Imaging of the post-radiation chest in lung cancer.

Radiation therapy using conventional fractionated external-beam or high-precision dose techniques including three-dimensional conformal radiotherapy, stereotactic body radiation therapy, intensity-modulated radiation therapy, and proton therapy, is a key component in the treatment of patients with lung cancer. Knowledge of the radiation technique used, radiation treatment plan, expected temporal evolution of radiation-induced lung injury and patient-specific parameters, such as previous radiotherapy, concurrent chemoradiotherapy, and/or immunotherapy, is important in imaging interpretation. This review discusses factors that affect the development and severity of radiation-induced lung injury and its radiological manifestations with emphasis on the differences between conventional radiation and high-precision dose radiotherapy techniques.

Morbidity following salvage esophagectomy for squamous cell carcinoma: the MD Anderson experience.

The survival advantage associated with the addition of surgical therapy in esophageal squamous cell carcinoma (ESCC) patients who demonstrate a complete clinical response to chemoradiotherapy is unclear, and many institutions have adopted an organ-preserving strategy of selective surgery in this population. We sought to characterize our institutional experience of salvage esophagectomy (for failure of definitive bimodality therapy) and planned esophagectomy (as a component of trimodality therapy) by retrospectively analyzing patients with ESCC of the thoracic esophagus and GEJ who underwent esophagectomy following chemoradiotherapy between 2004 and 2016. Of 76 patients who met inclusion criteria, 46.1% (35) underwent salvage esophagectomy. Major postoperative complications (major cardiovascular and pulmonary events, anastomotic leak [grade ≥ 2], and 90-day mortality) were frequent and occurred in 52.6% of the cohort (planned resection: 36.6% [15/41]; salvage esophagectomy: 71.4% [25/35]). Observed rates of 30- and 90-day mortality for the entire cohort were 7.9% (planned: 7.3% [3/41]; salvage: 8.6% [3/35]) and 13.2% (planned: 9.8% [4/41]; salvage: 17.1% [6/35]), respectively. In summary, esophagectomy following chemoradiotherapy for ESCC at our institution has been associated with frequent postoperative morbidity and considerable rates of mortality in both planned and salvage settings. Although a selective approach to surgery may permit organ preservation in many patients with ESCC, these results highlight that salvage esophagectomy for failure of definitive-intent treatment of ESCC may also constitute a difficult clinical undertaking in some cases.

The effectiveness of ICSI versus conventional IVF in couples with non-male factor infertility: study protocol for a randomised controlled trial.

STUDY QUESTIONS: Does ICSI result in a higher live birth rate as compared with conventional IVF in couples with non-male factor infertility? WHAT IS KNOWN ALREADY: ICSI is primarily indicated for severe male factor infertility. While the use of ICSI for couples with non-male factor infertility has been increasing worldwide, this is not supported by data from randomised controlled trials. Evidence from non-randomised studies suggest no benefit from ICSI compared with conventional IVF in non-male factor infertility, if not a harm. STUDY DESIGN SIZE DURATION: This randomised, open-label, multi-centre trial aims to compare the effectiveness of one ICSI cycle and one conventional IVF cycle in infertile couples with non-male factor infertility. A total of 1064 couples will be randomly allocated to an ICSI group and a conventional IVF group. The estimated duration of the study is 30 months. PARTICIPANTS/MATERIALS SETTING METHODS: Eligible couples are those whose husbands' total sperm count and motility are normal, have undergone ≤2 previous IVF/ICSI attempts, use antagonist protocol for ovarian stimulation, agree to have ≤2 embryos transferred and are not participating in another IVF study at the same time. Women undergoing IVM cycles, using frozen semen or having a poor fertilisation (≤25%) in previous cycle will not be eligible. Couples will be randomised to undergo ICSI or conventional IVF (1:1) with ongoing pregnancy resulting in live birth after the first embryo transfer of the started treatment cycle as the primary endpoint. All analyses will be conducted on an intention-to-treat basis. Effect sizes will be summarised as relative risk (RR), with precision evaluated by 95% CIs. STUDY FUNDING/COMPETING INTERESTS: All authors declare having no conflict of interests with regards to this trial. This work was supported by a grant from MSD [MISP #57508]. TRIAL REGISTRATION NUMBER: NCT03428919. TRIAL REGISTRATION DATE: 8 February 2018. DATE OF FIRST PATIENT'S ENROLMENT: 16 March 2018.

