An uncommon presentation of segmental Becker's nevus involving the T4 dermatome.

This case report explores a rare manifestation of Becker's nevus, where the patient exhibited an unusual dermatomal distribution featuring a hyperpigmented, irregular patch with associated hypertrichosis on the T4 segment. While Becker's nevus is a well-known dermatological condition typically observed in the upper back region, instances of dermatomal distribution are exceptionally uncommon. This case presents a unique occurrence of segmental Becker's nevus, highlighting the atypical presentation of this condition.

Comparison of brain nicotine accumulation from traditional combustible cigarettes and electronic cigarettes with different formulations.

Rapid brain accumulation is critical for the acute reinforcing effects of nicotine. Although nicotine formulation (free-base vs. protonated or salt) in electronic cigarette (E-cig) liquid affects user satisfaction, its impact on brain nicotine accumulation (BNA) from E-cig use has not been evaluated in comparison with traditional combustible cigarettes (C-cigs) using a within-subjects design. BNA was directly assessed with 29 adult dual users (13 females) of E-cigs and C-cigs, using [11C]nicotine and positron emission tomography (PET). Participants underwent two 15-min upper body (from chest to head) scanning sessions during which they inhaled a single puff of [11C]nicotine-labeled vapor from E-cigs with free-base nicotine or C-cig smoke in a randomized order. Seventeen of them also went through another session during which they inhaled from E-cigs with nicotine salt. A full-body scan was also conducted at each session to measure total absorbed dose of [11C]nicotine. Mean maximum nicotine concentration (Cmax) in brain following inhalation of free-base nicotine E-cig vapor was 19% and 15% lower relative to C-cig smoke and nicotine salt E-cig vapor (ps = 0.014 and 0.043, respectively). The Cmax values did not differ significantly between the C-cig and nicotine salt E-cig. Mean values of time to the maximum concentration (Tmax) were not significantly different between the two types of E-cig, but they were 64% and 40% longer than that for C-cig smoking (ps = 0.0005 and 0.004, respectively). Mean Cmax with C-cigs and free-base nicotine E-cigs were greater in females relative to males and correlated with T1/2 of lung nicotine clearance and participants' pack-years. These results suggest that while E-cigs with free-base nicotine formulation can deliver nicotine rapidly to the brain, those with nicotine salt formulation are capable of even more efficient brain nicotine delivery closely resembling combustible cigarettes. Therefore, nicotine formulation or pH in E-liquid should be considered in evaluation of E-cigs in terms of abuse liability and potential in substituting for combustible cigarettes.

Continuous Remote Monitoring in Moderate and Severe COVID-19 Patients.

Background COVID-19 steadily built up the pressure on healthcare systems worldwide, creating the need for novel methods to alleviate the burden. Continuous remote monitoring of vital parameters reduces morbidity and mortality in hospitals by providing real-time disease data that can be analyzed through web portals. It enables healthcare workers to identify which patients require prompt administration of healthcare. Patients remain under the purview of their doctors and can be notified early if there are any deteriorations in the parameters being monitored. Aims To evaluate the use of remote monitoring in moderate and severe COVID-19 patients and to correlate the Dozee Early Warning Score (DEWS) with severity and outcome in moderate and severe COVID-19 patients. Materials and methods We conducted a prospective study on adult (>18 years old) moderate and severe COVID-19 patients during the second wave of COVID-19. The vitals of the subjects were continuously monitored using Dozee, a contactless remote patient monitoring system enabled with DEWS that reflects the overall patient condition based on respiratory rate (RR), heart rate (HR), and oxygen saturation (SpO2). We assessed the correlation of DEWS with patients' clinical outcomes: deteriorated or recovered. Results Thirty-nine COVID-19 patients were recruited for the study, of whom 29 were discharged after recovery and 10 deteriorated and died. Respiratory rate trend, respiratory rate DEWS, SpO2 DEWS, and total DEWS showed a significant reduction in recovered patients, while the same parameters showed a significant increase followed by consistently high scores in patients who deteriorated and died due to the disease. Total DEWS was proportional to the risk of mortality in a patient. Conclusion We concluded that continuous vitals monitoring and the resulting DEWS in moderate and severe COVID-19 patients were indicators of their improvement or deterioration. DEWS uses continuous remote monitoring of routinely collected vitals (HR, RR, and SpO2) to serve as a predictor of patient outcome.

