disease when appropriately selected patients are treated with meticulous technique. The therapeutic ratio is favorable, with a high rate of disease control and no persistent severe late complications. Patients whose neck disease responds completely to treatment with this schedule do not appear to need a planned neck dissection.

Ultrasonically guided transperineal seed implantation of the prostate: modification of the technique and qualitative assessment of implants.

During the period 1988-1991, 23 patients with prostatic carcinoma were treated by transperineal iodine seed implantation guided by transrectal ultrasound. We introduce a refinement of the implantation technique using a rigid column of seeds and spacers. The uniformity parameter based on the peak width of the natural volume-dose histogram demonstrated quantitatively that this refinement resulted in a more accurate seed arrangement.

A conformation number to quantify the degree of conformality in brachytherapy and external beam irradiation: application to the prostate.

PURPOSE: This article presents a method of quantitative assessment of the degree of conformality and its designation by a single numerical value. METHODS AND MATERIALS: A conformation number is introduced to evaluate objectively the degree of conformality. A comparison is made between the conformation number as found for external beam treatment plans and ultrasonically guided 125I seed implants for localized prostate cancer. RESULTS: The conformation number in case of a planning target volume irradiated with two opposed open beams, three open beams, and three beams with customized blocks amounted to 0.17, 0.39, and 0.65, respectively. The conformation number as found for ultrasonically guided permanent prostate implants using 125I seeds averaged 0.72. CONCLUSIONS: The conformation number is a convenient instrument for indicating the degree of conformality by a single numerical value. Treatments with a conformation number greater than 0.60 might be termed conformal radiotherapy.

Verification of source position in interstitial and intralumenal brachytherapy.

In brachytherapy afterloading, the treatment is simulated using dummy sources. In this study, imaging during treatment was performed to see whether the radioactive sources accurately replaced the dummy sources. In low-dose rate afterloading (manually or remote controlled) X-ray radiography was applied for verification. In high dose rate afterloading, the radioactive source was visualised under remote controlled X-ray fluoroscopy. Differences between dummy and treatment source position were observed, justifying verification imaging in brachytherapy.

Comparison between predicted and actual dose distribution in interstitial therapy of the oral cavity.

During the period 1985-1986, 10 patients with lesions of the floor of the mouth or of the mobile part of the tongue were treated by interstitial curietherapie with iridium-192. In the patients treated with the looping technique essential differences were found between the predicted source configuration and that actually achieved, resulting in a disagreement between precalculated and actual dose distribution. To avoid this undesirable situation, a simple oral cavity applicator was constructed which guarantees parallelism and equidistance between the implanted needles. It was found that the use of this applicator resulted in an almost complete agreement between forecast and actual dose distribution.

Dose determination in bladder and rectum during intracavitary irradiation of cervix carcinoma.

The radiation dosage in the base of the bladder and in the anterior wall of the rectum during intracavitary irradiation of cervix carcinoma can be determined easily by use of intracavitary transvesical and transrectal ultrasound and simultaneous radiography. In case of excessive doses to the organs at risk, the dose can be lowered by rearrangement of the vaginal gauze packing in the same sitting.

HDR brachytherapy applied to cervical carcinoma with moderate lateral expansion: modified principles of treatment.

BACKGROUND AND PURPOSE: In order to meet the deficiencies of endocavitary applications, a combined technique was introduced with the aim of achieving better target coverage for improvement of loco-regional tumour control. In high dose rate (HDR) endocavitary applications with tandem and ovoids, enlargement of the distance between the ovoids, shifting of dwell times and also optimization often fail to achieve sufficient expansion of the cervical parametrial area encompassed by the reference isodose. MATERIALS AND METHODS: The Deventer method, whereby HDR endocavitary and HDR interstitial brachytherapy are applied in the same session, was applied for tumours with a lateral expansion of 25 mm or more from the axis of the cervical canal. For the addition of HDR interstitial brachytherapy, each ovoid was provided with a channel which allowed insertion of an afterloading needle into the cervix up to a fixed depth. The dose specifications and dosimetry in neighbouring organs are presented in detail. RESULTS: Seventy-six combined applications were given to 41 patients. The follow-up averaged at 23 months, with a maximum of 59 months. No severe early or persistent late complications were observed. In stage IIB tumours, the most important evaluation of the merits of this technique, the disease-free 3-year survival determined with the Kaplan-Meier method was 75% (n=20). CONCLUSIONS: The Deventer method of HDR endocavitary and HDR interstitial brachytherapy applied in the same session is a feasible method for enlargement of the reference isodose envelope in the cervical parametrial area. The 3-year disease-free survival in stage IIB patients and the low complication rates in all stages together, justify its continuation.

