Effects of genistein following fractionated lung irradiation in mice

Background and purpose

This study investigated protection of lung injury by genistein following fractionated doses of radiation and its effect on tumor response.

Material and methods

C3H/HeJ mice were irradiated (100 kVp X-rays) with 9 fractions of 3.1 Gy over 30 days (approximately equivalent to 10 Gy single dose) and were maintained on a genistein diet (∼10 mg/kg). Damage was assessed over 28 weeks in lung cells by a cytokinesis block micronucleus (MN) assay and by changes in breathing rate and histology. Tumor protection was assessed using a colony assay to determine cell survival following in situ irradiation of small lung nodules (KHT fibrosarcoma).

Results

Genistein caused about a 50% reduction in the MN damage observed during the fractionated radiation treatment and this damage continued to decrease at later times to background levels by 16 weeks. In mice not receiving Genistein MN levels remained well above background out to 28 weeks after irradiation. Genistein reduced macrophage accumulation by 22% and reduced collagen deposition by 28%. There was minimal protection against increases in breathing rate or severe morbidity during pneumonitis. No tumor protection by genistein treatment was observed.

Conclusions

Genistein at the dose levels used in this study partially reduced the extent of fibrosis developing in mouse lung caused by irradiation but gave minimal protection against pneumonitis. There was no evidence that genistein caused protection of small tumors growing in the lung.     

An evaluation of an automated 4D-CT contour propagation tool to define an internal gross tumour volume for lung cancer radiotherapy

Background and purpose

To evaluate an automated 4D-CT contouring propagation tool by its impact on the inter- and intra-physician variability in lung tumour delineation.

Materials and methods

In a previous study, six radiation oncologists contoured the gross tumour volume (GTV) and nodes on 10 phases of the 4D-CT dataset of 10 lung cancer patients to examine the intra- and inter-physician variability. In this study, a model-based deformable image registration algorithm was used to propagate the GTV and nodes on each phase of the same 4D-CT datasets. A blind review of the contours was performed by each physician and edited. Inter- and intra-physician variability for both the manual and automated methods was assessed by calculating the centroid motion of the GTV using the Pearson correlation coefficient and the variability in the internal gross tumour volume (IGTV) overlap using the Dice similarity coefficient (DSC).

Results

The time for manual delineation was (42.7 ± 18.6) min versus (17.7 ± 5.4) min when the propagation tool was used. A significant improvement in the mean Pearson correlation coefficient was also observed. There was a significant decrease in mean DSC in only 1 out of 10 primary IGTVs and 2 out of 10 nodal IGTVs. Intra-physician variability was not significantly impacted (DSC > 0.742).

Conclusions

Automated 4D-CT propagation tools can significantly decrease the IGTV delineation time without significantly decreasing the inter- and intra-physician variability.     

Inter-individual and inter-cell type variation in residual DNA damage after in vivo irradiation of human skin

Purpose

The aim of this study was to compare inter-individual and inter-cell type variation in DNA double-strand break (DSB) repair following in vivo irradiation of human skin.

Materials and methods

Duplicate 4 mm core biopsies of irradiated and unirradiated skin were collected from 35 patients 24 h after 4 Gy exposure using 6 MeV electrons. Residual DSB were quantified by scoring 53BP1 foci in dermal fibroblasts, endothelial cells, superficial keratinocytes and basal epidermal cells.

Results

Coefficients of inter-individual variation for levels of residual foci 24 h after in vivo irradiation of skin were 39.9% in dermal fibroblasts, 44.3% in endothelial cells, 32.9% in superficial keratinocytes and 46.4% in basal epidermal cells (p < 0.001, ANOVA). In contrast, the coefficient of inter-cell type variation for residual foci levels was only 11.3% in human skin between the different epidermal and dermal cells (p = 0.034, ANOVA). Foci levels between the different skin cell types were correlated (Pearson’s R = 0.855-0.955, p < 0.001).

Conclusions

Patient-specific factors appear to be more important than cell type-specific factors in determining residual foci levels following in vivo irradiation of human skin.     

