Evaluation of bone thickness at infra-zygomatic crest region compared with cervical vertebrae maturation index.

Orthodontists should know variation in thickness of infrazygomatic crest region according to maturation status of patients. Therefore, it is of interest to evaluate the thickness of bone at infrazygomatic crest region and to correlate the thickness of bone with cervical vertebrae maturation index (CVMI) incorporating CBCT.A retrospective analysis of 120 patients' CBCT scans60 of them male and 60 female-was carried out. The thickness of the bone was determined at five locations. Using CBCT, the cervical vertebral maturation was created and the Hassel-Farmann index was used for analysis. A lone researcher conducted all of the measurements. Bone thickness of infrazygomatic arch at all five locations was found to increase as the maturation stage progressed from initiation stage to maturation stage. Then there was decrease in the bone thickness in completion stages compared to maturation stage. The thickness of bone at infrazygomatic arch is significantly correlated with CVM stages as determined by CBCT.

Linking orthodontic treatment and sleep apnea among adult Indian patients.

The differences in the effects of orthodontic treatment on airway and craniocervical posture in patients with OSA (obstructive sleep apnea) having skeletal class II high-angle malocclusion is of interest. Hence, 48 individuals with OSA and skeletal class II high-angle malocclusion were chosen from among all patients in need of orthodontic therapy. Every patients had CBCT (cone beam computed tomography) taken both before and after receiving orthodontic therapy. All parameters were assessed on the lateral cephalogram from CBCT in order to assess the indices of craniocervical posture, hyoid position, skeletal and dental conditions. Parameters of upper airway (position of hyoid) showed statistically significant increase in values after orthodontic treatments. Thus, there was increase in values of dimensions of upper airway, post orthodontic treatment. Hence, orthodontic therapy help improve the upper airway morphology and craniocervical posture in patients of OSA with hyperdivergent skeletal class II malocclusion.

Investigating the Association between Obstructive Sleep Apnea and Temporomandibular Joint Disorders: A Case-Control Study.

Background: This study aims to explore the connection between obstructive sleep apnea (OSA) and temporomandibular joint disorders (TMD) through a case-control investigation. OSA is a sleep-related breathing disorder that affects breathing during sleep, whereas TMD involves pain and dysfunction in the jaw joint. Understanding any potential association between these two conditions could contribute to improved diagnostic and therapeutic approaches. Materials and Methods: A total of 50 participants were included in both the OSA group and the control group. Participants with diagnosed OSA constituted the OSA group, whereas individuals without OSA formed the control group. TMD symptoms were assessed using standardized diagnostic criteria. Statistical analysis was performed to compare the prevalence of TMD symptoms between the two groups. Results: In the OSA group, 36 out of 50 participants exhibited TMD symptoms, whereas in the control group, 18 out of 50 participants displayed such symptoms. The calculated P value was found to be 0.023, indicating a statistically significant association between OSA and TMD. Conclusion: The findings of this study suggest a notable association between OSA and TMD. Individuals with OSA are more likely to experience TMD symptoms compared to those without OSA. This underscores the importance of considering TMD symptoms in individuals with OSA and vice versa for a comprehensive approach to diagnosis and management.

3D assessment of alveolar bone alterations in orthodontic movement among Indians.

Apical root resorption, which is characterised as a biological or abnormal phenomenon that shortens the length of the root apex, is additional typical iatrogenic impact of orthodontic tooth movement that may jeopardise the effectiveness of treatment and tooth lifespan. The main goals of the current retrospective investigation were to assess the dimensions of alveolar bone alterations that come along with orthodontic movement and to look into the frequency and extent of resorption of root in maxillary incisors across categories that were similarly managed with clear aligners (OCA) and fixed appliances (OFA) using CBCT. The study included 50 subjects who were divided into two categories with 25 study subjects in each category. Category OFA: Subjects receiving OFA (n=25). A CBCT scan was used to get three-dimensional pictures at the beginning of therapy as well as at the end of therapy. The overall resorption of root at apical region in OFA group was 0.63±0.21 mm. The overall resorption of root at apical region in OCA group was 0.32 ±0.36 mm. The difference in observation was statistically significant (p= 0.000) with reduced resorption of root at apical region in clear aligners. It was concluded that the decrease in thickness of alveolar bone was greater in orthodontic fixed appliances group as compared to clear aligners. The resorption of root at apical region was lesser in clear aligners group as compared to fixed appliances.

Physics-Inspired Quantum Simulation of Resonating Valence Bond States─A Prototypical Template for a Spin-Liquid Ground State.