Evaluation of brachytherapy implants using the "natural" volume-dose histogram.

The "natural" volume-dose histogram as described by Anderson visualises graphically even small differences between source arrangements, making it a useful tool to compare planned and realised source configurations. In this study the histogram is applied to demonstrate that the introduction of an applicator in oral cavity implants or of iridium wire spacers used as templates in bladder implants improved the quality of the implants considerably, resulting in close agreement between the planned and the realised source configuration.

[Breast preserving therapy: shorter treatment duration by the peroperative introduction of iridium guide needles]. / Mammasparende therapie: kortere behandelingsduur door peroperatief plaatsen van iridiumgeleidenaalden.

In the Deventer Radiotherapeutic Institute from January 1981 through December 1989, 359 patients who had undergone a breast-saving operation were irradiated. Since 1987, iridium guiding needles were introduced peroperatively in 79 of these patients. Subsequently, irradiation was administered. With this method the total duration of treatment was 16 days shorter on average than in patients who postoperatively were treated with iridium or external irradiation; also, the patients treated peroperatively needed only to be anaesthetized once. In addition, better positioning of the needles was possible, reducing the risk of faulty localization. The follow-up was short but the preliminary results of the treatment were good (one local recurrence after an average follow-up of 20 months) and no adverse effect on wound healing was seen.

Malignant tumours of the parotid glands.

In malignant tumours of the parotid gland the tumour size, the function of the facial nerve before treatment and the presence of metastatic regional lymph nodes are important prognostic factors. An internationally accepted TNM-Classification is mandatory for deciding on treatment and for reviewing the results.

Computerized tomography in carcinoma of the prostate: treatment volume and morbidity in radiotherapy.

Fifty-five patients with adenocarcinoma of the prostate were treated with external beam irradiation. In 31 of them conventional localization was used and in 24 computerized tomography was used in the localization of the treatment volume. In these 24 patients we see a larger treatment volume with a wider distribution. This method would appear to be superior to the use of standard irradiation fields. The larger treatment volume did not increase morbidity.

The significance of DNA-ploidy and S-phase fraction in node-positive (stage D1) prostate cancer treated with androgen ablation.

BACKGROUND: The prognostic significance of primary tumor DNA-ploidy and S-phase fraction (SPF) was evaluated in patients treated with androgen ablation for regionally localized node-positive prostate cancer. METHODS: All patients were diagnosed with lymph node involvement by pelvic lymphadenectomy between 1984 and 1992 and were treated only with androgen ablation. Median follow-up was 45 months. Adequate material for DNA/nuclear protein flow cytometric analysis was available in 33 patients. RESULTS: The tumors were classified as diploid in 11, near-diploid in 4, tetraploid in 10, and aneuploid in 8 cases. Grouping the patients by nonaneuploidy (diploid and near-diploid and tetraploid) and aneuploidy revealed actuarial 4-year disease progression rates of 14 and 48% (log-rank, P = 0.04), and overall survival rates of 100 and 61% (P = 0.008); however, biochemical progression (rising prostate-specific antigen profile) rates were similar at around 70%. In contrast, SPF was not significantly related to any of the endpoints tested. Several other potential prognostic factors were examined and none correlated significantly with disease progression or survival. CONCLUSIONS: The biochemical progression rates for patients with nonaneuploid and aneuploid tumors were comparable and high, while the disease progression rates were higher and survival rates lower for those with aneuploid tumors. These data indicate that the lead time from biochemical to disease progression and death was shorter with aneuploidy. That these relationships were observed in such a small patient population attest to the strength of DNA-ploidy as a prognostic factor in this cohort.