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations.

G-protein-coupled receptor 119 (GPR119) has emerged as a promising target for treating type 2 diabetes mellitus. Activating GPR119 improves glucose homeostasis, while suppressing appetite and weight gain. Measuring GPR119 levels in vivo could significantly advance GPR119-based drug development strategies including target engagement, occupancy, and distribution studies. To date, no positron emission tomography (PET) ligands are available to image GPR119. In this paper, we report the synthesis, radiolabeling, and preliminary biological evaluations of a novel PET radiotracer [18F]KSS3 to image GPR119. PET imaging will provide information on GPR119 changes with diabetic glycemic loads and the efficacy of GPR119 agonists as antidiabetic drugs. Our results demonstrate [18F]KSS3's high radiochemical purity, specific activity, cellular uptake, and in vivo and ex vivo uptake in pancreas, liver, and gut regions, with high GPR119 expression. Cell pretreatment with nonradioactive KSS3, rodent PET imaging, biodistribution, and autoradiography studies showed significant blocking in the pancreas showing [18F]KSS3's high specificity.

Binding Parameters of [11C]MPC-6827, a Microtubule-Imaging PET Radiopharmaceutical in Rodents.

Impairment and/or destabilization of neuronal microtubules (MTs) resulting from hyper-phosphorylation of the tau proteins is implicated in many pathologies, including Alzheimer's disease (AD), Parkinson's disease and other neurological disorders. Increasing scientific evidence indicates that MT-stabilizing agents protect against the deleterious effects of neurodegeneration in treating AD. To quantify these protective benefits, we developed the first brain-penetrant PET radiopharmaceutical, [11C]MPC-6827, for in vivo quantification of MTs in rodent and nonhuman primate models of AD. Mechanistic insights revealed from recently reported studies confirm the radiopharmaceutical's high selectivity for destabilized MTs. To further translate it to clinical settings, its metabolic stability and pharmacokinetic parameters must be determined. Here, we report in vivo plasma and brain metabolism studies establishing the radiopharmaceutical-binding constants of [11C]MPC-6827. Binding constants were extrapolated from autoradiography experiments; pretreatment with a nonradioactive MPC-6827 decreased the brain uptake >70%. It exhibited ideal binding characteristics (typical of a CNS radiopharmaceutical) including LogP (2.9), Kd (15.59 nM), and Bmax (11.86 fmol/mg). Most important, [11C]MPC-6827 showed high serum and metabolic stability (>95%) in rat plasma and brain samples.

CC group of chemokines and associated gene expression of transcription factors: Deciphering immuno-pathogenetic aspect of oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSMF) is a chronic disease with significantly increasing malignant transformation rate. To date the pathogenesis of OSMF has been considered to be associated with areca nut constituents and their action on fibroblasts. However, fibrosis is also associated with immunological factors such as chemokines. In-depth analysis of such factors is the need of the hour in OSMF to better understand the pathogenesis so that effective therapeutic strategies can be developed in the future. MATERIALS AND METHOD: Clinically diagnosed cases of OSMF (n=21) and healthy individuals (n=10) were enrolled in the present study. Chemokines such as CCL2, CCL3, CCL4, CCL5, CCL11, CCL17, CCL28, CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, and CXCL11 were assessed using the chemokine bead array in conjunction with the flow cytometry, along with real-time PCR (RT-PCR). The transcription factors CREB, NF-κB and NFAT5 were also studied for their expressions. The analysis of pg/ml (picogram/milliliter) values was done by using LEGENDplex™ Data Analysis Software. RESULTS: The results obtained demonstrated early phase transient increase in CXCL-11, CCL20, CXCL9, CCL3, CCL2, CXCL10 and CXCL8. However, the expression of CCL3, CXCL10 and CXCL8 was higher in the late stage as compared to the early stage. The relative gene expression of CREB, NF-κB, NFAT5 were upregulated in the late stage of OSMF when compared to normal. CONCLUSION: Distinctive sets of chemokine expression during the early and late stages of OSMF suggest a unique pattern of disease progression playing an important role in the pathogenesis.