Cisplatin- and cyclophosphamide-induced primordial follicle depletion is caused by direct damage to oocytes.

It is well established that DNA-damaging chemotherapies can cause infertility and ovarian endocrine failure by depleting the ovarian reserve of primordial follicles. Currently, no effective pharmacological therapies exist for the preservation of long-term fertility and ovarian function in female cancer patients, due to a limited understanding of the mechanisms of chemotherapy-induced follicle depletion. This study investigated the cellular targets, molecular mechanisms, and temporal course of ovarian reserve depletion following treatment with commonly used chemotherapeutic drugs. Adult female C57BL/6 mice were injected i.p. with saline, cisplatin (5mg/kg), or cyclophosphamide (300mg/kg); ovaries were harvested after 8 or 24 hours. Follicle counts showed depletion of all follicular stages 24 hours after administration of cisplatin or cyclophosphamide. Eight hours post-treatment, H2A histone family member X (γH2AX) immunofluorescence showed DNA double-stranded breaks at all follicular stages, including within primordial follicle oocytes. This staining was resolving by 24 hours, indicating that primordial follicle oocytes begin to undergo either apoptosis or repair in this timeframe. γH2AX-positive follicles were further examined to identify the specific cell types damaged. In primordial, transitional, and primary follicles, only oocytes sustained DNA damage, whereas in secondary and antral follicles, only somatic cells were affected. TUNEL staining confirmed that apoptosis occurs in these targeted cell types. Whilst multi-drug and multi-dose regimens were not examined, this study conclusively shows that cyclophosphamide and cisplatin cause direct damage to primordial follicle oocytes, which then undergo apoptosis. Therefore, future pharmacological strategies to prevent chemotherapy-induced infertility in females must specifically prevent primordial follicle oocyte death.

Computational and Experimental Study of Thermodynamics of the Reaction of Titania and Water at High Temperatures.

Gaseous titanium hydroxide and oxyhydroxide species were studied with quantum chemical methods. The results are used in conjunction with an experimental transpiration study of titanium dioxide (TiO2) in water vapor-containing environments at elevated temperatures to provide a thermodynamic description of the Ti(OH)4(g) and TiO(OH)2(g) species. The geometry and harmonic vibrational frequencies of these species were computed using the coupled-cluster singles and doubles method with a perturbative correction for connected triple substitutions [CCSD(T)]. For the OH bending and rotation, the B3LYP density functional theory was used to compute corrections to the harmonic approximations. These results were combined to determine the enthalpy of formation. Experimentally, the transpiration method was used with water contents from 0 to 76 mol % in oxygen or argon carrier gases for 20-250 h exposure times at 1473-1673 K. Results indicate that oxygen is not a key contributor to volatilization, and the primary reaction for volatilization in this temperature range is TiO2(s) + H2O(g) = TiO(OH)2(g). Data were analyzed with both the second and third law methods using the thermal functions derived from the theoretical calculations. The third law enthalpy of formation at 298.15 K for TiO(OH)2(g) at 298 K was -838.9 ± 6.5 kJ/mol, which compares favorably to the theoretical calculation of -838.7 ± 25 kJ/mol. We recommend the experimentally derived third law enthalpy of formation at 298.15 K for TiO(OH)2, the computed entropy of 320.67 J/mol·K, and the computed heat capacity [149.192 + (-0.02539)T + (8.28697 × 10-6)T2 + (-15614.05)/T + (-5.2182 × 10-11)/T2] J/mol-K, where T is the temperature in K.

Addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer.

BACKGROUND: Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain. PATIENTS AND METHODS: We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. RESULTS: Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P = 0.004). Recursive partitioning analysis of men without ADT classified Gleason 4 + 3 = 7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P = 0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P = 0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P = 0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P = 0.380). CONCLUSION: The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.

