Dosimetric comparison of AP/PA and bilateral geometries for total body irradiation treatment.

Total body irradiation (TBI) is an external radiotherapy technique. Its aim is to deliver a therapeutic dose uniformly within ± 10% of the absorbed dose to the prescription point. In the present study, the TBI technique was implemented in anterior/posterior (AP/PA), and bilateral geometry with photons from a 6 [Formula: see text] and 18 [Formula: see text] accelerator. The TBI technique was implemented on an Alderson Rando phantom at 312 [Formula: see text] source surface distance. During bilateral fraction, rice bags were applied as tissue compensators. To reduce the lung's absorbed dose to the acceptance level, in AP/PA geometry lung blocks made of Cerrobend were used. The required monitor unit (MU) for each fraction was calculated regarding depending on the prescribed dose and beam output. Gafchromic EBT3 films were used for dosimetry between the phantom layers in eight selected points. It is demonstrated that dose uniformity for AP/PA geometry with 6 [Formula: see text] and 18 [Formula: see text] photons was within ± 10%. In contrast, for the bilateral geometry the dose uniformity was not acceptable for both studied energies; However, the results for 18 [Formula: see text] were better than those for 6 [Formula: see text]. Dose accuracy for all measurements was within ± 5 of the prescribed dose. The absorbed dose to the lungs was successfully reduced using the lung blocks. By combining different therapeutic geometries and energies over six fractions, the results of uniformity and accuracy of dose delivery could be improved. It is concluded that the introduced TBI method achieved good dose accuracy and acceptable dose uniformity. Lungs absorbed dose was lower than 10 [Formula: see text] using the lungs blocks. Based on these results, the TBI technique can now be implemented in radiotherapy at Tehran's Imam Hospital. The approach developed in the present study can be used and adapted to match with the conditions at other hospitals.

Treatment-related complications in patients with esophageal cancer: A systematic review and network meta-analysis.

BACKGROUND: The aim of this review was to compare the available treatments of esophageal cancer, in terms of pulmonary, cardiovascular complications, anastomotic leakage, and esophagitis after treatment in patients with esophageal squamous cell carcinoma (SCC). METHODS: Medline, Web of Science, Scopus, the Cochrane Library and Embase were searched. The randomized controlled trials (RCT) that had compared the treatment -related complications of treatments for esophageal SCC were included. We included 39 randomized control trials in a network meta-analysis. The Chi2-test was used to assess of heterogeneity. The loop-specific and design-by-treatment interaction methods were used for assessment of consistency assumption. The risk ratio with 95% confidence interval (CI) was used to report the effect-sizes in the network meta-analysis. RESULTS: The pulmonary complication, cardiac complication, anastomotic leakage, and esophagitis were reported in 31, 11, 17, and 15 RCTs respectively. Video-assisted thoracoscopy + laparoscopy (VATS) was rank as the first and second treatment in terms of lower risk for pulmonary complication and anastomotic leakage. There was no statistically significant difference between treatments in terms of lower risk of cardiovascular complications. However, Surgery + Cisplatin + Fluorouracil (SCF) was ranked as better treatment. 3-dimensional conformal radiotherapy + Docetaxel + Cisplatin (3DCRTDC) was the best treatment in terms of lower risk for esophagitis. CONCLUSION: According to the results of this study, it seems the risk of pulmonary, cardiovascular, anastomotic leakage and esophagitis complications for VATS, SCF, surgery + radiotherapy (SRT), and 3DCRTDC was lower than other treatments respectively in the networks.

Management of colon and rectal cancers during COVID-19 pandemic: A clinical guideline (TUMS-CRC-CoV19 Guideline).

Background: In a resource-demanding COVID-19 pandemic, guidelines can free up health care resources needed for providing better care to those with COVID-19 and other patients. This study was performed to design a guideline to manage patients with colorectal cancers during the COVID-19pandemic. Methods: To design this guideline, major topics and headings of colon and rectal cancers (CRC) were selected and included. Based on the extent of COVID-19 infection in the community and availability of hospital resources, the guideline has been designed for 2 major COVID-19 phases. Several multidisciplinary discussion sessions were held to review the comments of experts, finalize the data, and write the guideline. Results: This guideline has been prepared in 2 main COVID-19 phases of the community/hospital. Phase A refers to the condition where a large number of COVID-19 patients are admitted to the hospital, but limited surgical ICU beds and facilities are still accessible. In phase B, many people are affected by COVID-19, and all hospital resources are allocated for COVID 19 patients. In phase A, 4 major groups are discussed, including malignant and suspicious colorectal polyps, colon cancers, rectal cancers, and recurrent cancers. The approach to emergent cases, including obstruction, bleeding, and perforation, will be presented in phase B. Conclusion: This guideline is a comprehensive instruction on the approach to colorectal cancers during the COVID-19 pandemic that covers the major topics of colon and rectal cancers in detail.

