Estimation of the optimal radiotherapy utilization rate for childhood neuroblastoma.

BACKGROUND AND PURPOSE: The optimal utilization rate of radiotherapy (oRUR) serves as a benchmark for assessing service demand and improving access to cancer care. While it is estimated that approximately 50 % of adult cancer patients require external beam radiotherapy during their treatment, there is a scarcity of data regarding the optimal use of radiotherapy in pediatric cancer. In this study, we adopted an established method and developed a model to estimate the oRUR in childhood neuroblastoma. MATERIALS AND METHODS: We developed a decision tree model to calculate the oRUR using indications for radiotherapy and corresponding epidemiological data collected through systematic review and meta-analysis. Sensitivity analyses were performed to evaluate the impact of variations in radiotherapy indications between treatment protocols and variables in the model. We calculated and compared the oRUR for global, high-income, and low- and middle-income settings. RESULTS: The oRUR for pediatric neuroblastoma was 64 % (95 % CI: 58 %-71 %) in the global setting, 50 % in high-income countries, and 68 % in low- and middle-income countries. The impact of variation in radiotherapy indications between major international treatment protocols was negligible. CONCLUSION: The knowledge of oRUR is crucial for evaluating current practices, identifying gaps in access, and planning future radiotherapy services for treating childhood cancer. Based on our results, 64 % of children with neuroblastoma have an indication for radiotherapy. Patients in low- and middle-income countries have more indications for radiotherapy than those in high-income countries, due to a more adverse tumour stage distribution caused by limited access to healthcare resources.

Artificial neural network-assisted prediction of radiobiological indices in head and neck cancer.

Background and purpose: We proposed an artificial neural network model to predict radiobiological parameters for the head and neck squamous cell carcinoma patients treated with radiation therapy. The model uses the tumor specification, demographics, and radiation dose distribution to predict the tumor control probability and the normal tissue complications probability. These indices are crucial for the assessment and clinical management of cancer patients during treatment planning. Methods: Two publicly available datasets of 31 and 215 head and neck squamous cell carcinoma patients treated with conformal radiation therapy were selected. The demographics, tumor specifications, and radiation therapy treatment parameters were extracted from the datasets used as inputs for the training of perceptron. Radiobiological indices are calculated by open-source software using dosevolume histograms from radiation therapy treatment plans. Those indices were used as output in the training of a single-layer neural network. The distribution of data used for training, validation, and testing purposes was 70, 15, and 15%, respectively. Results: The best performance of the neural network was noted at epoch number 32 with the mean squared error of 0.0465. The accuracy of the prediction of radiobiological indices by the artificial neural network in training, validation, and test phases were determined to be 0.89, 0.87, and 0.82, respectively. We also found that the percentage volume of parotid inside the planning target volume is the significant parameter for the prediction of normal tissue complications probability. Conclusion: We believe that the model has significant potential to predict radiobiological indices and help clinicians in treatment plan evaluation and treatment management of head and neck squamous cell carcinoma patients.

Capacity building for pediatric neuro-oncology in Pakistan- a project by my child matters program of Foundation S.

Introduction: Initiated in June 2019, this collaborative effort involved 15 public and private sector hospitals in Pakistan. The primary objective was to enhance the capacity for pediatric neuro-oncology (PNO) care, supported by a My Child Matters/Foundation S grant. Methods: We aimed to establish and operate Multidisciplinary Tumor Boards (MTBs) on a national scale, covering 76% of the population (185.7 million people). In response to the COVID-19 pandemic, MTBs transitioned to videoconferencing. Fifteen hospitals with essential infrastructure participated, holding monthly sessions addressing diagnostic and treatment challenges. Patient cases were anonymized for confidentiality. Educational initiatives, originally planned as in-person events, shifted to a virtual format, enabling continued implementation and collaboration despite pandemic constraints. Results: A total of 124 meetings were conducted, addressing 545 cases. To augment knowledge, awareness, and expertise, over 40 longitudinal lectures were organized for healthcare professionals engaged in PNO care. Additionally, two symposia with international collaborators and keynote speakers were also held to raise national awareness. The project achieved significant milestones, including the development of standardized national treatment protocols for low-grade glioma, medulloblastoma, and high-grade glioma. Further protocols are currently under development. Notably, Pakistan's first pediatric neuro-oncology fellowship program was launched, producing two graduates and increasing the number of trained pediatric neuro-oncologists in the country to three. Discussion: The initiative exemplifies the potential for capacity building in PNO within low-middle income countries. Success is attributed to intra-national twinning programs, emphasizing collaborative efforts. Efforts are underway to establish a national case registry for PNO, ensuring a comprehensive and organized approach to monitoring and managing cases. This collaborative initiative, supported by the My Child Matters/Foundation S grant, showcases the success of capacity building in pediatric neuro-oncology in low-middle income countries. The establishment of treatment protocols, fellowship programs, and regional tumor boards highlights the potential for sustainable improvements in PNO care.

