Electrophilic nitrated fatty acids are potential therapeutic candidates for inflammatory and fibrotic lung diseases.

Several types of exposures can cause acute or chronic inflammatory reactions in the lungs often leading to asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute lung injury, lung cancer, and other deleterious health outcomes. Current therapy, with inhaled or oral glucocorticoids, successfully targets inflammation but also produces adverse effects that limit their enthusiastic use. Accordingly, the need remains for interventions that are safer and more effective. Nitrated fatty acids (NFAs) are highly electrophilic and are produced endogenously by non-enzymatic reactions of nitric oxide with conjugated unsaturated fatty acids. The literature indicates that NFAs are detected in humans at the nanomolar range and are produced more robustly under inflammatory conditions. Recent studies on novel NFAs report antiinflammatory, antioxidant, and antifibrotic effects, while also acting as partial agonists of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Furthermore, these functions of NFAs occur via reversible electrophilic alkylation of cysteine residues and regulation of antiinflammatory, antioxidant signaling through modulation of transcription factors, including nuclear factor E2-related factor 2 (Nrf2), PPAR-γ, and NF-κB. Here, we review and update the role of NFA signaling mechanisms and their therapeutic potential in various lung diseases. As NFAs display strong electrophilic interaction with multimechanistic pathways, they can be considered promising drug candidates for challenging lung diseases.

Intra-operative interstitial brachytherapy in a novel infra-zygomatic approach for partially resectable head and neck cancers around the base of skull: A technical note.

Purpose: To report an intra-operative catheter insertion technique into the base of skull tumor bed following surgical resection for maxillary tumors. Material and methods: A 42-year-old male patient diagnosed with carcinoma of the maxilla was treated with neoadjuvant chemotherapy followed by chemo-radiation using external beam technique combined with brachytherapy boost to post-operative bed. Brachytherapy was delivered via intra-operative catheter placement at the base of skull to residual disease, which was surgically unresectable. Initially, catheters were placed cranio-caudally. This was later changed into an infra-zygomatic approach to improve planning and dose coverage. High-risk clinical tumor volume (CTV) was generated with a 3 mm margin to residual gross tumor. Planning was done using Varian Eclipse brachytherapy planning system, and an optimal plan was generated. Conclusions: An innovative, beneficial, and safe brachytherapy approach is necessary in a difficult and critical area, such as the base of skull. Our novel method of implant insertion through infra-zygomatic approach resulted in a safe and successful procedure.

Comparison of dosimetric analysis of organs at risk and target volumes for ovoids and cylinders in endometrial carcinoma.

Purpose: To compare dose volume parameters of target and organs at risk in vaginal vault brachytherapy using ovoids or cylinder in post-operative endometrial carcinoma. Material and methods: The study was done among 25 histologically proven post-operative endometrial carcinoma patients requiring vaginal brachytherapy. All patients underwent both cylinder and ovoids application alternatively on weekly basis. Ovoids size ranged from 2 to 3 cm diameter. Diameters of cylinder ranged between 2.5 and 3.5 cm. Bladder, rectum, urethra, and clinical target volume (CTV) were contoured on CT simulation images. Prescribed dose was 6-7 Gy in 2-3 fractions at 0.5 cm from the surface of applicator. Results: The mean values of D90, D50, V150, V100, V90, and V50 of CTV were comparable between cylinder and ovoids plans. The mean dose of CTV was significantly higher with cylinder than with ovoids, and D100 was significantly higher with ovoids (mean = 15.63 Gy vs. 14.64 Gy, p = 0.016, and D100 = 37.82% vs. 42.86%, p = 0.042, for cylinder vs. ovoids). In the dosimetry of the vault, D90, D50, V100, V90, V50, and mean of the vault did not show any significant difference between cylinder and ovoids. The V150 was significantly higher with cylinder plans than ovoids, and D100 of the vault was significantly higher with ovoids plans (V150 = 14.81% vs. 6.86%, p = 0.02, and D100 = 37.77% vs. 44.80%, p = 0.029, for cylinder vs. ovoids). D0.1cc, D1cc, D2cc, and mean for the bladder, rectum, and urethra were comparable between the cylinder and ovoid plans. Conclusions: The present study showed that the dose to organs at risk, most of the dosimetric parameters of CTV, and vault were comparable between the cylinder and ovoid plans. Both applicators provide good reproducibility. The choice of applicator will ultimately depend on the institutional policies and oncologist decision. However, in patients with dog-ear configuration of the vagina, ovoids may be preferred as per ABS guidelines.

Nitrated fatty acid, 10-nitrooleate protects against hyperoxia-induced acute lung injury in mice.