Spin liquids─an emergent, exotic collective phase of matter─have garnered enormous attention in recent years. While experimentally many prospective candidates have been proposed and realized, theoretically modeling real materials that display such behavior may pose serious challenges due to the inherently high correlation content of such phases. Over the last few decades, the second-quantum revolution has been the harbinger of a novel computational paradigm capable of initiating a foundational evolution in computational physics. In this report, we strive to use the power of the latter to study a prototypical model, a spin-1/2-unit cell of a Kagome antiferromagnet. Extended lattices of such unit cells are known to possess a magnetically disordered spin-liquid ground state. We employ robust classical numerical techniques such as the density-matrix renormalization group (DMRG) to identify the nature of the ground state through a matrix-product state (MPS) formulation. We subsequently use the gained insight to construct an auxiliary Hamiltonian with reduced measurables and also design an ansatz that is modular and gate-efficient. With robust error-mitigation strategies, we are able to demonstrate that the said ansatz is capable of accurately representing the target ground state even on a real IBMQ backend within 1% accuracy in energy. Since the protocol is linearly scaling O(n) in the number of unit cells, gate requirements, and the number of measurements, it is straightforwardly extendable to larger Kagome lattices that can pave the way for efficient construction of spin-liquid ground states on a quantum device.

Effectiveness of Short-Term Lifestyle Modification on Reducing Body- Weight-Related Parameters in Persons with Severe Mental Illness: A Randomized Controlled Trial.

Background: Persons with severe mental illness (SMI) reportedly have a high mortality rate due to metabolic syndrome (MS). However, lifestyle modification (LM) offers effective management of some components of MS. This study aimed to evaluate the effectiveness of LM in reducing body-weight-related parameters in SMIs. Method: Eighty participants with SMI were assigned randomly to either LM (n = 40) or treatment as usual (TAU; n = 40) groups using block randomization (eight blocks of n = 10). The LM group and their caregivers received a structured LM package that included nutrition counselling, recommendations on a balanced diet, and physical activity. The two groups were assessed on body weight, body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and quality of life (QOL) at baseline and after three months. Thirty-one LM and 33 TAU participants completed the study. Results: The LM and TAU groups were comparable on sociodemographic and clinical characteristics and baseline variables of body weight, BMI, WC, and WHR (all P > 0.08). Repeated-measures analysis of variance (RM ANOVA) showed that the LM group had significantly reduced body weight, BMI, WC, and WHR (all P < 0.001) than the TAU group. Similarly, the LM group also showed improvement in their QOL (P < 0.001), whereas TAU showed no improvement. Conclusions: LM is an effective way to reduce body-weight-related parameters of MS and improves the QOL among persons with SMI in the short term. The caregivers' inclusion during LM contributed to the weight reduction. However, the long-term effect of the intervention could not be assessed.

Neurological Adverse Effects of Immune Checkpoint Inhibitors and Chimeric Antigen Receptor T-Cell Therapy.

Immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cell constitute recently approved novel therapies targeted to treat a wide number of malignancies. Both the treatments modulate the immune system and can cause a number of immune-related adverse events (irAEs), including polyendocrinopathies, gastrointestinal and neurological complications. This literature review focuses on the neurological side effects of these therapies as these are uncommon and alter the course of the treatment. Neurological complications involve the peripheral and central nervous system, including polyneuropathy, myositis, myasthenia gravis, demyelinating polyradiculopathy, myelitis, and encephalitis. If early recognized, the neurological complications can be treated effectively with steroids to reduce the potential of short-term and long-term complications. Therefore, early identification and treatment of irAEs are needed to optimize the outcomes associated with ICPI and CAR T-cell therapies.

Systems approach to enhance Lynch syndrome diagnosis through tumour testing.