A comparison of conventional and accelerated hypofractionated radiotherapy in definitive chemoradiation for locally advanced head and neck carcinoma: a retrospective cohort study.

PURPOSE: The study evaluates accelerated hypofractionated radiotherapy (AHRT) compared to conventional fractionation radiotherapy (CFRT) in patients with locally advanced head and neck cancer (LAHNC) receiving definitive chemoradiation therapy. MATERIALS AND METHODS: The study includes a retrospective cohort analysis of 120 patients. CFRT arm (n = 65) received 2 Gy per fraction to a dose of 70 Gy over 7 weeks in a three-volume approach, whereas the AHRT arm (n = 55) received 2.2 Gy per fraction to a dose of 66 Gy in 6 weeks with a two-volume approach. The primary outcome was overall survival (OS). RESULTS: With a median follow-up of 18.9 months, 23 patients died in the AHRT arm, and 45 deaths in the CFRT arm. The median OS was 23.4 and 37.63 months in the CFRT and AHRT arms, respectively (hazard ratio [HR] = 0.709; 95% confidence interval [CI], 0.425-1.18; p = 0.189). The median time to loco-regional control was 33.3 months in the CFRT arm and was not reached in the patient group receiving AHRT (HR = 0.558; 95% CI, 0.30-1.03; p = 0.065). The median progression-free survival was 15.9 months in the CFRT arm and 26.9 months in the AFRT arm (HR = 0.801; 95% CI, 0.49-1.28; p = 0.357). Out of 11 acute toxic deaths, eight were in the CFRT arm. CONCLUSION: The study showed a trend towards benefit in terms of locoregional control in the AHRT arm and similar OS. A longer follow-up of patients receiving AHRT is required to assess the benefit.

Volumetric image guidance for intravaginal brachytherapy: A dosimetric and clinical study.

Background: The present retrospective dosimetric and clinical study aims to explore the subset of patients who will benefit from volumetric image guidance in intravaginal brachytherapy (IVBT). Materials and Methods: Sixty-three consecutive patients who underwent IVBT using single-channel intravaginal cylinder were analyzed. The most common IVBT dose protocol was 1100 cGy in two fractions (with external beam radiotherapy [EBRT]) and 2200 cGy in four fractions (when used alone). The factors affecting the dose to organs at risk (OARs) (such as treated length, orientation of applicator, EBRT) and target volume were analyzed. Local control rate and late toxicities were reported. Results: There was a statistically significant increase in equivalent dose at 2 Gy per fraction (EQD2) doses of all OARs with the addition of EBRT. In 39.4%, EQD2 D2cc dose of rectum was more than 65 Gy. There was a statistically significant positive correlation with increasing treated length in D5cc (Gy) of rectum and D5cc (Gy) of urethra (Pearson's correlation coefficient of 0.375, P = 0.002 and Pearson's correlation coefficient of 0.394, P = 0.001, respectively). There was a statistically significant increase in D2cc and D5cc of rectum with posterior orientation. Air gaps were noted in 81% of applications. Median duration of follow-up was 30 months. One patient had vaginal recurrence in lower third of vagina. One patient was recorded with grade 2 hemorrhagic radiation proctitis. Conclusion: Computed tomography (CT)-based volumetric planning is an effective method to evaluate doses to OARs and confirm the adequacy of dose coverage, and we recommend routine use of the same. Image guidance is most beneficial in patients being treated with a combination of IVBT and EBRT, posterior orientation, and those who are treated for the entire length of vagina.

RhoC in association with TET2/WDR5 regulates cancer stem cells by epigenetically modifying the expression of pluripotency genes.

