Quality Assurance in Radiotherapy (RT)-Specific Trials: Indian Scenario.

AIMS: There is evidence that proper radiotherapy trial quality assurance (RTTQA) translates into improved outcomes for patients. However, the practice of RTTQA is heterogeneous and implemented in a diverse manner across trials. In this paper, we review the RTTQA report for randomised trials (RCT) conducted in India and present our experience with RTTQA for various clinical trials and highlight the key achievements and challenges. MATERIALS AND METHODS: Search was performed using the keywords and the variations thereof for "radiotherapy" and author affiliations from India, its states and major metropolitan cities. Pubmed search filters were used to restrict results to RCT published in the past 5 years (2019-2024). Reporting of RTTQA procedures from publications and protocols was documented along with the protocol-specified dosimetric goals. We also evaluated a few clinical trials performed in the Department of Radiation Oncology at Tata Medical Center. The different RTTQA procedures and results for four representative clinical trials have been described. RESULTS: A formal RTTQA process was reported by only one out of 24 randomised controlled trials and formal dosimetric goals were pre-specified by 9 of 13 trials where IMRT was used as treatment. RTTQA requirements were tailored for each clinical trial at Tata Medical Center. For the HYPORT trial, the RTTQA process focused on ensuring the matchline doses were homogenous. HYPORT B trial commissioned the use of a simultaneous integrated boost technique which emphasised conformal avoidance of dose spillage to contralateral breast and lung. HYPORT Adjuvant and PROPARA trials are multicentre clinical trials. While HYPORT Adjuvant focussed on ensuring that the dose delivery met the predefined constraints, segmentation of the target volume was important for the PROPARA trial. CONCLUSION: We demonstrate different RTTQA procedures required for representative clinical trials and highlight key challenges encountered.

Binuclear palladacycles with ionisable and non-ionisable tethers as anticancer agents.

The search for novel anticancer agents to replace the current platinum-based treatments remains an ongoing process. Palladacycles have shown excellent promise as demonstrated by our previous work which yielded BTC2, a binuclear palladadycle with a non-ionisable polyethylene glycol (PEG) tether. Here, we explore the importance of the PEG-tether length on the anticancer activity of the binuclear palladacycles by comparing three analogous binuclear palladacycles, BTC2, BTC5 and BTC6, in the oestrogen receptor positive MCF7 and triple-negative MDA-MB-231 breast cancer cell lines. In addition, these are compared to another analogue with an ionisable morpholine tether, BTC7. Potent anticancer activity was revealed through cell viability studies (MTT assays) revealed that while BTC6 showed similar potent anticancer activity as BTC2, it was less toxic towards non-cancerous cell lines. Interestingly, BTC7 and BTCF were less potent than the PEGylated palladacycles but showed significantly improved selectivity towards the triple-negative breast cancer cells. Cell death analysis showed that BTC7 and BTCF significantly induced apoptosis in both the cancer cell lines while the PEGylated complexes induced both apoptosis and secondary necrosis. Furthermore, experimental and computational DNA binding studies indicated partial intercalation and groove binding as the modes of action for the PEGylated palladacycles. Similarly, experimental and computational BSA binding studies indicated and specific binding sites in BSA dependent on the nature of the tethers on the complexes.

Differential expression of genes during recovery of Nicotiana tabacum from tomato leaf curl Gujarat virus infection.

MAIN CONCLUSION: Nicotiana tabacum exhibits recovery response towards tomato leaf curl Gujarat virus. Transcriptome analysis revealed the differential expression of defense-related genes. Genes encoding for cysteine protease inhibitor, hormonal- and stress-related to DNA repair mechanism are found to be involved in the recovery process. Elucidating the role of host factors in response to viral infection is crucial in understanding the plant host-virus interaction. Begomovirus, a genus in the family Geminiviridae, is reported throughout the globe and is known to cause serious crop diseases. Tomato leaf curl Gujarat virus (ToLCGV) infection in Nicotiana tabacum resulted in initial symptom expression followed by a quick recovery in the systemic leaves. Transcriptome analysis using next-generation sequencing (NGS) revealed a large number of differentially expressed genes both in symptomatic as well as recovered leaves when compared to mock-inoculated plants. The virus infected N. tabacum results in alteration of various metabolic pathways, phytohormone signaling pathway, defense related protein, protease inhibitor, and DNA repair pathway. RT-qPCR results indicated that Germin-like protein subfamily T member 2 (NtGLPST), Cysteine protease inhibitor 1-like (NtCPI), Thaumatin-like protein (NtTLP), Kirola-like (NtKL), and Ethylene-responsive transcription factor ERF109-like (NtERTFL) were down-regulated in symptomatic leaves when compared to recovered leaves of ToLCGV-infected plants. In contrast, the Auxin-responsive protein SAUR71-like (NtARPSL) was found to be differentially down-regulated in recovered leaves when compared to symptomatic leaves and the mock-inoculated plants. Lastly, Histone 2X protein like (NtHH2L) gene was found to be down-regulated, whereas Uncharacterized (NtUNCD) was up-regulated in both symptomatic as well as recovered leaves compared to the mock-inoculated plants. Taken together, the present study suggests potential roles of the differentially expressed genes that might govern tobacco's susceptibility and/or recovery response towards ToLCGV infection.

