Estimation of dose-volume parameters of female urethra as organ-at-risk during interstitial brachytherapy in gynecological malignancies.

PURPOSE: Interstitial brachytherapy (ISBT) is often used as post-external beam radiotherapy (EBRT) to treat locally advanced gynecological malignancies. Female urethra is in close proximity to the target during ISBT. However, it has not been evaluated as an organ-at-risk (OAR). Overlapping symptoms caused by radiation-induced bladder toxicity vs. urethral toxicity make it difficult to identify and report urethral toxicities separately. This was a retrospective study to estimate dose-volume parameters of female urethra during high-dose-rate ISBT. MATERIAL AND METHODS: Data of 24 patients with gynecological malignancies treated by ISBT were selected. Urethra and periurethral regions were retrospectively contoured. Mean volume, Dmax, Dmean, D2cc, D1cc, D0.5cc, D0.2cc, and D0.1cc were documented. Unpaired t-test was used for comparison of means. RESULTS: 20/24 Ca. cervix, 1/24 Ca. vagina, and 3/24 Ca. vaginal vault received 6-6.5 Gy in 4 ISBT fractions. Mean urethral length was 3.54 ±0.55 cm. Mean doses received by urethra per BT fraction were Dmax = 4.23 ±1.32 Gy, Dmean = 2.71 ±1.01 Gy, D0.2cc = 3.31 ±1.07, and D0.1cc = 3.54 ±1.09 Gy. Comparison of total BT 2 Gy equivalent dose (EQD2) with 4 fractions for urethra between patients with (9/24) and without anterior vaginal wall (15/24) involvement included Dmean = 18.79 ±7.49 Gy vs. 11.14 ±6.15 Gy*, D1cc = 10.90 ±10.03 Gy vs. 4.54 ±3.93 Gy*, D0.5cc = 19.50 ±8.69 Gy vs. 11.97 ±6.54 Gy*, D0.2cc = 23.78 ±8.94 Gy vs. 15.51 ±7.39 Gy*, and D0.1cc = 25.88 ±9.37 Gy vs. 17.39 ±8.03 Gy*, respectively (*p < 0.05). CONCLUSIONS: Female urethra receives significant doses during ISBT for gynecological malignancies, especially when the anterior vaginal wall is within the target volume. Reporting doses to urethra would enable to develop clinical correlation and dose-volume constraints for urethra as organ-at-risk in future.

Cell-free circulating tumor DNA in patients with high-grade glioma as diagnostic biomarker - A guide to future directive.

BACKGROUND: Owing to the aggressive nature of high-grade gliomas (HGGs), its early diagnosis holds the key to a favorable prognosis. Currently, tissue biopsy is the gold standard to verify HGG's initial diagnosis and can be challenging due to its invasive nature. In this study, our objective was a noninvasive panel for timely detection of HGG and its progression using cell-free circulating tumor DNA (cfTDNA). MATERIALS AND METHODS: Twenty-seven patients with HGG were tested with a 50-gene tumor panel. cfTDNA isolated from serum was checked for single-nucleotide variations (SNVs) or copy number alterations using targeted next-generation sequencing, with further validation of results by checking respective formalin-fixed paraffin-embedded tumor tissues for the same genetic alterations. RESULTS: About 88.8% of the patients were detected with HGG-associated cfTDNA. Around 25% patients were detected with one, 25% patients had three, 25% patients had four, and 12.5% patients each had five and six genetic alterations. About 12 of 50 genes were detected in the serum samples. The SNVs detected included TP53 in 87.5% of patients; PIK3CA and EGFR in 50% of patients; PTEN in 37.5%; KIT and VHL in each 25% of patients; and RB1, NF2, MET, ATRX, CDK2A, and CTNNB1 each in 8.3%-16.6%. On combining EGFR, KIT, PTEN, PIK3CA, TP53, and VHL genes (Govardhan Diagnostic Genetic Module for high-grade glioma), at least one of the genetic alterations was found in 100% of patients. CONCLUSION: These findings illustrate that cfTDNA is easily demonstrable and can be used as a surrogate to tissue biopsy in brain tumor.

Chemoradiation in elderly patients with head and neck cancers: a single institution experience.

AIMS: To evaluate the efficacy and toxicity of concurrent chemoradiation in patients with head and neck cancers aged 65 and older. MATERIALS AND METHODS: Thirty-two elderly patients were treated with radical chemoradiation. Twenty-six (81.3%) out of thirty-two patients had stage III-IV disease. Twenty-nine (90.6%) patients received concurrent weekly cisplatin or carboplatin, 3 (9.4%) patients received concurrent cetuximab or nimotuzumab. Total dose of radiotherapy ranged from 66Gy to 70Gy. RESULTS: Twenty-nine patients (90.6%) completed at least 5cycles of concurrent chemotherapy. Twenty-four (77.6%) patients achieved complete response. Fourteen (45.2%) patients experienced grade 3 mucositis. None of our patients developed grade 3 or above hematological toxicity. Loco-regional control and overall survival at 2year were 71.6% and 88.9%, respectively. CONCLUSIONS: Chemoradiation in elderly patients with high precision radiotherapy is a feasible option.