Chemoradiation with and without adjuvant extrafascial hysterectomy for IB2 cervical carcinoma.

The optimal treatment strategy for stage IB2 cervical carcinoma that maximizes survival while minimizing toxicity remains controversial. The purpose of this study was to compare survival and toxicity in stage IB2 cervical cancer patients treated with chemoradiation and adjuvant extrafascial hysterectomy (cRT + H) versus definitive chemoradiation (cRT). Data were abstracted from patients with IB2 cervical carcinoma primarily treated at a single institution from January 1994 to December 2004. All patients received chemotherapy concurrent with external beam radiation therapy. Patients were subsequently treated with either a single low-dose rate brachytherapy applicator followed by adjuvant extrafascial hysterectomy (n = 24) or a second brachytherapy application to complete full-dose definitive chemoradiation (n = 30). Analyses were conducted using Kaplan-Meier survival and Chi-square statistics. Groups did not differ demographically with the exception of smoking. Smokers were significantly (P = 0.04) more likely to have been treated with definitive chemoradiation. Median tumor size was similar between groups. There was no difference in overall or disease-free survival between patients who received cRT + H versus cRT (P = 0.82 and 0.75, respectively). All recurrences in the cRT arm were in smokers. There were two grade 3-4 toxicities in each group. No treatment-related deaths occurred. In this small retrospective cohort study, we observed no difference in survival between patients treated with cRT + H versus cRT. These data complement published results of Gynecologic Oncology Group studies in patients with IB2 cervical cancer. Definitive comparison between the two treatment strategies would require a randomized prospective trial with stratification based on smoking.

Mutational analysis of Turnip crinkle virus movement protein p8.

Summary Turnip crinkle virus encodes two proteins, p8 and p9, that are both required for cell-to-cell movement. The p8 movement protein has been demonstrated to bind RNA in a cooperative manner, although, similar to many other plant virus movement proteins, it contains no canonical RNA binding domain(s). However, three positively charged regions of p8 may potentially form ionic interactions with the RNA backbone. To identify functional regions of p8, a series of alanine and deletion scanning mutations were produced. The effects of these mutations were analysed using both in vitro RNA binding assays and in vivo infections of susceptible (Di-3) and resistant (Di-17) Arabidopsis thaliana plants. Several mutants that have reduced RNA binding ability were also demonstrated to be movement deficient and replication competent. Based on these results, there appear to be two regions, located between amino acids 18 and 31, and 50 and 72, that are required for RNA binding. Furthermore, additional regions (amino acids 12-15, and 34-37) appear to play a role in vivo unrelated to in vitro RNA binding activity.

Role of protein-phosphorylation events in the anoxia signal-transduction pathway leading to the inhibition of total protein synthesis in isolated hepatocytes.

Incubation of isolated hepatocytes under N2/CO2 (no O2) produced a rapid and strong inhibition of overall polypeptide biosynthesis, which was neither related to cell death nor to the appearance of specific stress proteins. Treatment of the cells with the tyrosine-kinase inhibitor genistein or with the serine/threonine-protein-kinase inhibitor H7 did not modify the impairment of protein synthesis induced by oxygen deprivation, indicating that such signal-transduction pathways are probably not involved in the anoxia-mediated effect. Okadaic acid (100 nM) and Na3VO4 (1 mM) reduced the incorporation of [14C]Leu into proteins of hepatocytes maintained under aerobic conditions (93.3 kPa O2). The effects of oxygen deprivation and okadaic acid were additive, whereas sodium vanadate did not enhance the impairment of protein synthesis induced by anoxia. This observation suggests that a common mechanism, involving the net phosphorylation of protein tyrosine residues, that is insensitive to genistein might participate in the negative control of the translation induced by oxygen deprivation. The effect of anoxia on the synthesis of proteins was fully and rapidly reversible upon the restoration of oxygen supply, thus indicating that hepatocytes are able to sense O2. Although high concentrations of cobalt chloride partially mimic the effect of oxygen deprivation on protein biosynthesis, the nature of such an oxygen sensor remains unknown, and appears unlikely to be a part of a classic haem protein.