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.

BACKGROUND: For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. METHODS: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. FINDINGS: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79­1·02] during years 5­9 and 0·75 [0·62­0·90] in later years; breast cancer mortality RR 0·97 [0·79­1·18] during years 5­9 and 0·71 [0·58­0·88] in later years). The cumulative risk of recurrence during years 5­14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5­14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89­1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13­3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83­1·36), ischaemic heart disease 0·76 (0·60­0·95, p=0·02), and endometrial cancer 1·74 (1·30­2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5­14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). INTERPRETATION: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. FUNDING: Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

The role of external beam radiation therapy in the management of thyroid carcinomas: A retrospective study in Iran Cancer Institute.

BACKGROUND: Thyroid cancers are histologically classified into three types; differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). Among the several therapeutic strategies for treatment and management of thyroid cancer, surgical resection in combination with radioactive iodine therapy (RAI) is indicated for moderate to high-risk differentiated thyroid cancer (DTC) patients- according to current guidelines. However, external radiation therapy (EBRT) can be a viable alternative treatment option for these patients and scarce evidence is available regarding the efficacy and effectiveness of EBRT on thyroid cancer. AIM: This study aims at evaluating the role of EBRT in the management of thyroid carcinomas. METHODS AND RESULTS: In this retrospective cohort study, the records of 59 patients with thyroid cancer were accessed who were treated by EBRT from 2008 to 2016. The indications for EBRT included unresectable primary (definitive) or loco-regional recurrences (salvage) not suitable for RAI, palliation for local disease or metastatic foci (palliative), and the adjuvant treatment for suspected residual disease following resection. Progression-free survival (PFS) and overall survival (OS) were calculated for different types of cancer. PFS was measured from the start of EBRT to the last uneventful follow-up, recurrence, or death. Kaplan-Meier model was used for the survival analysis. Fifty-nine patients were evaluated. The histopathology of the tumors was differentiated and poorly-differentiated, medullary and anaplastic thyroid carcinomas in 22 and 6, 15 and 16 patients, respectively. Twenty-seven patients received external beam radiotherapy (EBRT) as adjuvant therapy and 18 of the cases as palliative therapy while the remaining received salvage or definitive primary EBRT. The stage of patients' cancer was as follows: stage II in 3 and III in 1, IVA in 18 and IVB in 18 and IVC in 19. Stage-based median overall survival was 26 months for IVA, 44 for IVB, and 29 for IVC. The median PFS was 18, 22 and 21 months for stages IVA, IVB and IVC, respectively. CONCLUSION: Based on our findings, EBRT may still play a role in the management of patients with thyroid carcinoma and should be considered in the armamentarium against thyroid cancers.

Assessment of Tolerability, Response and Complications of Concurrent Chemoradiation With Capecitabine and Cisplatin in Muscle-Invasive Bladder Cancer; A Single Arm Study.