Channel Activities of the Full-Length Prion and Truncated Proteins.

Prion diseases are fatal neurodegenerative disorders characterized by the conversion of the cellular prion protein (PrPC) into a misfolded prion form, which is believed to disrupt the cellular membranes. However, the exact mechanisms underlying prion toxicity, including the formation of membrane pores, are not fully understood. The prion protein consists of two domains: a globular domain (GD) and a flexible N-terminus (FT) domain. Although a proximal polybasic amino acid (FT(23-31) sequence of FT is a prerequisite for cellular membrane permeabilization, other functional domain regions may modulate its effects. Through single-channel electrical recordings and cryo-electron microscopy (cryo-EM), we discovered that the FT(23-50) fragment forms pore-shaped oligomers and plays a dominant role in membrane permeabilization within the full-length mouse prion protein (mPrP(23-230)). In contrast, the FT(51-110) domain or the C-terminal domain downregulate the channel activity of FT(23-50) and mPrP(23-230). The addition of prion mimetic antibody, POM1 significantly amplifies mPrP(23-230) membrane permeabilization, whereas POM1_Y104A, a mutant that binds to PrP but cannot elicit toxicity, has a negligible effect on membrane permeabilization. Additionally, the anti-N-terminal antibody POM2 or Cu2+ binds to the FT domain, subsequently enhancing the FT(23-110) channel activity. Importantly, our setup provides a novel approach without an external fused protein to examine the channel activity of truncated PrP in the lipid membranes. We therefore propose that the primary N-terminal residues are essential for membrane permeabilization, while other functional segments of PrP play a vital role in modulating the pathological effects of PrP-mediated neurotoxicity.

Acute Oral Mucositis During Hypo-Fractionated Radiation in Squamous Cell Carcinoma of Oral Cavity.

Oral mucositis remains a concern in the treatment of head and neck malignancies. This small study included 11 patients treated by hypo-fractionated radiotherapy and assessed for oral mucositis. All patients received a radiation dose of 55 Gy in 20 fractions (2.75 Gy/fraction). At the end of the first week of radiation, three patients had Grade I oral mucositis. During the last week of radiation, most of the patients developed Grade II and III mucositis, 7 (64%) and 4 (36%), respectively. At one month follow-up, 5 (46%) of them had Grade I, while 2 (18%) had developed Grade II mucositis. At three months, 2 (18%) had Grade I mucositis, and none of the patients showed Grade II/III oral mucositis. Grade II oral mucositis was the most common grade found mainly in the last week of radiation therapy. None had Grade IV oral mucositis. Key Words: Acute oral mucositis, Hypo-fractioned radiation, Oral carcinoma.

Pakistan National Guidelines for Pediatric High-Grade Gliomas.

Pediatric high-grade glioma (pHGG) is highly malignant central nervous system tumor and constitute 10% of the pediatric gliomas. Effective treatment needs a functioning multi-disciplinary team including pediatric neuro oncologist, neurosurgeon, neuroradiologist, neuropathologist and radiation oncologist. Despite surgical resection, radiotherapy and chemotherapy, most HGG will recur resulting in early death. A significant proportion of HGG occurs in context of cancer predisposition syndromes like Constitutional Mismatch Repair Deficiency (CMMRD) also known as Biallelic Mismatch Repair Deficiency (bMMRD) characterized by high mutational burden. The incidence of HGG with CMMRD is one per million patients. bMMRD is caused by homozygous germline mutations in one of the four Mis Match Repair (MMR) genes (PMS2, MLH1, MSH2, and MSH6). The use of TMZ is now avoided in CMMRD related HGG due to its limited response and known ability to increase the accumulation of somatic mutations in these patients, increasing the risk of secondary tumors. HGG should be managed under the care of multidisciplinary team to receive optimum treatment. This is particularly important for low middle-income countries (LMIC) with limited resources like Pakistan.

Kidney Disease in Childhood Cancer Survivors Treated With Radiation Therapy: A Comprehensive PENTEC Genitourinary Review.