Evaluation of the SUV values calculation and 4D PET integration in the radiotherapy treatment planning system

Background and Purpose

To evaluate the SUV calculation and integration of the gated (4D) PET in the iPlan 4.0 treatment planning software (BrainLAB).

Materials and Methods

Phantom and patient data for different tracers were used. Two comparisons were performed for each patient: for the delineated VOI, the maximum value of SUV in iPlan was compared with the results from TrueD software. For 10 patients lesion volumes were defined in both systems for a given SUV threshold and differences were calculated. For four patients examined with respiratory gated PET, SUV_max and volume analysis was performed in each phase of the breathing cycle in the gated and the ungated PET.

Results

Maximum differences of 6% and 10% were found for phantom and patient measurements of SUV_max. For patient data, maximal differences in delineated volume of 10% for ungated and up to 27% for gated PET were found in both systems.

Conclusion

This study suggests that for the safe implementation of PET data and delineation algorithms in the radiotherapy planning system, one has to be aware of the differences in SUVs and volumes found in the two systems.     

Metastatectomy for extra-cranial extra-adrenal non-small cell lung cancer solitary metastases: systematic review and analysis of reported cases

Back ground

Although patients with stage IV non-small cell lung cancer (NSCLC) have a poor prognosis, a subset of patients with solitary brain or adrenal metastasis have more favorable outcome following surgical resection. Nevertheless, the outcome and predictive factors for survival following metastatectomy for patients with other metastatic sites are not well defined.

Methods

We performed a systematic review using PUBMED database for all articles which included patients with NSCLC and solitary metastasis to sites other than the adrenal gland or the brain who had undergone resection of their metastasis and definitive treatment of the primary lung cancer. Potential prognostic factors on survival including age, sex, histology, T and N stage of the primary tumor, synchronous vs. metachronous presentation, visceral vs. non-visceral metastasis and the use of perioperative chemotherapy were analyzed using multi-variable Cox proportional hazard model.

Results

62 cases were eligible for the analysis. The 5-year survival rate was 50% for the entire cohort. Mediastinal lymph node involvement was independently predictive of inferior outcome; 5-year survival rate 0% vs. 64% in favor of no involvement, p < 0.001. Similarly, patients with intra-thoracic stage III disease had an inferior outcome compared to patients with stage II and stage I disease: 5-year survival rate 0% vs. 77% and 63%, respectively, p < 0.001. Other factors have no effect on outcome.

Conclusion

Selected patients with distant metastatic NSCLC can achieve long term survival following metastatectomy and definitive treatment of the primary tumor. Mediastinal lymph node involvement is associated with poor prognosis.     

Assessment of two novel ventilatory surrogates for use in the delivery of gated/tracked radiotherapy for non-small cell lung cancer

Background

In selected patients with NSCLC the therapeutic index of radical radiotherapy can be improved with gating/tracking technology. Both techniques require real-time information on target location. This is often derived from a surrogate ventilatory signal. We assessed the correlation of two novel surrogate ventilatory signals with a spirometer-derived signal. The novel signals were obtained using the VisionRT stereoscopic camera system. The VisionRT-Tracked-Point (VRT-TP) signal was derived from tracking a point located midway between the umbilicus and xiphisternum. The VisionRT-Surface-Derived-Volume (VRT-SDV) signal was derived from 3D body surface imaging of the torso. Both have potential advantages over the current surrogate signals.

Methods

Eleven subjects with NSCLC were recruited. Each was positioned as for radiotherapy treatment, and then instructed to breathe in five different modes: normal, abdominal, thoracic, deep and shallow breathing. Synchronous ventilatory signals were recorded for later analysis. The signals were analysed for correlation across all modes of breathing, and phase shifts. The VRT-SDV was also assessed for its ability to determine the mode of breathing.

Results

Both novel respiratory signals showed good correlation (r > 0.80) with spirometry in 9 of 11 subjects. For all subjects the correlation with spirometry was better for the VRT-SDV signal than for the VRT-TP signal. Only one subject displayed a phase shift between the VisionRT-derived signals and spirometry. The VRT-SDV signal could also differentiate between different modes of breathing. Unlike the spirometer-derived signal, neither VisionRT-derived signal was subject to drift.