Global Health System Resilience during Encounters with Stressors - Lessons Learnt from Cancer Services during the COVID-19 Pandemic.

AIMS: The protracted COVID-19 pandemic has overwhelmed health systems globally, including many aspects of cancer control. This has underscored the multidimensional nature of cancer control, which requires a more comprehensive approach involving taking a wider perspective of health systems. Here, we investigated aspects of health system resilience in maintaining cancer services globally during the COVID-19 pandemic. This will allow for health systems to be resilient to different types of system stressors/shocks in the future, to allow cancer care to be maintained optimally. MATERIALS AND METHODS: Using the World Health Organization health system framework (capturing aspects of service delivery, health workforce, information, medical products, vaccines and technologies, financing and governance and leadership), we carried out a comparative analysis of the impact of COVID-19 and the synthesis of the findings in responses in cancer care in 10 countries/jurisdictions across four continents comprising a wide diversity of health systems, geographical regions and socioeconomic status (China, Colombia, Egypt, Hong Kong SAR, Indonesia, India, Singapore, Sri Lanka, UK and Zambia). A combination of literature and document reviews and interviews with experts was used. RESULTS: Our study revealed that: (i) underlying weaknesses of health systems before the pandemic were exacerbated by the pandemic (e.g. economic issues in low- and middle-income countries led to greater shortage of medication and resource constraints compounded by inadequacies of public financing and issues of engagement with stakeholders and leadership/governance); (ii) no universal adaptive strategies were applicable to all the systems, highlighting the need for health systems to design emergency plans based on local context; (iii) despite the many differences between health systems, common issues were identified, such as the lack of contingency plan for pandemics, inadequate financial policies for cancer patients and lack of evidence-based approaches for competing priorities of cancer care/pandemic control. CONCLUSION: We identified four key points/recommendations to enhance the resilient capacity of cancer care during the COVID-19 pandemic and other system stressors: (i) effective pandemic control approaches in general are essential to maintain the continuity of cancer care during the emergency health crises; (ii) strong health systems (with sufficient cancer care resources, e.g. health workforce, and universal health coverage) are fundamental to maintain quality care; (iii) the ability to develop response strategies and adapt to evolving evidence/circumstances is critical for health system resilience (including introducing systematic, consistent and evidence-based changes, national support and guidance in policy development and implementation); (iv) preparedness and contingency plans for future public health emergencies, engaging the whole of society, to achieve health system resilience for future crises and to transform healthcare delivery beyond the pandemic.

Intense chorus waves are the cause of flux-limiting in the heart of the outer radiation belt.

Chorus waves play a key role in outer Van Allen electron belt dynamics through cyclotron resonance. Here, we use Van Allen Probes data to reveal a new and distinct population of intense chorus waves excited in the heart of the radiation belt during the main phase of geomagnetic storms. The power of the waves is typically ~ 2-3 orders of magnitude greater than pre-storm levels, and are generated when fluxes of ~ 10-100 keV electrons approach or exceed the Kennel-Petschek limit. These intense chorus waves rapidly scatter electrons into the loss cone, capping the electron flux to a value close to the limit predicted by Kennel and Petschek over 50 years ago. Our results are crucial for understanding the limits to radiation belt fluxes, with accurate models likely requiring the inclusion of this chorus wave-driven flux-limiting process, that is independent of the acceleration mechanism or source responsible for enhancing the flux.

Migrated and Impacted Foreign Body of Retropharyngeal Space: A Case Report.