PURPOSE: Kidney injury is a known late and potentially devastating complication of abdominal radiation therapy (RT) in pediatric patients. A comprehensive Pediatric Normal Tissue Effects in the Clinic review by the Genitourinary (GU) Task Force aimed to describe RT dose-volume relationships for GU dysfunction, including kidney, bladder, and hypertension, for pediatric malignancies. The effect of chemotherapy was also considered. METHODS AND MATERIALS: We conducted a comprehensive PubMed search of peer-reviewed manuscripts published from 1990 to 2017 for investigations on RT-associated GU toxicities in children treated for cancer. We retrieved 3271 articles with 100 fulfilling criteria for full review, 24 with RT dose data and 13 adequate for modeling. Endpoints were heterogenous and grouped according to National Kidney Foundation: grade ≥1, grade ≥2, and grade ≥3. We modeled whole kidney exposure from total body irradiation (TBI) for hematopoietic stem cell transplant and whole abdominal irradiation (WAI) for patients with Wilms tumor. Partial kidney tolerance was modeled from a single publication from 2021 after the comprehensive review revealed no usable partial kidney data. Inadequate data existed for analysis of bladder RT-associated toxicities. RESULTS: The 13 reports with long-term GU outcomes suitable for modeling included 4 on WAI for Wilms tumor, 8 on TBI, and 1 for partial renal RT exposure. These reports evaluated a total of 1191 pediatric patients, including: WAI 86, TBI 666, and 439 partial kidney. The age range at the time of RT was 1 month to 18 years with medians of 2 to 11 years in the various reports. In our whole kidney analysis we were unable to include chemotherapy because of the heterogeneity of regimens and paucity of data. Age-specific toxicity data were also unavailable. Wilms studies occurred from 1968 to 2011 with mean follow-ups 8 to 15 years. TBI studies occurred from 1969 to 2004 with mean follow-ups of 4 months to 16 years. We modeled risk of dysfunction by RT dose and grade of toxicity. Normal tissue complication rates ≥5%, expressed as equivalent doses, 2 Gy/fx for whole kidney exposures occurred at 8.5, 10.2, and 14.5 Gy for National Kidney Foundation grades ≥1, ≥2, and ≥3, respectively. Conventional Wilms WAI of 10.5 Gy in 6 fx had risks of ≥grade 2 toxicity 4% and ≥grade 3 toxicity 1%. For fractionated 12 Gy TBI, those risks were 8% and <3%, respectively. Data did not support whole kidney modeling with chemotherapy. Partial kidney modeling from 439 survivors who received RT (median age, 7.3 years) demonstrated 5 or 10 Gy to 100% kidney gave a <5% risk of grades 3 to 5 toxicity with 1500 mg/m2 carboplatin or no chemo. With 480 mg/m2 cisplatin, a 3% risk of ≥grade 3 toxicity occurred without RT and a 5% risk when 26% kidney received ≥10 Gy. With 63 g/m2 of ifosfamide, a 5% risk of ≥grade 3 toxicity occurred with no RT, and a 10% toxicity risk occurred when 42% kidney received ≥10 Gy. CONCLUSIONS: In patients with Wilms tumor, the risk of toxicity from 10.5 Gy of WAI is low. For 12 Gy fractionated TBI with various mixtures of chemotherapy, the risk of severe toxicity is low, but low-grade toxicity is not uncommon. Partial kidney data are limited and toxicity is associated heavily with the use of nephrotoxic chemotherapeutic agents. Our efforts demonstrate the need for improved data gathering, systematic follow-up, and reporting in future clinical studies. Current radiation dose used for Wilms tumor and TBI appear to be safe; however, efforts in effective kidney-sparing TBI and WAI regimens may reduce the risks of renal injury without compromising cure.

Impact of COVID-19 pandemic on delivery of pediatric radiotherapy: A critical review.

The COVID-19 pandemic has prevented the timely diagnosis and treatment of many diseases, including pediatric cancer. Its impact on pediatric oncologic treatments warrants investigation. As radiotherapy is an integral component of cancer care, we reviewed the published data regarding the impact of COVID-19 on the delivery of pediatric radiotherapy to inform actions for future global events. We found that disruptions in radiotherapy were reported amongst interruptions in other therapies. Disruptions were more common in low-income countries (78%) and low middle-income countries (68%) compared with upper middle-income countries (46%) and high-income countries (10%). Several papers included recommendations for mitigation strategies. Altered treatment regimens were common, including increasing the use of active surveillance and systemic therapy to delay local therapies, and accelerated/hypofractionated dose delivery. Our findings suggest that COVID-19 has impacted radiotherapy delivery in the pediatric population globally. Countries with limited resources may be more affected. Various mitigation strategies have been developed. The efficacy of mitigation measures warrants further investigation.