Conclusion

Both the VRT-TP and VRT-SDV signals have potential applications in ventilatory-gated and tracked radiotherapy. They can also be used as a signal for sorting 4DCT images, and to drive 4DCT single- and multiple-parameter motion models.     

Volumetric response analysis during chemoradiation as predictive tool for optimizing treatment strategy in locally advanced unresectable NSCLC

Purpose

To study the feasibility of measuring volumetric changes in the primary tumor on megavoltage-computed tomography (MVCT) during chemoradiation and to examine the correlation with local response.

Patients and methods

Fifteen consecutive patients with stage III, inoperable, locally advanced non-small cell lung cancer (NSCLC) were treated in a prospective dose escalation study protocol of concurrent chemoradiation. They were monitored for acute toxicity and evaluated with daily MVCT imaging. The volumetric changes were fitted to a negative exponential resulting in a regression coefficient (RC). Local response evaluation was done with positron emission tomography using the radio-labeled glucose analogue F18 fluorodeoxyglucose (FDG-PET).

Results

The mean volume decrease (±standard deviation) was 73% (±18%). With a mean treatment time of 42 days this treatment schedule resulted in a mean decrease of 1.74%/day. Of the 13 evaluable patients seven developed a metabolic complete remission (MCR). The mean RC of the patients with MCR is 0.050 versus a mean RC of 0.023 in non-responders (p = 0.0074). Using a proposed cut-off value for the RC of 0.03 80% of the non-responders will be detected correctly while misclassifying 16.4% of patients who will eventually achieve an MCR. The total cumulative percentage of esophageal grade 3 or more toxicity was 46.7%.

Conclusion

The RC derived from volumetric analysis of daily MVCT is prognostic and predictive for local response in patients treated with chemoradiation for a locally advanced NSCLC. Because this treatment schedule is toxic in nearly half of the patient population, MVCT is a tool in the implementation of patient-individualized treatment strategies.     

Correlating quantitative MR measurements of standardized tumor lines with histological parameters and tumor control dose

Purpose

To correlate non-invasively acquired radiobiologically relevant magnetic resonance (MR) parameters with functional histology and tumor control doses (TCD₅₀).

Materials and methods

The MR parameters relative perfusion, re-oxygenation and lactate (Lac) concentration from eight human xenograft squamous tumor lines were compared with the histologically acquired pimonidazole hypoxic fraction, the perfused vessel area and TCD₅₀.

Results

Good spatial correlation in the parameter maps could be observed between the pimonidazole staining and tumor regions, which can be reoxygenated when breathing carbogen. A strong positive correlation (R = 0.74) was found between whole tumor pimonidazole hypoxic fraction and re-oxygenation, as one would expect. A good correlation was also observed between Lac concentration and re-oxygenation (R = 0.71) and between TCD₅₀ and re-oxygenation (R = 0.64), whereas Lac and TCD₅₀ showed a moderate relation (R = 0.44). The in vivo measurement of relative perfusion could be validated to reflect the perfused vessel area (R = 0.63). No correlation was detected between perfusion and re-oxygenation or TCD₅₀.

Conclusions

Lac and re-oxygenation were shown to be pretreatment predictive markers independent from the pathophysiological changes induced during a fractionated course of radiotherapy. These parameters hold promise to be acquired non-invasively with results just a few minutes after measurement and to tailor radiotherapy to individual patterns of a tumor microenvironment.     

Rectal dosimetry following prostate brachytherapy with stranded seeds - Comparison of transrectal ultrasound intra-operative planning (day 0) and computed tomography-postplanning (day 1 vs. day 30) with special focus on sources placed close to the rectal wall

Background and purpose

The aim of the study was to compare intra-operative and postplanning at different intervals with special focus on sources placed close to the rectal wall.