The antioxidant and anti-inflammatory effects of electrophilic nitrated fatty acid (NFA); 10-nitrooleate, have been reported. The present study investigated whether 10-nitrooleate has a protective role against hyperoxic-induced acute lung injury (HALI). Using a C57BL/6 mice model of HALI, we investigated the protective effect of 10-nitrooleate. C57BL/6 mice were administered with NFA intratracheally, exposed to hyperoxia for 48 h to induce HALI, and kept at room air for 24 h. Bronchoalveolar lavage (BAL) fluid and lung samples were collected after 24 h of post hyperoxia to analyze markers associated with HALI. Intratracheal (IT) and intraperitoneal (IP) administration of NFA notably attenuated hyperoxia-induced infiltration of inflammatory cells, alveolar-capillary leakage, upregulation of proinflammatory cytokine levels (IL-6 and TNFα) into the BAL fluid, and resolution of inflammation in the lung. Western blot analyses showed that 10-nitrooleate reduced the expression of the inflammatory transcription factor NFκB p65 subunit and increased antioxidant proteins HO-1 and NQO1 expression in the lung tissues compared to vehicle-treated animals. Moreover, 10-nitrooleate reversed the hyperoxia-induced expression of mitophagy-associated markers (PINK1 and p62/SQSTM1), thereby protecting the HALI/ acute respiratory distress syndrome (ARDS). IT and IP delivery of 10-nitrooleate reduces hyperoxia-induced ALI/ARDS by regulating the antioxidant pathways and restoring the mitochondrial homeostasis by regulating mitophagy. It is suggested that NFAs can be further evaluated as supplementary therapy for critically ill patients like COVID-19/ARDS.

Prostate permanent implant brachytherapy with BARC I-125 Ocu-Prosta seeds.

AIM: The aim of this study is implementation and establishment of standard operating procedure for permanent prostate implant brachytherapy technique using BARC I-125 Ocu-Prosta seeds. MATERIALS AND METHODS: The transrectal ultrasound (US)-guided procedure was used for permanent implant procedure. The Best® Sonalis™ US Imaging System and Best NOMOS™ Treatment Planning system was used for volume study and implant procedure. The BARC provided I-125 Ocu-Pro radioactive seeds were implanted into the patient with help of Mick@ Applicator. The implant was performed based on pre-implant dosimetry and intraoperative planning performed during implant procedure. RESULTS: The necessary quality assurance tests were performed for US system before clinical use. The boost dose of 110 Gy was prescribed to the prostate volume of 34.71 cc. About 48 seeds with activity of 0.35 mCi (each) implanted into the prostate volume with reference to intraoperative planning. At the end of procedure, the patient underwent abdomen fluoroscopic examination, to ensure the seed counts in the prostate volume. The day after the implant, the patient was discharged. One month later a planning computed tomography and treatment planning was performed for seed position and dose verification. CONCLUSIONS: Low dose rate permanent implant brachytherapy has the advantage of being a one-time procedure and the existing long term follow-up supports its excellent outcome and low morbidity. BARC-BRIT is supplying the loose 125I seeds. These seeds can be easily implanted into the patient using Mick applicator. However, the pre-implant seed preparation and implant procedure may result some radiation exposure to staff involved. The radiation dose can be minimized with good practice. This report is one patient pilot study and intended to test the implant systems and standard operative procedure henceforth for permanent implant brachytherapy procedure.

Intrathecal neostigmine with bupivacaine for infants undergoing lower abdominal and urogenital procedures: dose response.

BACKGROUND: Intrathecal (IT) neostigmine produces dose-dependent analgesia in adults. However, the dose of spinal neostigmine has not been investigated in infants. The purpose of this study was to assess spinal anesthesia (SA) duration provided by four doses of spinal neostigmine added to bupivacaine for lower abdominal and urogenital procedures in infants. METHODS: Seventy-five infants were randomized into five groups. The control group B received IT plain 0.5% hyperbaric bupivacaine. Groups BN.25, BN.50, BN.75, and BN1.0 received bupivacaine with 0.25, 0.5, 0.75, and 1 microg/kg of neostigmine, respectively. The primary variable was the duration of anesthesia assessed by recovery of hip flexion. Postoperative pain with facial expression, leg activity, arm activity, crying and consolability scale score, and rescue analgesic requirements were the secondary variables measured, and the side effects were noted. RESULTS: Seventy-three infants completed the study. There was a significant linear increase in SA duration with IT neostigmine to 65.2 (4.3) min with 0.5 microg/kg (P<0.01), 88.2 (5.1) with 0.75 microg/kg (P<0.001) and 92 (4.3) with 1 microg/kg (P<0.001) from 52.4 (4.3) min with bupivacaine alone. SA duration showed no significant difference between plain bupivacaine and BN.25 (P=0.100) or between groups BN.75 and BN1.0 (P=0.451). Groups BN.75 and BN1.0 had significantly reduced pain scores, and the median duration before the first dose rescue analgesic was requested prolonged significantly (P<0.001) compared with the other three groups. CONCLUSIONS: IT neostigmine at a dose of 0.75 microg/kg added to bupivacaine significantly prolonged SA duration with reduced postoperative pain scores and rescue analgesic requirements in infants undergoing lower abdominal and urogenital procedures. No additional benefits were provided on increasing it to 1 microg/kg.

Biological tailoring of adjuvant radiotherapy in head and neck and oral malignancies - The potential role of p53 and eIF4E as predictive parameters.