Emerging evidence illustrates that RhoC has divergent roles in cervical cancer progression where it controls epithelial to mesenchymal transition (EMT), migration, angiogenesis, invasion, tumor growth, and radiation response. Cancer stem cells (CSCs) are the primary cause of recurrence and metastasis and exhibit all of the above phenotypes. It, therefore, becomes imperative to understand if RhoC regulates CSCs in cervical cancer. In this study, cell lines and clinical specimen-based findings demonstrate that RhoC regulates tumor phenotypes such as clonogenicity and anoikis resistance. Accordingly, inhibition of RhoC abrogated these phenotypes. RNA-seq analysis revealed that RhoC over-expression resulted in up-regulation of 27% of the transcriptome. Further, the Infinium MethylationEPIC array showed that RhoC over-expressing cells had a demethylated genome. Studies divulged that RhoC via TET2 signaling regulated the demethylation of the genome. Further investigations comprising ChIP-seq, reporter assays, and mass spectrometry revealed that RhoC associates with WDR5 in the nucleus and regulates the expression of pluripotency genes such as Nanog. Interestingly, clinical specimen-based investigations revealed the existence of a subset of tumor cells marked by RhoC+/Nanog+ expression. Finally, combinatorial inhibition (in vitro) of RhoC and its partners (WDR5 and TET2) resulted in increased sensitization of clinical specimen-derived cells to radiation. These findings collectively reveal a novel role for nuclear RhoC in the epigenetic regulation of Nanog and identify RhoC as a regulator of CSCs. The study nominates RhoC and associated signaling pathways as therapeutic targets.

[18F]KS1, a novel ascorbate-based ligand images ROS in tumor models of rodents and nonhuman primates.

Over production of reactive oxygen species (ROS) caused by altered redox regulation of signaling pathways is common in many types of cancers. While PET imaging is recognized as the standard tool for cancer imaging, there are no clinically-approved PET radiotracers for ROS-imaging in cancer diagnosis and treatment. An ascorbate-based radio ligand promises to meet this urgent need. Our laboratory recently synthesized [18F] KS1, a fluoroethoxy furanose ring-containing ascorbate derivative, to track ROS in prostate tumor-bearing mice. Here we report cell uptake assays of [18F]KS1 with different ROS-regulating agents, PET imaging in head and neck squamous cell carcinoma (HNSCC) mice, and doxorubicin-induced rats; PET imaging in healthy and irradiated hepatic tumor-bearing rhesus to demonstrate its translational potential. Our preliminary evaluations demonstrated that KS1 do not generate ROS in tumor cells at tracer-level concentrations and tumor-killing properties at pharmacologic doses. [18F]KS1 uptake was low in HNSCC pretreated with ROS blockers, and high with ROS inducers. Tumors in high ROS-expressing SCC-61 took up significantly more [18F]KS1 than rSCC-61 (low-ROS expressing HNSCC); high uptake in doxorubicin-treated rats compared to saline-treated controls. Rodent biodistribution and PET imaging of [18F]KS1 in healthy rhesus monkeys demonstrated its favorable safety, pharmacokinetic properties with excellent washout profile, within 3.0 h of radiotracer administration. High uptake of [18F]KS1 in liver tumor tissues of the irradiated hepatic tumor-bearing monkey showed target selectivity. Our strong data in vitro, in vivo, and ex vivo here supports the high translational utility of [18F]KS1 to image ROS.

Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model.

BACKGROUND: Microtubules (MTs) are critical for cell structure, function, and survival. MT instability may contribute to Alzheimer's disease (AD) pathogenesis as evidenced by persistent negative regulation (phosphorylation) of the neuronal microtubule-associated protein tau. Hyperphosphorylated tau, not bound to MTs, forms intraneuronal pathology that correlates with dementia and can be tracked using positron emission tomography (PET) imaging. The contribution of MT instability in AD remains unknown, though it may be more proximal to neuronal dysfunction than tau accumulation. Our lab reported the first brain-penetrant MT-based PET ligand, [11C]MPC-6827, and its PET imaging with this ligand in normal rodents and non-human primates demonstrated high brain uptake and excellent pharmacokinetics. Target engagement and mechanism of action using in vitro, in vivo, and ex vivo methods were evaluated here. METHODS: In vitro cell uptake assay was performed in SH-SY5Y neuronal cells with [11C]MPC-6827, with various MT stabilizing and destabilizing agents. To validate the in vitro results, wild type (WT) mice (n = 4) treated with a brain-penetrant MT stabilizing drug (EpoD) underwent microPET/CT brain imaging with [11C]MPC-6827. To determine the influence of tau protein on radiotracer binding in the absence of protein accumulation, we utilized tau knockout (KO) mice. In vivo microPET imaging, ex vivo biodistribution, and autoradiography studies were performed in tau KO and WT mice (n = 6/group) with [11C]MPC-6827. Additionally, α, ß, and acetylated tubulin levels in both brain samples were determined using commercially available cytoskeleton-based MT kit and capillary electrophoresis immunoblotting assays. RESULTS: Cell uptake demonstrated higher radioactive uptake with MT destabilizing agents and lower uptake with stabilizing agents compared to untreated cells. Similarly, acute treatment with EpoD in WT mice decreased [11C]MPC-6827 brain uptake, assessed with microPET/CT imaging. Compared to WT mice, tau KO mice expressed significantly lower ß tubulin, which contains the MPC-6827 binding domain, and modestly lower levels of acetylated α tubulin, indicative of unstable MTs. In vivo imaging revealed significantly higher [11C]MPC-6827 uptake in tau KOs than WT, particularly in AD-relevant brain regions known to express high levels of tau. Ex vivo post-PET biodistribution and autoradiography confirmed the in vivo results. CONCLUSIONS: Collectively, our data indicate that [11C]MPC-6827 uptake inversely correlates with MT stability and may better reflect the absence of tau than total tubulin levels. Given the radiotracer binding does not require the presence of aggregated tau, we hypothesize that [11C]MPC-6827 may be particularly useful in preclinical stages of AD prior to tau deposition. Our study provides immediate clarity on high uptake of the MT-based radiotracer in AD brains, which directly informs clinical utility in MT/tau-based PET imaging studies.