Foreign body upper aerodigestive tract is a common presentation but foreign body migrating into retropharyngeal space is not only uncommon, but its management also differs and is challenging too. Here we present a case of a foreign body migrating into the retropharyngeal space which was removed intraorally. A 28- year old male patient presented with complaints of pain while swallowing following consumption of sausage and pork two days earlier to the onset of symptoms. X-Ray Neck AP and lateral view were done which revealed a thin metallic foreign body at the level of the T4 vertebra. Upper gastrointestinal endoscopy and rigid esophagoscopy were done in which a foreign body was not visualized in the esophageal lumen. NCCT neck was done which gave precise location and was removed intraorally with the patient in Rose position. A repeat x-ray was done on the 5th day which revealed no foreign body, the patient was discharged on the 7th day. Although the upper aerodigestive tract foreign body is common, foreign body migrating to the posterior pharyngeal wall or into the retropharyngeal space is not common and it is difficult to remove a migrated foreign body many cases requiring open procedures, thoracoscopy, thoracotomy.

Interacting Genetic Lesions of Melanoma in the Tumor Microenvironment: Defining a Viable Therapy.

Melanoma is the most aggressive form of skin cancer with an estimated 106,110 newly diagnosed cases in the United States of America in 2021 leading to an approximated 7180 melanoma-induced deaths. Cancer typically arises from an accumulation of somatic mutations and can be associated with mutagenic or carcinogenic exposure. A key characteristic of melanoma is the extensive somatic mutation rate of 16.8 mutations/Mb, which is largely attributed to UV exposure. Bearing the highest mutational load, many of them occur in key driver pathways, most commonly the BRAFV600E in the mitogen-activated protein kinase (MAPK) pathway. This driver mutation is targeted clinically with FDA-approved therapies using small molecule inhibitors of oncogenic BRAFV600E and MEK, which has greatly expanded therapeutic intervention following a melanoma diagnosis. Up until 2011, therapeutic options for metastatic melanoma were limited, and treatment typically fell under the spectrum of surgery, radiotherapy, and chemotherapy.Attributed to the extensive mutation rate, as well as having the highest number of neoepitopes, melanoma is deemed to be extremely immunogenic. However, despite this highly immunogenic nature, melanoma is notorious for inducing an immunosuppressive microenvironment which can be relieved by checkpoint inhibitor therapy. The two molecules currently approved clinically are ipilimumab and nivolumab, which target the molecules CTLA-4 and PD-1, respectively.A plethora of immunomodulatory molecules exist, many with redundant functions. Additionally, these molecules are expressed not only by immune cells but also by tumor cells within the tumor microenvironment. Tumor profiling of these cell surface checkpoint molecules is necessary to optimize a clinical response. The presence of immunomodulatory molecules in melanoma, using data from The Cancer Genome Atlas and validation of expression in two model systems, human melanoma tissues and patient-derived melanoma cells, revealed that the expression levels of B and T lymphocyte attenuator (BTLA), TIM1, and CD226, concurrently with the BRAFV600E mutation status, significantly dictated overall survival in melanoma patients. These molecules, along with herpesvirus entry mediator (HVEM) and CD160, two molecules that are a part of the HVEM/BTLA/CD160 axis, had a higher expression in human melanoma tissues when compared to normal skin melanocytes and have unique roles to play in T cell activation. New links are being uncovered between the expression of immunomodulatory molecules and the BRAFV600E genetic lesion in melanoma. Small molecule inhibitors of the MAPK pathway regulate the surface expression of this multifaceted molecule, making BTLA a promising target for immuno-oncology to be targeted in combination with small molecule inhibitors, potentially alleviating T regulatory cell activation and improving patient prognosis.

Posterior spinal cord indentation: imaging findings and clinical outcome.

AIM: To identify the imaging findings associated with worse clinical outcome in posterior spinal cord indentation. MATERIALS AND METHODS: A retrospective search for cases of dorsal cord indentation on magnetic resonance imaging (MRI) from April 2009 to March 2016 was undertaken. Imaging follow-up and clinical data were recorded. Two neuroradiologists blinded to the clinical data assessed the imaging findings. Differences and association of imaging and clinical findings were assessed via t-test and Fisher's exact and chi-squared tests for continuous and categorical data. Inter-rater agreement was calculated. RESULTS: Seventy-three patients were included, 65 were clinically stable, or the finding was incidental and eight had clinical worsening or required surgery. There was a significant difference in the percentage of cord diameter decrease between the two clinical groups (p=0.013, reader 1; p=0.027 reader 2). The clinical course was significantly associated with subjective cord indentation depth assessment (p=0.03 reader 1) and presence of syrinx (p=0.017 reader 2) on original MRI and worsening on imaging follow-up (p=0.03). The interrater agreement was moderate for syrinx identification (k=0.58). There was only fair agreement for the scalpel sign classification and in the final diagnosis (k=0.35 and 0.28). CONCLUSION: The degree of cord indentation, the presence of syrinx, and worsening of imaging findings on follow-up are associated with worse clinical course and can be useful in guiding management and directing subspecialty referrals.