Solitary rib metastasis from primary nasopharyngeal carcinoma: A rare clinical presentation.

We report a case of a middle age male who presented to our tertiary care university hospital with the complaints of nasal obstruction and decrease hearing. The CT scan of head and neck exhibited a mass in nasopharynx and enlarged bilateral cervical lymph nodes. Biopsy from nasopharynx confirmed the lesion as poorly differentiated non-keratinizing squamous cell carcinoma and staged as cT2N2M0. He received neoadjuvant chemotherapy. Subsequently, he underwent chemo radiation therapy. He represented with left chest wall pain. Imaging confirmed isolated lesion on left sided 6th rib. Rib lesion was resected followed by radiation therapy to surgical bed and systemic treatment. The patient remained disease free for 4.5 years. Later, his disease relapsed, and he died of systemic disease progression. To the best of the author's knowledge, only few cases have been reported with isolated rib metastasis from nasopharyngeal carcinoma and this is the first case in which metastasectomy was considered.

Thicker Ice Improves the Integrity and Angular Distribution of CDC48A Hexamers on Cryo-EM Grids.

Many cryogenic electron microscopy (cryo-EM) single particle analyses are constrained by the sample preparation step upon which aggregation, dissociation, and/or preferential orientation of particles can be introduced. Here, we report how we solved these problems in the case of CDC48A, a hexameric AAA ATPase from Arabidopsis thaliana. CDC48A hexamers are well preserved under negative staining conditions but disassemble during grid freezing using the classical blotting method. Vitrification of grids using the blot-free Chameleon method preserved the integrity of particles but resulted in their strong preferential orientation. We then used a strategy where we improved in parallel the purification of CDC48A and the conditions for cryo-EM data acquisition. Indeed, we noted that images taken from thicker ice presented an even distribution of intact particles with random orientations, but resulted in a lower image resolution. Consequently, in our case, distribution, orientation, image resolution, and the integrity of particles were tightly correlated with ice thickness. By combining the more homogeneous and stable CDC48A hexamers resulting from our improved purification protocol with an iterative search across different ice thicknesses, we identified an intermediate thickness that retained sufficiently high-resolution structural information while maintaining a complete distribution of particle orientations. Our approach may provide a simple, fast, and generally applicable strategy to record data of sufficient quality under standard laboratory and microscope settings. This method may be of particular value when time and resources are limited.

Total skin electron beam therapy (TSEBT) in management of mycosis fungoides: A case series.

A retrospective review was conducted In Aga Khan University from January 2013-December 2020 for patients who received Total Skin Electron Beam Therapy (TSEBT) on the management of Mycosis Fungoides (MF). The clinical response rate and disease-free interval (DFI) was evaluated for three patients. All of the patients received a 3600 cGy dose of radiation. Clinical complete remission (cCR) was observed in two out of three patients, while one patient showed clinical partial response. Following the cCR to TSEBT, the DFI of the first patient with stage 1B lasted 30 months, while the second patient with stage IIB remained disease free for five months. TSEBT is an effective treatment for MF disease. It can thus be expected that patients with limited disease in the early stage can acquire a cCR with a longer DFI. The clinical outcomes of our study show concordance with the literature. The patients who had extensive (T3) skin involvement and had refractory diseases showed lower DFI with radiation.

Building the ecosystem for pediatric neuro-oncology care in Pakistan: Results of a 7-year long twinning program between Canada and Pakistan.