Materials and methods

In 61 consecutive patients, CT scans were performed on day 1 and day 30 after an I-125 implant with stranded seeds. The number of sources ?7 mm to the rectal wall was determined, and displacements were analyzed. The angulation of strands relative to rectal wall was compared between intra-operative transrectal ultrasound (TRUS) and both postplanning CT scans.

Results

Sources close to the rectum on day 1 (n = 204) have been the most apical in a strand in 98.5% (n = 201). By comparing day 1 and day 30 data, significant inferior source displacements (mean 3.6 mm; p = 0.02) relative to pelvic bones and a decreasing distance to the rectal wall (mean 1.2 mm; p < 0.01) - consequentially increasing rectal dose - were determined only for sources initially ?3 mm to the rectum. In contrast to an almost parallel arrangement of the needle track and the rectal wall in TRUS, strands and rectal wall converged towards the apex in the postplanning CT scans (mean >30°).

Conclusions

Posterior preplanning margins around the prostate should be particularly limited at the level of the prostate apex.     

Soy isoflavones radiosensitize lung cancer while mitigating normal tissue injury

Background

We have demonstrated that soy isoflavones radiosensitize cancer cells. Prostate cancer patients receiving radiotherapy (RT) and soy tablets had reduced radiation toxicity to surrounding organs. We have now investigated the combination of soy with RT in lung cancer (NSCLC), for which RT is limited by radiation-induced pneumonitis.

Methods

Human A549 NSCLC cells were injected i.v. in nude mice to generate lung tumor nodules. Lung tumor-bearing mice were treated with left lung RT at 12 Gy and with oral soy treatments at 1 mg/day for 30 days. Lung tissues were processed for histology.

Results

Compared to lung tumor nodules treated with soy isoflavones or radiation, lung tissues from mice treated with both modalities showed that soy isoflavones augmented radiation-induced destruction of A549 lung tumor nodules leading to small residual tumor nodules containing degenerating tumor cells with large vacuoles. Soy isoflavones decreased the hemorrhages, inflammation and fibrosis caused by radiation in lung tissue, suggesting protection of normal lung tissue.

Conclusions

Soy isoflavones augment destruction of A549 lung tumor nodules by radiation, and also mitigate vascular damage, inflammation and fibrosis caused by radiation injury to normal lung tissue. Soy could be used as a non-toxic complementary approach to improve RT in NSCLC.     

Comparison of gating around end-expiration and end-inspiration in radiotherapy for lung cancer

Purpose

To evaluate the advantages and disadvantages of gating around end-expiration and end-inspiration.

Materials and methods

We created five irradiation protocols to treat 15 patients with lung cancer. They were non-gated irradiation (protocol 1, P1), amplitude-based gating around end-expiration (P2) and end-inspiration (P3), and phase-based gating around end-expiration (P4) and end-inspiration (P5). We compared the lung dosimetric parameters and the treatment time.

Results

Compared to P2, in P3 the mean lung dose was reduced by 0.5 ± 0.4 Gy, V20 by 1.2 ± 0.9%, V10 by 1.4 ± 0.8%, and V5 by 1.5 ± 0.9% (p < 0.01). There was no statistically significant difference in these parameters between P4 and P5. At a dose rate of 600 monitor units/min (MUs/min), the average treatment time required for 100 MUs was 10, 26, 64, 33, and 33 s, respectively, for P1, P2, P3, P4, and P5.

Conclusions

With amplitude-based gating, gating around end-inspiration (P3) produced a greater decrease in the lung dose, however, the treatment time was longest among the four gated protocols. There was no significant difference between the two phase-based gating protocols (P4 and P5) with respect to the radiation dose to the lungs and the treatment time.     

A novel simple approach for incorporation of respiratory motion in stereotactic treatments of lung tumors

Purpose

An internal target volume (ITV) is often used for incorporating tumor motion into radiotherapy planning but it overestimates the margins necessary for breathing motion. We describe a pragmatic approach using maximum- and minimum-intensity projections (MIP and Min-IP) only, for reducing ITVs in stereotactic radiotherapy by using dosimetric margins that compensate for motion-induced dose blurring.