PURPOSE: To evaluate the feasibility, tolerance and efficacy of cisplatin+capecitabine as a proposed combination in concurrent chemoradiotherapy for patients with muscle-invasive bladder cancer (MIBC). METHODS: MIBC patients with stage T2-T4aN0M0 participated in this single-arm clinical trial. After maximal TURBT, 66Gy/33 daily fractions of radiation were administered with concurrent chemotherapy of cisplatin (35 mg/m2) and capecitabine (625 mg/m2). The primary endpoint was treatment tolerability, defined as receiving capecitabine+cisplatin combination for at least 5 weeks during radiation therapy. The secondary endpoints included complete response (CR) and acute toxicity rates. RESULTS: This study included 19 MIBC patients from 2018 to 2019. Eighteen patients (94.7%, 95%CI: 75.4-99.0) completed the planned treatment course. Only one patient (5.26%, 95%CI: 0.9-24.6) discontinued the treatment due to grade-3 GI toxicity. Among those who completed the treatment, CR was seen in 12 patients (66.7%, 95% CI = 44.4-88.9) with no grade ≥ 3 toxicities. The most common grade-2 side effects during therapy were renal complications (57.9%), and the only grade-2 complication after therapy was urinary-related (11.1%). The median follow-up was 31 months and the median overall survival (OS) was 31 months. The 2-year OS was 78% (95% CI 58.4-97.6), Cystectomy-free survival was 61% (95% CI: 37.5-84.5), and the median OS after recurrence was 13 months. Distant metastases were the first type of recurrence in most patients with a recurrence, which occurred in 7 (36.8%) patients. Median metastasis-free survival (MFS) was 30 months, and 2-year MFS was 66% (95% CI:45-87). CONCLUSION: The promising tolerability rate seen with concurrent cisplatin+capecitabine in this study was comparable to the available literature. Thus, this combination concurrently with radiation warrants further studies in the context of chemoradiotherapy of MIBC.

Current approaches in intensification of long-course chemoradiotherapy in locally advanced rectal cancer: a review.

Rectal cancer is one of the most prevalent cancers in the world. In many countries, the current standard of care is long-course chemoradiation (CRT), followed by total mesorectal excision. Some efforts have been made by intensifying radiation or chemotherapy components of the neoadjuvant therapy to further decrease the local recurrence and augment surgery's feasibility and improve the oncological outcomes. This paper reviews recent intensified neoadjuvant interventions in locally advanced rectal cancer (LARC) in terms of efficacy and treatment-related toxicity. Many maneuvers have been made so far to improve the oncological outcomes of rectal cancer with intensified neoadjuvant long-course CRT. Some of these approaches seem compelling and deserve further study, while some have just increased the treatment-related toxicities without evident benefits. Those endeavors with greater pathological complete response than the standard of care may make us await the long-term results on survival rates and chronic treatment-related toxicity. After introduction of neoadjuvant CRT for LARC there have been many efforts to improve its outcomes. Here, this study gathered most of these efforts that intensified the neoadjuvant therapy with some being promising and some being futile.

Network meta-analysis of palliative treatments in patients with esophageal cancer.

We aimed to compare available palliative treatments in terms of survival and to rank these treatments for esophageal cancer. Web of Science, Medline, Scopus, Cochrane Library and Embase were searched. The risk of bias was judged using Cochrane's tools. Statistical heterogeneity was assessed using the Chi2 test and was quantified by I2. The results were summarized using the hazard ratio (HR). The rank probability for each treatment was calculated using the p-score. Nineteen RCTs met the eligibility criteria for this study. Treatments formed three networks including networks A, B, and C. The Ultraflex stent (p-score = 0.93), irradiation stent (p-score = 0.89), and thermal ablative therapy (p-score = 0.85) were the first ranking treatments in networks A, B, and C, respectively. Based on the results of this network meta-analysis, it appears that the ultraflex stent, the irradiation stent, and thermal ablative therapy are the better treatments among the networks.

Low-dose whole-lung irradiation in severe COVID-19 pneumonia: a controlled clinical trial.

INTRODUCTION: The COVID-19 pandemic has caused significant morbidity and mortality thus far. Considering the historical uses of high-voltage X-ray beams for unresolvable pneumonia, we aimed to assess whether low-dose whole-lung irradiation (WLI) could provide any benefits for patients with refractory COVID-19 pneumonia. METHODS: Eleven patients with refractory COVID-19 pneumonia were treated with WLI to a total dose of 1 Gy and compared to 11 patients in a matched control group from June to November 2020. The study's primary endpoint was improvement of chest X-ray severity score (CXRS), followed by changes in mean oxygen (O2) saturation and 28-day mortality as secondary endpoints. RESULTS: The final CXRS was significantly lower in the WLI group (8.7 ± 2.5) compared to the control group (12.3 ± 3.3) (P: 0.016). Change of CXRS from the first to the last chest X-ray was -2.2 ± 3.1 for the WLI group and 0.7 ± 3.9 for the control group, which showed a trend for lower CXRS in the WLI group (U = 30, p: 0.085). Mean O2 saturation showed insignificant improvement in the first 24 hours after radiotherapy (mean difference: 2.5 ± 4.1, Z=-1.6, P value: 0.11). Overall survival after 28 days was 32% in the WLI group and 11% in the control group (P: 0.48). The reason for death in many patients was not merely respiratory failure, but also other adverse situations like pneumothorax, cardiogenic shock and pulmonary thromboembolism. CONCLUSIONS: Low-dose WLI could improve the CXR severity score and O2 saturation in severely ill COVID-19 patients, but larger studies are required to determine its impact on mortality.