BACKGROUND: Low- and middle-income countries sustain the majority of pediatric cancer burden, with significantly poorer survival rates compared to high-income countries. Collaboration between institutions in low- and middle-income countries and high-income countries is one of the ways to improve cancer outcomes. METHODS: Patient characteristics and effects of a pediatric neuro-oncology twinning program between the Hospital for Sick Children in Toronto, Canada and several hospitals in Karachi, Pakistan over 7 years are described in this article. RESULTS: A total of 460 patients were included in the study. The most common primary central nervous system tumors were low-grade gliomas (26.7%), followed by medulloblastomas (18%), high-grade gliomas (15%), ependymomas (11%), and craniopharyngiomas (11.7%). Changes to the proposed management plans were made in consultation with expert physicians from the Hospital for Sick Children in Toronto, Canada. On average, 24% of the discussed cases required a change in the original management plan over the course of the twinning program. However, a decreasing trend in change in management plans was observed, from 36% during the first 3.5 years to 16% in the last 3 years. This program also led to the launch of a national pediatric neuro-oncology telemedicine program in Pakistan. CONCLUSIONS: Multidisciplinary and collaborative efforts by experts from across the world have aided in the correct diagnosis and treatment of children with brain tumors and helped establish local treatment protocols. This experience may be a model for other low- and middle-income countries that are planning on creating similar programs.

Outcome of Buried Versus Exposed Kirchner Wires in Terms of Infection in Fractures of Phalanges and Metacarpal Bones of Hand.

Introduction and objective The fracture of hand bones is very common among manual hand workers and a fractured hand imparts a great effect on a person's productivity both socioeconomically and from a body image point of view. The most common method of hand fractures fixation is with the help of Kirschner wires. Kirchner wires can be inserted in exposed or in buried manner. There are a few studies that provide a comparative analysis of rate of infection between these two techniques. This study aimed to assess the rate of infection in buried versus exposed Kirschner (K)-wires for hand fractures. Material and method The study was designed as a randomized controlled trial with consecutive non-random sampling. It was conducted in the Department of Plastic Surgery, Holy Family Hospital, Rawalpindi, Pakistan, and lasted from June to December 2019. Blinding was not possible as both the operating surgeon and patient were aware of the procedure being done; however, the assessor was blinded and was not aware which group got which treatment. Total 122 patients with fractures of metacarpals and phalanges of hand were included in the study and were divided into two groups with 61 patients in each. Group A was treated with buried K-wires and group B with exposed K-wires. The patients were followed for one month for the outcomes in terms of infection in the patients. Results Group A had 24 females (39.3%) and 37 males (60.7%). Group B had 16 females (26.2%) and 45 males (73.8%). In group A, nine (14.8%) patients had ages between 10 and 20 years, 18 (29.5%) patients between 21 and 30 years, 14 (23.0%) patients between 31 and 40 years, 11 (18.0%) patients between 41 and 50 years, and nine (14.8%) were between 51 and 60 years. The mean duration of surgery was 35.16 minutes for group A and 27.30 minutes for group B. Based on modified Oppenheim scoring system for pin site infection, out of 61 patients, seven (11.5%) with buried K-wires while 14 (23%) with exposed K-wires developed pin site infection. Conclusion Rate of infection is low in buried K-wires as compared to exposed K-wires though not statistically significant (p>0.05) for the fractures of metacarpals and phalangeal fractures of hand.

Fertility preservation is an imperative goal in the clinical practice of radiation oncology: a narrative review.

With reduced cancer mortality in recent years, increased efforts must be put into safeguarding cancer survivors' long-term quality of life (QOL). Fertility preservation is recognised as a key component of QOL in survivorship. Concerns about fertility have been seen to significantly impact cancer patients' emotional and mental health as, generally, both malignancy and its treatment may cause a temporary or permanent reduction in infertility. This article reviews the primary effects of radiation therapy on male and female gonads and has further highlighted procedures through which the functioning of these organs can be protected before or during radiation treatment. We have also emphasised the importance of the establishment of multidisciplinary tumour boards and patient education regarding future reproductive function which is an important component of the care of individuals with cancer. This article highlights that infertility is a persistent and major concern that can add to long-term stress in cancer survivors, and education about fertility preservation before the initiation of any treatment is especially important.

Central nervous system metastases: a rare presentation of nasopharyngeal carcinoma.

We report a case of a male patient. He presented with nasal obstruction and epistaxis. The MRI of the brain showed a mass in the nasopharynx and enlarged cervical lymph nodes. Besides this, there was an extra-axial, dural-based lesion in brain and subcentimetre nodules in both lungs. He received induction chemotherapy followed by chemoradiation therapy to the primary site and dural-based metastatic deposit. He re-presented with bilateral lower limb weakness. The MRI of the spine showed metastatic deposits within the thoracic cord parenchyma and meningeal deposits at the lumbar region. Palliative radiation was used to treat spinal cord and meningeal metastases. He died a few months later because of systemic disease progression. Considering the rarity of this presentation in nasopharyngeal carcinoma and lack of clear guidelines for standard treatment, we report this case to share our experience of management.