Down Regulation of FOXO1 Promotes Cell Proliferation in Cervical Cancer.

The Forkhead transcription factor FOXO1, an important downstream target of phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway, regulates cellular homeostasis by maintaining cell proliferation, apoptosis and viability in normal cells. Though, the function and regulation of FOXO1 is well documented in many cancers, the molecular mechanism of its regulation in cervical cancer is largely unknown. In the present study we have investigated the role of PI3K inhibition on FOXO1 regulation. Expression profiling of primary tumors and cell lines show over expression of PIK3CA and AKT1; and down regulation of FOXO1. Lack of FOXO1 promoter methylation and inability of hypomethylating drug 5-Aza-2'-deoxycytidine and HDAC inhibitor trichostatin A to reactivate FOXO1 expression suggest that loss of FOXO1 expression is due to mechanisms other than promoter methylation/acetylation. Inhibition of PI3K by LY294002 decreased the level of p-AKT1 and activated FOXO1 transcription factor. We demonstrate that activation of FOXO1 induces apoptosis, cell proliferation arrest, and decreased cell viability in cervical cancer cell lines. Our data suggest that frequent down regulation of FOXO1 and its functional inactivation may be due to post-translational modifications in cervical cancer. Together, these observations suggest that activation of FOXO1 and its nuclear sequestration is critical in the regulation of cell proliferation, cell viability and apoptosis in cervical cancer. Hence, PI3K/AKT pathway may be a potential molecular target for cervical cancer therapy.

Adaptive radiotherapy in lung cancer: dosimetric benefits and clinical outcome.

OBJECTIVE: Anatomical changes during radiotherapy (RT) might introduce discrepancies between planned and delivered doses. This study evaluates the need for adaptive treatment in lung cancer RT. METHODS: 15 patients with non-small-cell lung cancer, undergoing radical RT with or without concurrent chemotherapy, consecutively underwent planning CT scans at baseline and after 44-46 Gy. Target volumes were delineated on both scans. Phase I delivered 44-46 Gy to the initial planning target volume (PTV). Two Phase II plans for 16-20 Gy were developed on initial and mid-treatment scans, the treatment being delivered with the mid-treatment plan. The second CT structure set was fused with the initial scan data set using dose wash. Volumetric and dosimetric changes in target volumes and critical structures were assessed. RESULTS: There was significant reduction in primary gross tumour volume (34.00%; p = 0.02) and PTV (34.70%; p < 0.01) in the second scan. In Plan 2, delivering the same dose to the initial PTV would have resulted in a significantly higher dose to the lung PTV (V20, 52.18%; V5, 21.76%; mean, 23.93%), contralateral lung (mean, 29.43%), heart (V10, 81.47%; V5, 56.62%; mean, 35.21%) and spinal cord (maximum dose, 37.53%). CONCLUSION: Treatment replanning can account for anatomical changes during RT and thereby enable better normal tissue sparing, while allowing radical target doses with the possibility of maximizing local control. ADVANCES IN KNOWLEDGE: This study supports the sparse dosimetric data regarding the quantitative tumour volume reduction, re-emphasizing the need for adaptive replanning for minimizing normal tissue toxicity without compromising local control, and adds to the existing body of literature.

Dosimetric comparison between Volumetric Modulated Arc Therapy (VMAT) vs Intensity Modulated Radiation Therapy (IMRT) for radiotherapy of mid esophageal carcinoma.