Enhancement of resistance to chemo-radiation by hsa-miR-1290 expression in glioblastoma cells.

One of the resistance mechanisms to chemo-radiation is the efficiency of the DNA repair systems. MicroRNAs can alter the expression of their involved proteins; therefore, it may lead to a change in the response of cancer cells to adjuvant treatments. Here, the present study is aimed to investigate the role of hsa-miR-1290 on the chemo-radiation resistance and the target genes in the glioblastoma cells. First, we altered miR-1290 expression in the U-87 cells by using hsa-miR-1290 mimic and anti-miR-1290. Then, the Annexin V, CCK-8, MTT, colony formation, invasion, migration, and wound healing tests were utilized to study hsa-miR-1290 influences on cellular behavior such as proliferation, apoptosis, and metastasis. Moreover, the qRT-PCR and Western blot analyses were used to evaluate the effects of miR-1290 on the SOCS4 gene expression. Our results represented that the overexpression of miR-1290 could increase cell proliferation, migration, invasion, and resistance to chemo-radiation. The results showed miR-1290 directly targeted the 3՛UTR of the SOCS4 gene and suppressed its expression. Moreover, the suppression of hsa-miR-1290 led to an increase of apoptosis and cellular sensitivity to chemotherapy drugs and could also lead to decrease cell proliferation, migration, and invasion. Our findings proposed that miR-1290 can function as a novel oncomiR in glioblastoma cells by regulating its downstream genes such as SOCS4. Moreover, hsa-miR-1290 may be employed as a therapeutic target for clinical therapy of glioblastoma.

Evaluation of the treatment strategies on patient-derived xenograft mice of human breast tumor.

Since only a minority of patients may respond to single-agent therapies, methods to test the potential antitumor activity of rational combination therapies are still needed. This study aimed to characterize the efficacy of antitumor combination therapies in vivo within the primary tumor using patient-derived xenograft (PDX) models by gamma-irradiation-induced immune suppression. We employed four Luminal A PDX models obtained from human mammary tumors grown in mice. PDX models were implanted into the right flank of mice, and treatments have ensued once tumor volume reached ~150 mm3. Four of the active drugs- Adriamycin, Cyclophosphamide, Taxotere, and Tamoxifen-were tested in vivo to treat mammary tumors. The tumor volume was measured during the study. The mice's immune system was inherently suppressed by gamma irradiation, thus allowing human tumors to grow. The results showed that the tumorigenesis rate of the PDX model was from 65 to 80%. PDX models were successfully established with a high frequency of tumor engraftment. Humanized mice treated with a two-drug regimen, that is, adriamycin + cyclophosphamide exhibited an increased antitumor response than a three-drug regimen, that is, adriamycin + cyclophosphamide + taxotere that correlated with tumor growth inhibition. Combination therapies with adriamycin + cyclophosphamide in PDX mice reduced tumor growth in four Luminal A PDX models. These preclinical results suggest that a two-drug regimen than a three-drug regimen can be useful for breast cancer patients. This study provides insights for future studies combining chemotherapeutics with targeted therapies using PDX models by gamma-irradiation-induced immune suppression.

Prediction of Response to Neoadjuvant Chemoradiotherapy by MRI-Based Machine Learning Texture Analysis in Rectal Cancer Patients.