Do patient-specific cutting guides and plates improve the accuracy of maxillary repositioning in hemifacial microsomia?

The aim of this retrospective study was to use computer-aided design and manufacturing (CAD/CAM) patient-specific plates and cutting guides for the waferless positioning and fixation of the maxilla after bimaxillary osteotomies in cases of hemifacial microsomia with condylar dysplasia or absence of the temporomandibular joint (TMJ), and to compare the results with the CAD/CAM fabricated surgical wafer by 3-dimensional analysis. Eighteen patients were selected from the hospital database, preoperative surgical planning and simulation were done on 3-dimensional computed tomographic models for all patients, and they were divided into Group I - in which CAD/CAM patient-specific cutting guides and plates were used; and Group II - in which CAD/CAM fabricated surgical wafers were used. Finally, the outcome was evaluated by comparing planned with postoperative outcomes. The largest discrepancies of the Le Fort I segment were 0.50 (0.18) mm in the anteroposterior direction and 0.82 (0.60)° in the yaw orientation with Group I. The largest discrepancies of the Le Fort I segment were 1.32 (1.40) mm in superioinferior direction and 8.48 (7.73)° in the yaw orientation with Group II. The CAD/CAM patient-specific cutting guides and plates proved to be reliable and have great value in improving the accuracy in repositioning the Le Fort I segment and in the efficacy of orthognathic treatment of hemifacial microsomia with condylar dysplasia or no TMJ. The CAD/CAM patient-specific cutting guides and plates are therefore a useful alternative to the wafer technique.

Correction to: Development of a new reproductive tissue cryopreservation clinical service for children: the Oxford programme.

In the published version, the Acknowledgements section was missing a funding note of co-author Dr C Verrill. The corrected version should read as follows.

A Phase I/II Study of Stereotactic Hypofractionated Once-weekly Radiation Therapy (SHORT) for Prostate Cancer.

AIMS: Stereotactic radiation therapy has been investigated predominantly in patients with low-intermediate-risk disease. We conducted a clinical trial of stereotactic hypofractionated radiation therapy delivered in once-weekly fractions on patients with all-risk non-metastatic disease to test feasibility, acute toxicities and patient-reported outcomes. MATERIALS AND METHODS: In this phase I/II study, 30 patients with prostatic adenocarcinoma, any Gleason score, T1-4N0 and prostate-specific antigen ≤60 ng/ml were treated with volumetric intensity modulated arc radiation therapy to a dose of 35 Gy in five fractions delivered once weekly. Patients with high-risk disease also received elective nodal irradiation to a dose of 25 Gy in five fractions simultaneously. Androgen deprivation was offered to intermediate- and high-risk patients. The primary outcome was acute toxicity. Secondary outcome measures included biochemical control and late toxicity. Patient-reported outcomes were measured using the International Prostate Symptom Score and European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ). RESULTS: All 30 patients completed treatment per-protocol. Most patients had T3 (60%) and Gleason 7 (50%) tumours. The median prostate-specific antigen was 17 ng/ml. High-risk disease was present in 20 patients (66.7%). There was a low incidence of acute toxicities (grade 2 + urinary 3.3%, grade 2 rectal 0%). Within the EORTC QLQ framework, only the urinary symptom score showed a clinically meaningful worsening from a mean of 20/100 at baseline to 34/100 at the end of treatment (P < 0.001), but reduced to 24/100 at 6 months (P = 0.08). With a median follow-up of 41.5 months, two patients each reported grade 2 late urinary and rectal toxicity. The 3- and 4-year biochemical control rates were 96.7 and 87.9%, respectively. CONCLUSION: In a cohort of mainly high-risk cancers, stereotactic once-weekly radiation therapy was easy to implement and well tolerated, with a low incidence of acute and late toxicity and excellent biochemical control.

Helical Radiotherapy in Early Laryngeal Cancers Could Lead to Excess Local Recurrence: Lessons From a Phase II Prospective Study.