Initial Evaluations of the Microtubule-Based PET Radiotracer, [11C]MPC-6827 in a Rodent Model of Cocaine Abuse.

Purpose: Microtubules (MTs) are structural units made of α and ß tubulin subunits in the cytoskeleton responsible for axonal transport, information processing, and signaling mechanisms-critical for healthy brain function. Chronic cocaine exposure affects the function, organization, and stability of MTs in the brain, thereby impairing overall neurochemical and cognitive processes. At present, we have no reliable, non-invasive methods to image MTs for cocaine use disorder (CUD). Recently we reported the effect of cocaine in patient-derived neuroblastoma SH-SY5Y cells. Here we report preliminary results of a potential imaging biomarker of CUD using the brain penetrant MT-based radiotracer, [11C]MPC-6827, in an established rodent model of cocaine self-administration (SA). Methods: Cell uptake studies were performed with [11C]MPC-6827 in SH-SY5Y cells, treated with or without cocaine (n = 6/group) at 30 and 60 min incubations. MicroPET/CT brain scans were performed in rats at baseline and 35 days after cocaine self-administration and compared with saline-treated rats as controls (n = 4/sex). Whole-body post-PET biodistribution, plasma metabolite assay, and brain autoradiography were performed in the same rats from imaging. Results: Cocaine-treated SH-SY5Y cells demonstrated a ∼26(±4)% decrease in radioactive uptake compared to non-treated controls. Both microPET/CT imaging and biodistribution results showed lower (∼35 ± 3%) [11C]MPC-6827 brain uptake in rats that had a history of cocaine self-administration compared to the saline-treated controls. Plasma metabolite assays demonstrate the stability (≥95%) of the radiotracer in both groups. In vitro autoradiography also demonstrated lower radioactive uptake in cocaine rats compared to the control rats. [11C]MPC-6827's in vitro SH-SY5Y neuronal cell uptake, in vivo positron emission tomography (PET) imaging, ex vivo biodistribution, and in vitro autoradiography results corroborated well with each other, demonstrating decreased radioactive brain uptake in cocaine self-administered rats versus controls. There were no significant differences either in cocaine intake or in [11C]MPC-6827 uptake between the male and female rats. Conclusions: This project is the first to validate in vivo imaging of the MT-associations with CUD in a rodent model. Our initial observations suggest that [11C]MPC-6827 uptake decreases in cocaine self-administered rats and that it may selectively bind to destabilized tubulin units in the brain. Further longitudinal studies correlating cocaine intake with [11C]MPC-6827 PET brain measures could potentially establish the MT scaffold as an imaging biomarker for CUD, providing researchers and clinicians with a sensitive tool to better understand the biological underpinnings of CUD and tailor new treatments.

Late toxicities in locally advanced head and neck squamous cell carcinoma treated with intensity modulated radiation therapy.