BACKGROUND: Recent advances in radiation technology has allowed to significantly reduce toxicity and improve the efficacy of radical radiotherapy in head and neck and oral squamous cell cancers. Insights into molecular biology of carcinogenesis has opened a window for identifying aggressive clinical situations that may benefit with larger clinical target volume (CTV ) margin, broader levels of nodal coverage, or alternative radiation sensitizers. AIM: To evaluate the potential role of eukaryotic translation initiation factor 4E (elF4E) and p53 as predictive biomarkers in resected margins of head and neck and oral cancers. MATERIAL AND METHODS: Forty patients with oral cancers and 26 patients with head and neck cancers were evaluated for p53 and eIF4E in their negative surgical margins, for pattern of distribution and outcome. RESULTS: In oral cancers, 27 patients (67.5%) were positive for p53 and 10 (25%) for eIF4E in surgically negative margins. For head and neck cancer, the values were 13 (50%) for p53 and 9 (34.6%) for eIF4E. Twelve patients with oral cancers and 8 patients with head and neck cancers had local failure or death. The association with these biomarkers did not achieve statistical significance. However, adjuvant radiotherapy had a significant protective value. It improved median survival from 15 to 21 months in patients positive for p53 (P = 0.018) and from 12 to 20 months (P = 0.03) in those with eIF4E. There was no predictive association of subsite, tumor size, or nodal status. CONCLUSION: The overexpression of p53 and eIF4E in pathologically negative margins may represent a subset of patients who would benefit from early initiation of adjuvant radiation and tailored intensity-modulated radiotherapy (IMRT).

Nimotuzumab provides survival benefit to patients with inoperable advanced squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb, 5-year study in Indian patients.

OBJECTIVE: Overexpression of epidermal growth factor receptor (EGFR) in many cancers makes it an attractive therapeutic target. This study evaluated the clinical utility of nimotuzumab, a monoclonal anti-EGFR antibody, used concurrently with radiotherapy (RT) and chemoradiotherapy (CRT) in squamous cell carcinoma of the head and neck (SCCHN). METHODS: This open-label study randomized 92 treatment-naïve patients (1:1) with advanced SCCHN into chemoradiation (CRT ± nimotuzumab) or radiation (RT ± nimotuzumab) group by investigator's discretion; these were further randomized into CRT + nimotuzumab or CRT and RT + nimotuzumab or RT groups, respectively. Treatment included 6 cycles each of cisplatin (50 mg/week), nimotuzumab (200 mg/week), and RT (total dose, 60-66 Gy). Response (tumor size reduction) was assessed at Month 6 post-treatment and survival, at Month 60. RESULTS: Forty and 36 patients in the chemoradiation and radiation groups, respectively (intent-to-treat population) were evaluated. Overall response at Month 6 post-treatment was 100% with CRT + nimotuzumab, 70% with CRT, 76% with RT + nimotuzumab, and 37% with RT. At Month 60, overall survival was 57% with CRT + nimotuzumab, 26% with CRT (P = 0.03), 39% with RT + nimotuzumab, and 26% with RT (P > 0.05). Median overall survival was not reached for CRT + nimotuzumab; it was 21.94 months for CRT (P = 0.0078), 14.36 months for RT + nimotuzumab, and 12.78 months for RT (P = 0.45). Risk of death was 64% lower with CRT + nimotuzumab than with CRT (95%CI: 0.37, 1.56), and 24% lower with RT + nimotuzumab than with RT (95%CI: 0.16, 0.79). Thus nimotuzumab was safe and well tolerated with few mild to moderate self-limiting adverse events. CONCLUSION: Concurrent use of nimotuzumab with CRT/RT is safe and provides long-term survival benefit.

Nitric oxide in fruit ripening: trends and opportunities.

Monitoring ethylene is crucial in regulating post-harvest life of fruits. The concept of nitric oxide (NO) involvement in antagonizing ethylene is new. NO mediated physiologies casted through regulation of plant hormones are widely reported during developmental and stress chemistry having no direct link with ripening. Research in NO biology and understanding its interplay with other signal molecules in ripening fruits suggest ways of achieving greater synergies with NO applications. Experiments focused at convincingly demonstrating the involvement of NO in altering ripening-related ethylene profile of fruits, would help develop new processes for shelf life extension. This issue being the central theme of this review, the putative mechanisms of NO intricacies with other primary and secondary signals are hypothesized. The advantage of eliciting NO endogenously may open up various biotechnological opportunities for its precise delivery into the target tissues.

Spindle cell sarcoma of esophagus: a rare case presentation.

Sarcomas of the esophagus, including carcinosarcoma, are rare neoplasm cases and comprise 0.1-1.5% of all esophageal tumors. Leiomyosarcoma is the most common of the pure mesenchymal tumors of the esophagus, but sarcomas with combined histological types such as carcinosarcoma occur more frequently than pure sarcomas. We report a rare case of spindle cell sarcoma of esophagus in a 55-year-old woman, managed with radical radiotherapy alone.