AIMS: A prospective study was conducted to investigate the feasibility and efficacy of carotid-sparing intensity-modulated radiotherapy (CSIMRT) in early glottic cancers (EGC). MATERIALS AND METHODS: Eighteen patients underwent CSIMRT using helical tomotherapy to a dose of 55 Gy/20 fractions/4 weeks. Carotid intimal thickness (CIT) at prespecified carotid levels was measured using B-mode ultrasound at 6, 18 and 36 months. Serial changes in CIT were also measured in a control prospective cohort of 18 patients with head and neck cancers receiving bilateral neck nodal radiation over the same time period (54-60 Gy/30 fraction/6 weeks). The outcomes of 18 patients undergoing CSIMRT were compared against a retrospective consecutive cohort of 41 patients with EGC to confirm comparable local control. RESULTS: No significant CIT differences were identified between patients undergoing CSIMRT versus the control group. However, four patients in the CSIMRT group had a local recurrence between 8 and 39 months. In all patients the epicentre of the recurrence was noted at the anterior part of the larynx. The 5-year local recurrence-free survival was 75.1% (95% confidence interval 56.6-99.7%). By contrast, in the group of EGC patients treated without carotid sparing, local recurrence was noted only in a single patient (patient treated with helical tomotherapy) and the 5-year local recurrence-free survival was 97.1% (95% confidence interval 91.8-100%) (Log-rank P = 0.01). CONCLUSION: We failed to show the safety of CSIMRT using helical tomotherapy in this population of EGC patients. Use of CSIMRT also did not translate into a substantial reduction in CIT until 36 months. Use of CSIMRT using rotational arc techniques such as helical tomotherapy may be associated with a greater risk of local recurrence due to intrafractional motion interplay effects.

Development of a new reproductive tissue cryopreservation clinical service for children: the Oxford programme.

PURPOSE: This article describes the development of a new reproductive tissue cryopreservation clinical service for children at high risk of infertility in the NHS during times of severe financial constraints in the health service. METHOD: A development plan with two phases was drawn up. Phase 1 restricted the service to childhood cancer patients referred to the Oxford Paediatric Oncology and Haematology Principle Treatment Centre. It was estimated that there would be 10 patients/year and used existing staff and facilities from paediatric oncology, surgery, anaesthetics radiology, pathology, psychology, teenage-young adult gynaecology, and an existing Human Tissue Authority tissue bank with a licence for storage of tissue under a Human Sector Licence. Phase 2 extended the service to include children and young adults across England, Wales and Ireland-patients from Scotland having access to a research programme in Edinburgh. The main challenge in phase 2 being resources and the need for patients to be able to be treated as close to home as safely as possible. RESULTS: The Oxford team developed information resources and eligibility criteria based on published best practice, referral and treatment pathways, multidisciplinary team meetings, a network of third party sites, and a dedicated case management and database. As the programme expanded, the Oxford team was able to justify to management the need for a dedicated theatre list. Patient feedback through questionnaires, qualitative work conducted as part of a Ph.D. thesis as well as direct patient stories and interviews in TV, and radio features underpins the positive impact the programme has on patients and their families. CONCLUSION: The Oxford Reproductive Cryopreservation programme delivers fertility preservation treatment to children and young adults at high risk of infertility safely, effectively and as close to home as possible. The onward view is to apply for national funding for this programme for recognition and sustainability.

Breast Cancer Demographics, Types and Management Pathways: Can Western Algorithms be Optimally used in Eastern Countries?

Over the past decade, breast cancer has overtaken cervical cancer to become the most common cancer among women in India, as in most Western nations. In addition to the high incidence, the morbidity and mortality associated with this malignancy are disproportionately higher in India. Although some efforts are being made to increase awareness about this disease, a large majority of Indian patients present with advanced disease. Here, important institutional data and treatment outcomes are reviewed and compared with data from the West. Additionally, we highlight recent efforts in setting up collaborative multicentre trials in breast cancer in India and suggest some ways forward to improve outcomes.

FNAC and Its Utility in Solitary Thyroid Nodule and Its Correlation with Histopathological Examination.

Discrete swelling in one lobe of thyroid gland with no palpable abnormality elsewhere is termed as a solitary thyroid nodule. FNAC is the investigation of choice in solitary nodule for selection of surgical cases due to compliance, simple and quick to perform. The aim of this study was to evaluate the utility of FNAC in solitary thyroid nodule with the relation of histopathological findings. In this prospective observational study fifty (50) patients of solitary thyroid nodule without multinodular goitre, diffuse goitre, dominant nodule and clinically hypothyroidism or hyperthyroidism were included from admitted patients of different institutes of Comilla both private and government Medical College Hospital, Bangladesh. All patients were clinically examined and investigation findings from thyroid scan, ultrasonogram of thyroid gland, FNAC of thyroid nodule, histopathological report of excised thyroid were collected and posted into data collection sheet. The data were analysed with simple statistical table. The result showed that among 50 patients 41 patients were detected as benign nodule after FNAC which is about 82%. Malignant lesions were 12% (6 patients) and 6% (3 patients) of the case was indeterminate as because the specimen were unsatisfactory. The sensitivity, specificity, and accuracy of FNAC diagnosis in relation to histopathological findings were 100%, 83.33% and 97.87%. So FNAC is sensitive and accurate method for evaluation of solitary thyroid nodules.