PURPOSE: The study aims to report late toxicities in locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) treated with intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: A retrospective study was conducted on 103 patients of LAHNSCC treated with IMRT. We analyzed the cumulative incidence of late xerostomia, dysphagia, and aspiration at an interval of 6-month, 1-year, 2-year, and 3-year from the start of IMRT. RESULTS: At a median follow up of 4.2 years (interquartile range, 3.5 to 6 years), the cumulative incidence of grade ≥2 late xerostomia was 5.5%, dysphagia was 6.9%, and aspiration was 11.1%. Logistic regression showed that Dmean of ≥26 Gy to parotids had higher risk of xerostomia (hazard ratio [HR] = 5.19; 95% confidence interval [CI], 1.90-14.22; p = 0.001). Late dysphagia was associated with Dmean of ≥45 Gy to pharyngeal constrictors (PC) (HR = 7; 95% CI, 1.84-26.61; p =0.004), ≥55 Gy to larynx (HR = 3.25; 95% CI, 1.15-9.11; p = 0.025), and adjuvant RT (HR = 5.26; 95% CI, 1.85-14.87; p = 0.002). Aspiration was associated with Dmean of ≥45 Gy to larynx (HR = 6.5; 95% CI, 1.93-21.88; p = 0.003), Dmean of ≥55 Gy to PC (HR = 3.54; 95% CI, 1.25-9.98; p = 0.017), and patients having late dysphagia (HR = 4.37; 95% CI, 1.55-12.31; p = 0.005). CONCLUSION: IMRT is a feasible radiation delivery technique in LAHNSCC with a decreased late toxicity profile.

Effect of ethanol and cocaine on [11C]MPC-6827 uptake in SH-SY5Y cells.

Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increased MT stability and decreased free tubulin monomers. Our initial cell-binding assay demonstrated that [11C]MPC-6827 may have high affinity to free/unbound tubulin units. Consistent with this mechanism of action, we observed lower [11C]MPC-6827 uptake in SH-SY5Y cells after EtOH and cocaine treatments (e.g., fewer free tubulin units). We are currently performing in vivo PET imaging and ex vivo biodistribution studies in rodent and nonhuman primate models of AUD and SUDs and Alzheimer's disease.

Optimal time management on linear accelerator: A logical model to reduce patient waiting time.

INTRODCTION: Optimal time management is of utmost importance in the radiotherapy department. Inappropriate allocation of time slots leads to prolonged waiting times and decreased patient satisfaction during external beam radiotherapy. The present study tests a logical model to improve the waiting time for the patients. MATERIALS AND METHODS: The treatment time, waiting time, and causes of delay were studied from November 4, 2014, to July 24, 2015. New rules were framed for treatment slot allocation from December 26, 2014. The treatment slots were classified based on the treatment technology (three-dimensional conformal radiotherapy and intensity-modulated radiotherapy) with inclusion of "buffer slots" and patient education. The results were compared before and after rules. RESULTS: A total of 1032 time slots were analyzed, of which 225 "before rules" and 807 "after rules," respectively. There was a significant reduction in the average waiting time for treatment in on-time patients (median [interquartile range (IQR)] of 25.2 min [31.75] vs. 3 min [3.5]; P< 0.00001) as well as in late-coming patients (median [IQR] of 38.2 min [13.795] vs. 21.11 min [12.75]; P= 0.00006). 59.7% (71 patients) of the treatment was delayed "before rules" as opposed to 32.2% (137 patients) "after rules" in on-time patients. Due to better patient education, there was a significant improvement in the patient punctuality toward the allotted time. CONCLUSION: The treatment slots classified based on the teletherapy technique with buffer slots, and patient education helps in better time management on linear accelerator. This methodology significantly reduces waiting time and thereby the number of patients having delay in the treatment.