BACKGROUND: Guidelines recommend universal mismatch repair (MMR) tumour testing of colorectal adenocarcinomas (CRCs) to screen for Lynch syndrome (LS). However, its implementation remains disjointed and referral for genetic testing dismal, particularly among minorities. We aimed to increase referral, cancer genetic testing and eventually LS diagnosis by developing the CLEAR LS (Closed Loop Enhanced Assessment and Referral for Lynch Syndrome) intervention, a systems approach which in the second phase was automated. METHODS: This is a cohort study of all patients diagnosed with CRC at an academic centre between 1 January 2012, when implementation of universal CRC testing began, and 31 January 2021. The original cohort spanned through 31 May 2015. Tumour testing included MMR immunohistochemistry, followed by BRAF V600E/MLH1 promoter methylation testing when indicated. The intervention included a manual phase (1 June 2015 through 31 July 2018), which systematised pathology screening and cancer genetics (CG) referral mechanisms, and an automated phase (1 August 2018 through 31 January 2021) using computer programming. RESULTS: A total of 249/1541 CRC (17.38%) had MMR loss of expression and 129 (8.37%) qualified for CG evaluation. Referral was 27.58% in the original cohort and 92.1% in the intervention (p<0.001). Patients seen by CG among referred were 27.58% in the original cohort and 74.3% in the intervention (p two-sided<0.001). The distribution of race/ethnicity among patients qualifying and referred for CG evaluation was not significantly different across cohorts. LS diagnosis increased from 0.56% (original cohort) to 1.43% (intervention). Cost per new diagnosis of LS decreased from US$173 675 to $87 960 from original cohort to intervention. CONCLUSION: Implementation of systematic case identification and referral support mechanisms significantly increased the proportion of patients undergoing genetic testing and doubled the percentage of patients diagnosed with LS with no referral differences across racial/ethnic groups.

Evaluation of different aesthetic indices for planning orthodontic treatment.

Three aesthetic indices namely aesthetic component of index of orthodontic treatment needs (IOTN -AC), dental aesthetic index (DAI) and dental aesthetics screening index (DESI) were compared in orthodontic treatment. 242 participants (160 female and 82 male) who were interested in orthodontic treatment participated. The individuals' ages ranged from 16-25 years. Three aesthetic indices namely IOTN -AC, DAI and DESI were evaluated for each participant. The overall accuracy of DAI, AC-IOTN and DESI in assessment of dental aesthetics in orthodontic treatment was 62%, 68% and 64% respectively. The Negative predictive value (NPV) was higher than Positive predictive value (PPV) for all indices. The sensitivity was greater than specificity for all indices. It was observed that values of sensitivity, specificity, PPV and NPV were high for AC-IOTN. The findings were significant statistically (p<0.05).

Epidemiology and Determinants of Survival for Primary Intestinal Non-Hodgkin Lymphoma: A Population-Based Study.

Background: Gastrointestinal tract is the most common site of extranodal non-Hodgkin lymphoma (EN-NHL). Most of the published data have been on gastric NHL with limited studies on primary intestinal non-Hodgkin lymphoma (PI-NHL) considering rare incidence. We performed epidemiological and survival analysis for PI-NHL from the Surveillance, Epidemiology, and End Results (SEER) 18 database. Methods: A total of 9,143 PI-NHL cases of age ≥ 18 years were identified from the SEER 18 database for the period 2000 - 2015. Totally, 8,568 patients were included for survival analysis. Cause-specific survival (CSS) and overall survival (OS) analysis were done for PI-NHL and PI-diffuse large B-cell lymphoma (PI-DLBCL) using sex, age of onset, treatment, histology, stage, and year of diagnosis. Survival analysis was done by using Cox proportional hazard model and Kaplan-Meier plot with log-rank test. Results: The percentage of PI-NHL of all the intestinal cancers and EN-NHL were 1.35%, and 10.52%, respectively. The age-adjusted incidence was 0.9145/100,000 population for the study population. PI-NHL was more common among patients aged ≥ 60 years, male and non-Hispanics Whites. Majority of patients were diagnosed at stage 1 and 2 (74%), and DLBCL (44.8%) was the most common histology. Overall median survival was 111 (95% confidence interval (CI): 105 - 117) months. In OS analysis, significant increased risk of mortality was seen with T-cell NHLs vs. DLBCL (hazard ratio (HR): 2.56), patients aged ≥ 60 vs. < 60 years (HR: 2.87), stage 4 vs. stage 1 (HR: 1.93), male vs. female (HR: 1.17), with best outcome seen in patient treated with combination of chemotherapy and surgery vs. none (HR: 0.45). Similar results were seen in CSS and for PI-DLBCL as well. Significant improvement in outcomes was observed for PI-DLBCL patients receiving chemotherapy with/without surgery. Conclusions: Findings from our large, population-based study reveal PI-NHL is a rare type of intestinal malignancy with significant difference in survival based on histological and epidemiological characteristics.

Quantum machine learning for chemistry and physics.