Patients and method

We studied tumor motion characteristics from 26 repeat 4DCT scans derived from 10 patients. These were used to calculate the shift in cranio-caudal direction of the 80% isodose due to dose blurring of the time-averaged dose distribution caused by respiratory motion. The dosimetric margins necessary to compensate for dose blurring were calculated relative to the ITV, which can be determined efficiently using the MIP. Peak-to-peak motion amplitude was determined using the MIP and Min-IP. A programmable respiratory motion phantom was used to investigate imaging artifacts in determining the ITV for realistic motion patterns. Dose profiles were both calculated and measured in lung- and water-equivalent tissue.

Results

Using margins for the 80% dose level permitted the use of smaller target volumes relative to the use of ITV-based volumes, with (i) greater reductions seen at the end-inspiration edge than at expiration side due to asymmetric breathing motion patterns and (ii) a linear relationship seen with breathing amplitude. The average reduction of the ITV at a 95% confidence level is given by 0.2 × A_pp − 1.3 mm at expiration side, where A_pp is the peak-to-peak breathing amplitude, and 0.3 × A_pp − 2.2 mm at inspiration side. Dosimetric margins did not differ significantly between water-equivalent and lung tissue for 80% isodose.

Conclusion

A simple margin recipe for breathing motion linear with breathing amplitude can be used to calculate the ITV reductions achievable for stereotactic radiotherapy of lung tumors.     

FDG-PET provides the best correlation with the tumor specimen compared to MRI and CT in rectal cancer

Purpose

To compare CT-, MR- and PET-CT based tumor length measurements in rectal cancer with pathology.

Patients and Methods

Twenty-six rectal cancer patients underwent both MR and PET-CT imaging followed by short-course radiotherapy (RT 5 × 5 Gy) and surgery within 3 days after RT. Tumor length was measured manually and independently by 2 observers on CT, MR and PET. PET-based tumor length measurements were also generated automatically using the signal-to-background-ratio (SBR) method. All measurements were correlated with the tumor length on the pathological specimen.

Results

CT-based measurements did not show a valuable correlation with pathology. MR-based measurements correlated only weakly, but still significantly (Pearson correlation = 0.55 resp. 0.57; p < 0.001). Manual PET measurements reached a good correlation with pathology, but less strong (Pearson correlation 0.72 and 0.76 for the two different observers) than automatic PET-CT based measurements, which provided the best correlation with pathology (Pearson correlation of 0.91 (p < 0.001)). Bland-Altman analysis demonstrated in general an overestimation of the tumor diameter using manual measurements, while the agreement of automatic contours and pathology was within acceptable ranges. A direct comparison of the different modalities revealed a significant better precision for PET-based auto-contours as compared to all other measurements.

Conclusion

Automatically generated PET-CT based contours show the best correlation with the surgical specimen and thus provide a useful and powerful tool to accurately determine the largest tumor dimension in rectal cancer. This could be used as a quick and reliable tool for target delineation in radiotherapy. However, a 3D volume analysis is needed to confirm these results.     

Treatment delivery time optimization of respiratory gated radiation therapy by application of audio-visual feedback

Purpose

The feasibility to use visually guided voluntary breath-hold with and without audio assistance to reduce the total treatment time was evaluated.

Materials and methods

Patients referred for gated SBRT received hypofractionation schedules for lung or liver treatments. The patients were treated with the Novalis^® system (BrainLAB AG, Feldkirchen, Germany) and IGRT was performed with ExacTrac5.0/NovalisBody^® allowing gated irradiation. Video glasses, used for visual feedback to guide voluntary breath-hold, allowed additional audio assistance during treatment.The technique was applied for 25 patients of whom 9 were treated in free breathing, 7 had only visual feedback and another 9 had both audio and visual feedback.

Results

The delivery time of gated treatment during free breathing had an average value of 1.7 min/100 MU (SD 0.6 min/100 MU). The introduction of visual feedback reduced the average delivery time to 1.4 min/100 MU (SD 0.4 min/100 MU). The treatments with additional audio assistance indicated a significant reduction (p = 0.004) of the average delivery time to 0.9 min/100 MU (SD 0.2 min/100 MU).