INTRODUCTION: Neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection is the standard treatment for locally advanced rectal cancer (LARC). Radiomics can be used as noninvasive biomarker for prediction of response to therapy. The main aim of this study was to evaluate the association of MRI texture features of LARC with nCRT response and the effect of Laplacian of Gaussian (LoG) filter and feature selection algorithm in prediction process improvement. METHODS: All patients underwent MRI with a 3T clinical scanner, 1 week before nCRT. For each patient, intensity, shape, and texture-based features were derived from MRI images with LoG filter using the IBEX software and without preprocessing. We identified responder from a non-responder group using 9 machine learning classifiers. Then, the effect of preprocessing LoG filters with 0.5, 1 and 1.5 value on these classification algorithms' performance was investigated. Eventually, classification algorithm's results were compared in different feature selection methods. RESULT: Sixty-seven patients with LARC were included in the study. Patients' nCRT responses included 11 patients with Grade 0, 19 with Grade 1, 26 with Grade 2, and 11 with Grade 3 according to AJCC/CAP pathologic grading. In MR Images which were not preprocessed, the best performance was for Ada boost classifier (AUC = 74.8) with T2W MR Images. In T1W MR Images, the best performance was for aba boost classifier (AUC = 78.1) with a σ = 1 preprocessing LoG filter. In T2W MR Images, the best performance was for naive Bayesian network classifier (AUC = 85.1) with a σ = 0.5 preprocessing LoG filter. Also, performance of machine learning models with CfsSubsetEval (CF SUB E) feature selection algorithm was better than others. CONCLUSION: Machine learning can be used as a response predictor model in LARC patients, but its performance should be improved. A preprocessing LoG filter can improve the machine learning methods performance and at the end, the effect of feature selection algorithm on model's performance is clear.

Author Correction: Prediction of Response to Neoadjuvant Chemoradiotherapy by MRI-Based Machine Learning Texture Analysis in Rectal Cancer Patients.

The original version of this article unfortunately contained a mistake. In the author group section, the correct name of the fourth author is "Reza Ghalehtaki." The authors apologize for this oversight and for any confusion it may have caused.

Short-course versus long-course neoadjuvant chemoradiotherapy in patients with rectal cancer: preliminary results of a randomized controlled trial.

PURPOSE: Colorectal cancer is becoming an increasing concern in the middle-aged population of Iran. This study aimed to compare the preliminary results of short-course and long-course neoadjuvant chemoradiotherapy treatment for rectal cancer patients. MATERIALS AND METHODS: Patients in group I received three-dimensional conformational radiotherapy with a dose of 25 Gy/5 fractions in 1 week plus concurrent XELOX regimen (capecitabine 625 mg/m2 from day 1-5 twice daily and oxaliplatin 50 mg/m2 on day 1 once daily). Patients in group II received a total dose of 50-50.4 Gy/25-28 fractions for 5 to 5.5 weeks plus capecitabine 825 mg/m2 twice daily. Both groups underwent delayed surgery at least 8 weeks after radiotherapy completion. The pathological response was assessed with tumor regression grade. RESULTS: In this preliminary report on complications and pathological response, 66 patients were randomized into study groups. Mean duration of radiotherapy in the two groups was 5 ± 1 days (range, 5 to 8 days) and 38 ± 6 days (range, 30 to 58 days). The median follow-up was 18 months. Pathological complete response was achieved in 32.3% and 23.1% of patients in the short-course and long-course groups, respectively (p = 0.558). Overall, acute grade 3 or higher treatment-related toxicities occurred in 24.2% and 22.2% of patients in group I and II, respectively (p = 0.551). No acute grade 4 or 5 adverse events were observed in either group. Within one month of surgery, no significant difference was seen regarding grade ≥3 postoperative complications (p = 0.333). CONCLUSION: For patients with rectal cancer located 5 cm above the anal verge, short-course radiotherapy with concurrent and consolidation chemotherapy and delayed surgery is not different in terms of acute toxicity, postoperative morbidity, complete resection, and pathological response compared to long-course chemoradiotherapy.

Neo-adjuvant chemoradiotherapy response prediction using MRI based ensemble learning method in rectal cancer patients.