Late toxicities in locally advanced head and neck squamous cell carcinoma treated with intensity modulated radiation therapy

Purpose@#The study aims to report late toxicities in locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) treated with intensity-modulated radiation therapy (IMRT). @*Materials and Methods@#A retrospective study was conducted on 103 patients of LAHNSCC treated with IMRT. We analyzed the cumulative incidence of late xerostomia, dysphagia, and aspiration at an interval of 6-month, 1-year, 2-year, and 3-year from the start of IMRT. @*Results@#At a median follow up of 4.2 years (interquartile range, 3.5 to 6 years), the cumulative incidence of grade ≥2 late xerostomia was 5.5%, dysphagia was 6.9%, and aspiration was 11.1%. Logistic regression showed that Dmean of ≥26 Gy to parotids had higher risk of xerostomia (hazard ratio [HR] = 5.19; 95% confidence interval [CI], 1.90–14.22; p = 0.001). Late dysphagia was associated with Dmean of ≥45 Gy to pharyngeal constrictors (PC) (HR = 7; 95% CI, 1.84–26.61; p =0.004), ≥55 Gy to larynx (HR = 3.25; 95% CI, 1.15–9.11; p = 0.025), and adjuvant RT (HR = 5.26; 95% CI, 1.85–14.87; p = 0.002). Aspiration was associated with Dmean of ≥45 Gy to larynx (HR = 6.5; 95% CI, 1.93–21.88; p = 0.003), Dmean of ≥55 Gy to PC (HR = 3.54; 95% CI, 1.25–9.98; p = 0.017), and patients having late dysphagia (HR = 4.37; 95% CI, 1.55–12.31; p = 0.005). @*Conclusions@#IMRT is a feasible radiation delivery technique in LAHNSCC with a decreased late toxicity profile.

Late toxicities in locally advanced head and neck squamous cell carcinoma treated with intensity modulated radiation therapy

Purpose@#The study aims to report late toxicities in locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) treated with intensity-modulated radiation therapy (IMRT). @*Materials and Methods@#A retrospective study was conducted on 103 patients of LAHNSCC treated with IMRT. We analyzed the cumulative incidence of late xerostomia, dysphagia, and aspiration at an interval of 6-month, 1-year, 2-year, and 3-year from the start of IMRT. @*Results@#At a median follow up of 4.2 years (interquartile range, 3.5 to 6 years), the cumulative incidence of grade ≥2 late xerostomia was 5.5%, dysphagia was 6.9%, and aspiration was 11.1%. Logistic regression showed that Dmean of ≥26 Gy to parotids had higher risk of xerostomia (hazard ratio [HR] = 5.19; 95% confidence interval [CI], 1.90–14.22; p = 0.001). Late dysphagia was associated with Dmean of ≥45 Gy to pharyngeal constrictors (PC) (HR = 7; 95% CI, 1.84–26.61; p =0.004), ≥55 Gy to larynx (HR = 3.25; 95% CI, 1.15–9.11; p = 0.025), and adjuvant RT (HR = 5.26; 95% CI, 1.85–14.87; p = 0.002). Aspiration was associated with Dmean of ≥45 Gy to larynx (HR = 6.5; 95% CI, 1.93–21.88; p = 0.003), Dmean of ≥55 Gy to PC (HR = 3.54; 95% CI, 1.25–9.98; p = 0.017), and patients having late dysphagia (HR = 4.37; 95% CI, 1.55–12.31; p = 0.005). @*Conclusions@#IMRT is a feasible radiation delivery technique in LAHNSCC with a decreased late toxicity profile.

RhoC regulates radioresistance via crosstalk of ROCK2 with the DNA repair machinery in cervical cancer.