Conclusion

The introduction of visually guided voluntary breath-hold with audio assistance led to treatment times for gated radiation therapy approaching conformal beam delivery times, which made gated treatments applicable in conventional treatment time slots.     

Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel

Background

In anthracycline-pretreated metastatic breast cancer (MBC) patients, it is unknown whether weekly single-agent docetaxel is preferable to 3-weekly docetaxel regarding its toxicity and efficacy profile.

Patients and methods

In this multicenter, randomised, open-label phase III trial, 162 patients were randomised to weekly docetaxel (group A) or 3-weekly docetaxel (group B). The primary end-point was tolerability; secondary end-points were efficacy and quality of life (QoL).

Results

Group A (weekly docetaxel, n = 79) experienced less haematological toxicity, with just 1.3% versus 16.9% febrile neutropenia in group B (3-weekly docetaxel, n = 77) (p = 0.001). Not this difference, but fatigue and general malaise foremost led to more patient withdrawals in group A (24 versus 12 patients, p = 0.032), less patients completing treatment (29 versus 43 patients, p = 0.014) and reduced dose-intensity (15.6 versus 26 mg/m²/week, 58% versus 70% of projected dose, p = 0.017). As a result, 3-weekly docetaxel was related to better overall survival in multivariate analysis (hazard ratio 0.70, p = 0.036), although in univariate analysis efficacy was similar in both groups. Reported QoL was similar in both groups, but less effective treatment with more general toxicity led to less completed QoL forms in group A (65.4% versus 50%, p=0.049).

Conclusion

Weekly docetaxel is less well tolerated than a 3-weekly schedule, due to more non-haematological toxicity, despite less febrile neutropenia. Also, no efficacy benefits can be demonstrated for weekly docetaxel, which may even be inferior based on multivariate analysis. Therefore, a 3-weekly schedule should be preferred in the setting of MBC.     

HDR endobronchial brachytherapy (HDRBT) in the management of advanced lung cancer - Comparison of two different dose schedules

Purpose

The aim of this work is to compare the results of various treatment protocols used in palliative HDRBT with the view of analyzing differences in survival and diminishing breathing difficulties.

Material and methods

A total of 648 patients with advanced lung cancer were divided into two groups according to their clinical stage and the Zubrod-ECOG-WHO score. 303 (46.8%) patients received a total dose of 22.5 Gy in 3 fractions once a week, and 345 (53.2%) patients received a single fraction of 10 Gy. They were under clinical and endobronchial observation taking into consideration survival rates, local remission and duration of symptom relief such as dyspnoea, breathing, cough and haemoptysis.

Results

There was no difference in the length of survival time between the two groups of patients (log-rank test, p = 0.055). Patients showing improvement (objective response) survived longer than those who showed no change or progression (F Cox, p = 0.000001). In multivariate analysis the other statistically important prognostic factors were: clinical stage of primary tumor (F Cox, p = 0.000002), Zubrod-ECOG-WHO score (F Cox, p = 0.002) and age of patients (F Cox, p = 0.004).

Conclusions

The two treatment protocols showed similar efficiency in overcoming difficulties in breathing. Prognostic factors that significantly correlated with survival length were: grade of remission after treatment, clinical stage and performance status.     

A study on the dosimetric accuracy of treatment planning for stereotactic body radiation therapy of lung cancer using average and maximum intensity projection images

Purpose

To assess the accuracy of current stereotactic body radiation therapy (SBRT) lung treatment planning methodologies on irregular breathing patterns, we have performed a systematic dosimetric evaluation in phantoms by utilizing maximum intensity projection (MIP) and average (AVG) images generated from four dimensional computed tomography (4DCT).

Methods

A custom built programmable lung phantom was used to simulate tumor motions due to various breathing patterns of patients. 4DCT scans were obtained in helical mode, and reconstructed AVG and MIP datasets were imported into the Pinnacle 8.0 h treatment planning system. SBRT plans were generated and executed, and delivered doses were measured by radiochromic film for analysis.