OBJECTIVES: The aim of this study was to investigate and validate the performance of individual and ensemble machine learning models (EMLMs) based on magnetic resonance imaging (MRI) to predict neo-adjuvant chemoradiation therapy (nCRT) response in rectal cancer patients. We also aimed to study the effect of Laplacian of Gaussian (LOG) filter on EMLMs predictive performance. METHODS: 98 rectal cancer patients were divided into a training (n = 53) and a validation set (n = 45). All patients underwent MRI a week before nCRT. Several features from intensity, shape and texture feature sets were extracted from MR images. SVM, Bayesian network, neural network and KNN classifiers were used individually and together for response prediction. Predictive performance was evaluated using the area under the receiver operator characteristic (ROC) curve (AUC). RESULTS: Patients' nCRT responses included 17 patients with Grade 0, 28 with Grade 1, 34 with Grade 2, and 19 with Grade 3 according to AJCC/CAP pathologic grading. In without preprocessing MR Image the best result was for Bayesian network classifier with AUC and accuracy of 75.2% and 80.9% respectively, which was confirmed in the validation set with an AUC and accuracy of 74% and 79% respectively. In EMLMs the best result was for 4 (SVM.NN.BN.KNN) classifier EMLM with AUC and accuracy of 97.8% and 92.8% in testing and 95% and 90% in validation set respectively. CONCLUSIONS: In conclusion, we observed that machine learning methods can used to predict nCRT response in patients with rectal cancer. Preprocessing LOG filters and EL models can improve the prediction process.

The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells. METHODS: Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib. RESULTS: We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal. CONCLUSIONS: Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.

Thermoluminescence dosimetry of the dose received by scrotum and testes in radiotherapy of rectal cancer, compared to the point doses calculated by 3D-planning software.

PURPOSE: Radiation received by the testes in the course of radiotherapy for rectal cancer may cause oligospermia and azospermia. We sought to determine the dose to the scrotum and testes with thermoluminescence dosimetry (TLD), and compare it to the dose calculated by 3D planning software. METHODS: The TLDs were fixed to the scrotum in six points anteriorly and posteriorly in two fractions of radiotherapy. All patients received a 50-50.4 Gy total dose in prone position with 3D-planning. The average dose of TLD measurements was compared to the average of 6 relevant point doses calculated by the planning software. RESULTS: The mean scrotal dose of radiation in 33 patients as measured by TLD was 3.77 Gy (7.5% of the total prescribed dose), and the mean of point doses calculated by the planning software was 4.11 Gy (8.1% of the total dose), with no significant difference. A significant relationship was seen between the position of the inferior edge of the fields and the mean scrotal dose (P = .04). Also body mass index (BMI) was inversely related with the scrotal dose (P = .049). CONCLUSION: We found a dose of about 4 Gy received by the scrotum and testes from a total prescribed dose of 50 Gy in the radiotherapy of rectal carcinoma patients, with TLD measurements confirming testicular dose estimations by the planning software. This dose could be significantly harmful for spermatogenesis. Thus careful attention to the testicular dose in radiotherapy of rectal cancer for men desiring continued fertility is a necessity.

Preoperative short course radiotherapy with concurrent and consolidation chemotherapies followed by delayed surgery in locally advanced rectal cancer: preliminary results.

PURPOSE: This study aimed to assess complications and outcomes of a new approach, that is, combining short course radiotherapy (SRT), concurrent and consolidative chemotherapies, and delayed surgery. MATERIALS AND METHODS: In this single arm phase II prospective clinical trial, patients with T3-4 or N+ M0 rectal adenocarcinoma were enrolled. Patients who received induction chemotherapy or previous pelvic radiotherapy were excluded. Study protocol consisted of three-dimensional conformal SRT (25 Gy in 5 fractions in 1 week) with concurrent and consolidation chemotherapies including capecitabine and oxaliplatin. Total mesorectal excision was done at least 8 weeks after the last fraction of radiotherapy. Primary outcome was complete pathologic response and secondary outcomes were treatment related complications. RESULTS: Thirty-three patients completed the planned preoperative chemoradiation and 26 of them underwent surgery (24 low anterior resection and 2 abdominoperineal resection). Acute proctitis grades 2 and 3 were seen in 11 (33.3%) and 7 (21.2%) patients, respectively. There were no grades 3 and 4 subacute hematologic and non-hematologic (genitourinary and peripheral neuropathy) toxicities and perioperative morbidities such as anastomose leakage. Grade 2 or higher late toxicities were observed among 29.6% of the patients. Complete pathologic response was achieved in 8 (30.8%) patients who underwent surgery. The 3-year overall survival and local control rates were 65% and 94%, respectively. CONCLUSION: This study showed that SRT combined with concurrent and consolidation chemotherapies followed by delayed surgery is not only feasible and tolerable without significant toxicity but also, associated with promising complete pathologic response rates.