BACKGROUND: Radioresistance remains a challenge to the successful treatment of various tumors. Intrinsic factors like alterations in signaling pathways regulate response to radiation. RhoC, which has been shown to modulate several tumor phenotypes has been investigated in this report for its role in radioresistance. In vitro and clinical sample-based studies have been performed to understand its contribution to radiation response in cervical cancer and this is the first report to establish the role of RhoC and its effector ROCK2 in cervical cancer radiation response. METHODS: Biochemical, transcriptomic and immunological approaches including flow cytometry and immunofluorescence were used to understand the role of RhoC and ROCK2. RhoC variants, siRNA and chemical inhibitors were used to alter the function of RhoC and ROCK2. Transcriptomic profiling was performed to understand the gene expression pattern of the cells. Live sorting using an intracellular antigen has been developed to isolate the cells for transcriptomic studies. RESULTS: Enhanced expression of RhoC conferred radioprotection on the tumor cells while inhibition of RhoC resulted in sensitization of cells to radiation. The RhoC overexpressing cells had a better DNA repair machinery as observed using transcriptomic analysis. Similarly, overexpression of ROCK2, protected tumor cells against radiation while its inhibition increased radiosensitivity in vitro. Further investigations revealed that ROCK2 inhibition abolished the radioresistance phenotype, conferred by RhoC on SiHa cells, confirming that it is a downstream effector of RhoC in this context. Additionally, transcriptional analysis of the live sorted ROCK2 high and ROCK2 low expressing SiHa cells revealed an upregulation of the DNA repair pathway proteins. Consequently, inhibition of ROCK2 resulted in reduced expression of pH2Ax and MRN complex proteins, critical to repair of double strand breaks. Clinical sample-based studies also demonstrated that ROCK2 inhibition sensitizes tumor cells to irradiation. CONCLUSIONS: Our data primarily indicates that RhoC and ROCK2 signaling is important for the radioresistance phenotype in cervical cancer tumor cells and is regulated via association of ROCK2 with the proteins of DNA repair pathway involving pH2Ax, MRE11 and RAD50 proteins, partly offering insights into the mechanism of radioresistance in tumor cells. These findings highlight RhoC-ROCK2 signaling involvement in DNA repair and urge the need for development of these molecules as targets to alleviate the non-responsiveness of cervical cancer tumor cells to irradiation treatment.

Burden of acute toxicities in head-and-neck radiation therapy: A single-institutional experience.

INTRODUCTION: Combined modality therapy is the standard of care in locally advanced head-and-neck cancer (HNC). The incidence of acute toxicities increases with additional therapy. The present study investigated the incidence and patterns of mucositis, dysphagia, aspiration, feeding tube use, admission for supportive care, and treatment compliance in patients with HNC treated curatively with radiation therapy (RT) with or without chemotherapy. METHODS AND MATERIAL: A retrospective review of 164 consecutive HNC patients treated with RT at St. John's Medical College Hospital, Bengaluru, from January 2013 to June 2017 was done. RESULTS: A total of 148 HNC patients were treated with a curative intent and 122 (82.4%) were locally advanced HNC. Combined Modality treatment was received by 119 (80.4%) patients. Eighty-four (56.7%) patients were treated by concurrent chemo-radiation. IMRT technique was used in 125 (84.5%) patients. The incidence of grade 3-4 mucositis, dysphagia and aspiration was 25%, 46%, and 10%, respectively. Nasogastric tube feeding was necessitated in 18.9% (n=28) and 27% (n = 40) required inpatient admission for supportive care. Twenty-nine (19.6%) patients did not complete planned RT dose and 46 (31%) patients had unscheduled RT break (>2days). Fifty-six (66.7%) patients did not receive planned chemotherapy. CONCLUSIONS: Acute toxicity due to RT in HNC remains a challenge despite using modern techniques. A significant proportion of patients require supportive therapy for more than 12 weeks and did not complete the scheduled treatment.

Optimal technique of radiotherapy for carcinoma cervix in developing countries: Dosimetric and logistic comparison.

PURPOSE: Carcinoma cervix is the most common malignancy affecting women in developing countries. Radical radiotherapy is the mainstay of treatment in more than 90% of patients. The present study is a dosimetric and logistic comparison of various techniques of radiotherapy, namely two-dimensional conventional radiotherapy (2DCRT), three-dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy (IMRT). METHODS: All the patients underwent contrast-enhanced computed tomography (CT) scans for simulation. 2DCRT, 3DCRT, and IMRT plans were generated in 24 patients and dosimetrically compared. Radiotherapy treatment time involved in each technique was analyzed in 27 treated patients. RESULTS: The planning target volume (PTV) coverage was best in 3DCRT technique with a median coverage of 99.9% as compared to IMRT (99.3%) and 2DCRT (82.2%). There was progressive sparing of all the organs at risk in IMRT as compared to 3DCRT. The total planning time was longest in IMRT (332.1 min) and shortest in 2DCRT (11.7 min). The mean treatment time for the delivery of each fraction of 2DCRT, 3DCRT, and IMRT were 14.3, 13.6, and 24.7 min, respectively. CONCLUSION: 3DCRT technique is the most optimal technique for radical radiotherapy of cervical cancers with optimum PTV coverage, acceptable planning time, and minimal treatment time as compared to IMRT. 2DCRT technique should be limited to the setting where CT simulation is unavailable.