Machine learning (ML) has emerged as a formidable force for identifying hidden but pertinent patterns within a given data set with the objective of subsequent generation of automated predictive behavior. In recent years, it is safe to conclude that ML and its close cousin, deep learning (DL), have ushered in unprecedented developments in all areas of physical sciences, especially chemistry. Not only classical variants of ML, even those trainable on near-term quantum hardwares have been developed with promising outcomes. Such algorithms have revolutionized materials design and performance of photovoltaics, electronic structure calculations of ground and excited states of correlated matter, computation of force-fields and potential energy surfaces informing chemical reaction dynamics, reactivity inspired rational strategies of drug designing and even classification of phases of matter with accurate identification of emergent criticality. In this review we shall explicate a subset of such topics and delineate the contributions made by both classical and quantum computing enhanced machine learning algorithms over the past few years. We shall not only present a brief overview of the well-known techniques but also highlight their learning strategies using statistical physical insight. The objective of the review is not only to foster exposition of the aforesaid techniques but also to empower and promote cross-pollination among future research in all areas of chemistry which can benefit from ML and in turn can potentially accelerate the growth of such algorithms.

A Persistent Parvovirus Infection Causing Anemia in an HIV Patient Requiring Intravenous Immunoglobulin Maintenance Therapy.

Anemia is a common finding in a human immunodeficiency virus (HIV)-positive patient with a wide range of possible causes and is a significant risk factor for mortality in acquired immunodeficiency syndrome (AIDS). Opportunistic parvovirus infection-causing pure red cell aplasia is one of its uncommon causes. It has been suggested that immunocompromised patients with abnormal antibody production are more susceptible to acquiring a chronic parvovirus infection requiring long-term intravenous immunoglobulin (IVIg) treatment; however, there are no specific guidelines for it. Here, we present a case of an HIV patient with persistent parvovirus infection resulting in chronic anemia requiring long-term maintenance immunoglobulin therapy with an excellent therapeutic response.

Survival Benefit of Pembrolizumab for Patients With Pancreatic Adenocarcinoma: A Case Series.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with 5-year survival rate of 10%. Evidence about pembrolizumab usage for PDAC is limited even though it is Food and Drug Administration (FDA)-approved for treatment of advanced pancreatic cancer with deficient mismatch repair expression (dMMR) or high tumor mutational burden (TMB) where as there is limited evidence for programmed death-ligand 1 (PD-L1)-positive PDACs. We present three patients with different stages of advanced PDAC treated with pembrolizumab as single maintenance therapy or combination with other therapy. Case 1 is a patient with borderline resectable PDAC, treated with neoadjuvant chemotherapy and surgical resection, followed with pembrolizumab as maintenance therapy with no progression for 4 years after test showed patient was dMMR positive. Case 2 is a patient who was found to have locally advanced PDAC, treated with neoadjuvant chemotherapy and surgical resection followed by multiple line of treatment with programmed cell death-1 (PD-1) and breast cancer gene 2 (BRCA2)-positive status treated with pembrolizumab and olaparib maintenance without any evidence of progression for more than 3 years. Case 3 is a patient with metastatic PDAC with PD-1 and BRCA2-positive status initially treated with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) and gemcitabine plus nab-paclitaxel switched to irinotecan liposomal, at the same time was started on maintenance pembrolizumab and olaparib with no progression on computed tomography (CT) surveillance for 8 months. For patient with different stages of PDAC with dMMR mutation or PD-1 expression, pembrolizumab should be explored more as maintenance therapy for patients with surgical operable PDAC to decrease recurrence, or as a combination with targeted therapy or chemotherapy to prolong survival in patients with advanced PDAC.

Site-Specific Survival of Extra Nodal Diffuse Large B-Cell Lymphoma and Comparison With Gastrointestinal Diffuse Large B-Cell Lymphoma.