AIMS: Dosimetric comparison of VMAT with IMRT in middle third esophageal cancer for planning target volume (PTV) and organs at risk (OAR). MATERIALS AND METHODS: Ten patients in various stages from I‒III were inducted in the neo-adjuvant chemoradiation protocol for this study. The prescribed dose was 4500 cGy in 25 fractions. Both VMAT and IMRT plan were generated in all cases and Dose Volume Histogram (DVH) comparative analysis was performed for PTV and OAR. Paired t-test was used for statistical analysis. RESULTS: The PTV Dmean and D95 in IMRT and VMAT plan were 4566.6±50.6 cGy vs 4462.8±81.8 cGy (P=0.1) and 4379.8±50.6 cGy Vs 4424.3±109.8 cGy (P=0.1), respectively. The CI and HI for PTV in IMRT vs VMAT plans were 0.96±0.02 vs 0.97±0.01 (P=0.4) and 10.58±3.07 vs 9.45±2.42 (P=0.2), respectively. Lung doses for VMAT vs IMRT were 4.19 vs 2.59% (P=0.03) for V35-7.63 vs 4.76% (P=0.01) for V30-13.6 vs 9.98% (P=0.01) for V25-24.77 vs 18.57% (P=0.04) for V20-46.5 vs 34.73% (P=0.002) for V15. The Mean Lung Dose (MLD) was reduced by VMAT technique compared to IMRT; 1524.6±308.37 cGy and 1353±186.32 cGy (P=0.012). There was no change in Dmax to spinal cord in both the techniques. There was a dose reduction by VMAT compared to IMRT to the heart but it was statistically insignificant; V35-6.75% vs 5.55% (P=0.223); V30-12.3% vs 10.91% (P=0.352); V25-21.81% vs 20.16% (P=0.459); V20-38.11% vs 32.88% (P=0.070); V15-61.05% vs 54.2% (P=0.10). CONCLUSION: VMAT can be a better option in treating mid esophageal carcinoma as compared to IMRT. The VMAT plans resulted in equivalent or superior dose distribution with a reduction in the dose to lung and heart.

Frame-based radiosurgery: Is it relevant in the era of IGRT?

PURPOSE: To assess the setup errors and intrafraction motion in patients treated with frame-based and frameless stereotactic radiosurgery (SRS). MATERIALS AND METHODS: Ten patients treated with frame-based and six patients treated with frameless radiosurgery were prospectively enrolled in the study. Leksell frame was used for frame-based and a customized uniframe orfit cast for frameless techniques. Cone beam computed tomography (CBCT) scans were taken immediately before and after each treatment to evaluate the positional accuracy and corrections applied with the use of hexapod couch for both groups. RESULTS: The mean translational shifts with frame-based SRS were 1.00 ± 0.30 mm in the lateral direction (X), 0.20 ± 1.20 mm in craniocaudal direction (Y) and -0.10 ± 0.31 mm in the anteroposterior direction (Z). The rotational shifts for frame-based treatments were as follows: roll 0.32 ± 0.70, pitch 0.44 ± 0.66 and yaw 0.20 ± 0.4. For frameless SRS, translational shifts were -0.40 ± 0.90, 1.10 ± 1.10, and 0.50 ± 1.30 mm in X, Y, and Z directions, respectively, and rotational shifts were -0.11 ± 0.78, 0.20 ± 0.44, and 0.29 ± 0.35 in roll, pitch, and yaw, respectively. Intrafraction shifts with frame-based SRS were: X = 0.60 ± 1.80 mm, Y = 0.20 ± 0.60 mm, and Z = 0.00 ± 0.05 mm; and rotational shifts were: roll 0.01 ± 0.27, pitch 0.06 ± 0.15, and yaw 0.01 ± 0.09. For frameless SRS, these were: X = 0.11 ± 0.20 mm, Y = 0.20 ± 0.40 mm, and Z = 0.20 ± 0.20 mm and rotational shifts were: roll 0.09 ± 0.23, pitch 0.00 ± 0.12, and yaw 0.00 ± 0.09. CONCLUSIONS: In our experience, set up accuracy of frameless SRS is as good as frame-based SRS. With availability of verification methods such as CBCT and hexapod couch, an accurate and precise treatment delivery is feasible with frameless techniques.

Over expression of minichromosome maintenance genes is clinically correlated to cervical carcinogenesis.

Minichromosome Maintenance (MCM) proteins play important roles in cell cycle progression by mediating DNA replication initiation and elongation. Among 10 MCM homologues MCM 2-7 form a hexamer and assemble to the pre-replication complex acting as replication licensing factors. Binding and function of MCM2-7 to pre-replication complex is regulated by MCM10 mediated binding of RECQL4 with MCM2-7. The purpose of this study is to explore the role of MCMs in cervical cancer and their correlation with the clinical parameters of cervical cancer. We have investigated sixty primary cervical cancer tissue samples, eight cervical cancer cell lines and thirty hysterectomised normal cervical tissue. The expression profiling of MCMs was done using semi-quantitative RT-PCR, immunoblotting and immunohistochemistry. MCM2, 4, 5, 6, 7, 10 and RECQL4 are significantly over-expressed in cervical cancer. Among these, MCM4, 6 and 10 show increased frequency of over expression along with advancement of tumor stages. MCM4, 5 and 6 also show differential expression in different types of lesion, while MCM2 and MCM10 are over expressed in cervical cancer irrespective of clinico-pathological parameters. Our data indicates the role of MCM4, MCM5, MCM6, MCM10 and RECQL4 in the progression of cervical cancer.