Results

For targets moving regularly or irregularly within a small range (7.0 ± 1.8 mm, n = 6), we observed good agreement between the measured and computed dose distributions. However, for targets moving irregularly with a larger range (20.8 ± 2.6 mm, n = 4), the measured isodose lines were found to be shifted relative to the planned distribution, resulting in an under-dosing (over 10%) in a portion of the PTV. We further observed that the discrepancy between planned and measured dose distribution is due to the inaccurate representation of irregular target motion in the MIP images generated from 4DCT.

Conclusions

Caution should be used when planning from 4DCT images in the presence of large and irregular target motion. The inaccuracy inherent in 4DCT MIP and AVG images can be mitigated through the application of methodologies to reduce respiratory motion, such as abdominal compression, and through the use of volumetric image guidance (e.g., cone beam CT - CBCT) to assure precise targeting with minimal shifts.     

Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies

Background

Diabetes mellitus (DM) is widely considered to be associated with risk of pancreatic cancer (PaC), however, whether DM is a cause or a consequence of PaC is still controversial. We examined this association by conducting a detailed meta-analysis of cohort studies.

Methods

Studies were identified by searching Medline and Embase through November 30, 2010. Summary relative risks (RRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model.

Results

A total of thirty-five cohort studies were included in this meta-analysis. DM was associated with an increased risk of PaC (the summary RRs = 1.94; 95% CI, 1.66-2.27), with significant evidence of heterogeneity among these studies (p < 0.001, I² = 93.6%). Subgroup analyses revealed that the increased risk of PaC was independent of geographic locations, sex, study design, alcohol consumption, body mass index (BMI) and smoking status. In addition, the relative risk of PaC was correlated negatively with the duration of DM, with the highest risk of PaC found among patients diagnosed within less than 1 year. There was no significant publication bias (p = 0.136 for Egger’s regression asymmetry test).

Conclusions

Findings from this meta-analysis strongly support that diabetes is associated with an increased risk of PaC in both males and females and that DM is both an early manifestation and an etiologic factor of pancreatic cancer.     

Endogenous and radiation-induced expression of γH2AX in biopsies from patients treated for carcinoma of the uterine cervix

Background and purpose

The possibility of using γH2AX foci as a marker of DNA damage and as a potential predictor of tumour response to treatment was examined using biopsies from 3 sets of patients with advanced carcinoma of the cervix. The relation between endogenous γH2AX expression and hypoxia was also examined.

Materials and methods

Set 1 consisted of 26 biopsies that included pre-treatment and 24 h post-radiation treatment samples. Pre-treatment biopsies from 12 patients in Set 2 were used to develop image analysis software while pre-treatment biopsies from 33 patients in Set 3 were examined for the relation between staining for the hypoxia marker pimonidazole and endogenous γH2AX expression. Formalin-fixed paraffin-embedded sections were analyzed after antigen retrieval and fluorescence antibody labeling for the hypoxia markers CAIX or pimonidazole in combination with γH2AX staining.

Results

Before treatment, 24 ± 19% of cells contained γH2AX foci, with most positive cells containing fewer than 5 foci per nucleus. Twenty-four hours after exposure to the first fraction of 1.8-2.5 Gy, 38 ± 19% contained foci. CAIX positive cells were 1.4 times more likely to exhibit endogenous γH2AX foci, and pimonidazole-positive cells were 2.8 times more likely to contain γH2AX foci. For 18 patients for whom both pre-treatment and 24 h post-irradiation biopsies were available, local control was unrelated to the fraction of cells that retained γH2AX foci. However, 24 h after irradiation, tumours that had received 2.5 Gy showed a significantly higher fraction of cells with residual γH2AX foci than tumours given 1.8 Gy.

Conclusions

Endogenous γH2AX foci are enriched in hypoxic tumour regions. Small differences in delivered dose can produce quantifiable differences in residual DNA damage that can overshadow inter-tumour differences in response.