Background: Diffuse large B-cell lymphoma (DLBCL) constitutes 30% of all non-Hodgkin's lymphomas. It can present as a nodal disease or as an extra nodal disease. Based on the site of origin, extra nodal DLBCL (EN-DLBCL) may have a distinct clinical outcome. Apart from the site of origin, factors including demographics, stage, and presence of any other primary malignancy also affect the outcome. The purpose of our study was to characterize prognostically distinct groups based on the site of presentation of EN-DLBCL. Methods: We used 18 registries in Surveillance, Epidemiology, and End Results database to identify the patients with EN-DLBCL for 2000 - 2015 with last follow-up till December 31, 2018. A total of 30,290 EN-DLBCL patients were selected and categorized based on 13 broad sites grouping. Demographic variables were summarized. We did overall survival analysis with univariate and multivariate Cox-proportional hazard modeling. Short-term survival trend was calculated as well. Results: The percentage of EN-DLBCL of all DLBCLs is 34.48%. EN-DLBCL was comparatively seen more in males (54.94%) and non-Hispanic whites (71.52%). In terms of clinical characteristics, patients with EN-DLBCL were mostly diagnosed at age ≥ 60 years (66.11%), early stage (69.33%), and presentation as first primary cancer (81.89%). A higher risk of mortality was seen in non-Hispanic black (hazard ratio (HR) 1.36), with late age of onset (HR 2.69), late stage at presentation (HR 1.42), and with history of other malignancy (HR 1.29). Compared to the intestinal tract, the risk of overall mortality was higher in individuals with involvement of nervous system (HR 1.85), pancreas and hepatobiliary system (HR 1.22), and respiratory system (HR 1.18) and the best outcomes were seen in heart and mediastinal site (HR 0.58) of DLBCL. Conclusion: Based upon our population-based study, we conclude that primary site of presentation of EN-DLBCL is an important prognostic factor with significant difference in survival based on histological and epidemiological characteristics.

A Trilogy of Submassive Pulmonary Embolism, Non-Small Cell Lung Cancer with Brain Metastasis, Kartagener's Syndrome and its Management with Aspiration Thrombectomy.

Venous thromboembolism is a common cause of morbidity and mortality in cancer patients. Given the bleeding risks, determining treatment for malignancy-related thrombosis is challenging, especially in the case of submassive pulmonary embolism (PE) because the risk-benefit ratio in terms of bleeding risk is uncertain. Here we discuss the case of a 53-year-old man with Kartagener syndrome with situs inversus totalis and stage IV non-small cell lung cancer with a recent brain mass resection, presenting with dyspnoea and palpitations. The patient was diagnosed with a submassive PE and only underwent suction thrombectomy through the left internal jugular vein with excellent response. In conclusion, when treating submassive PE, aspiration thrombectomy without thrombolysis is preferable to thrombolysis, which may be contraindicated due to the higher risk of bleeding. LEARNING POINTS: Anticoagulation and thrombolysis should be started after carefully weighing the risks and benefits in cancer patients.In some patients with submassive pulmonary embolism (PE), thrombolysis may be contraindicated due to the increased risk of bleeding, but aspiration thrombectomy can be a preferred treatment modality.Further research evaluating the risks and benefits of different therapeutic approaches for submassive PE could aid in determining the best course of action and establishing treatment guidelines.

Dysphagia as a Rare Presentation of Cervical Cancer with Mediastinal Metastasis.

Dysphagia has a broad aetiology and so it is essential to identify the precise cause. Cervical cancer metastasis is distinctive in that it usually involves local lymph node invasion; however, approximately 1% of cases have mediastinal involvement, which can cause severe compressive symptoms in rare situations. To highlight an uncommon severe manifestation of cervical cancer relapse, we describe a case of dysphagia in a woman with a history of cervical cancer. After a thorough investigation that included endoscopy, endoscopy with ultrasound, an oesophagogram and fine needle aspiration, we eventually reached the diagnosis of mediastinal metastatic cervical cancer. Following interventions, the patient's condition gradually improved, both clinically and radiographically. LEARNING POINTS: Mediastinal lymph node enlargement causing dysphagia can be a presenting sign of a metastatic lesion from treated cervical cancer.A PEG tube is helpful in relieving dysphagia caused by metastatic mediastinal lymph node enlargement and as bridge for nutrition during chemotherapy.The VEGF inhibitor bevacizumab can be used in advanced metastatic cervical cancer.Check-point inhibitors like pembrolizumab can be used in metastatic cervical cancer.

Liquid Presenting as Solid: A Rare Presentation of Acute Myeloid Leukaemia as a Solid Epidural Mass.

Myeloid sarcoma (MS) is a very rare malignant tumour composed of myeloblasts. It most commonly involves soft tissue, bone, periosteum and lymph nodes, but unusual presentation sites have also been reported. Typically, MS evolves concurrently with active leukaemia or following remission, when it is known as secondary MS. But rarely MS can occur de novo without evidence of concomitant haematological disease. Herein, we report an unusual case of central nervous system-MS in a patient without evidence of concomitant haematological disease. In this case, progressive thoracic and lumbar pain with paraplegia ultimately led to the diagnosis of acute myeloid leukaemia. We also conducted a PubMed search for case reports, case series and reviews of past literature regarding central nervous system-MS and report our findings. LEARNING POINTS: Myeloid sarcoma (MS) can present de novo in the absence of antecedent leukaemia.Clinical manifestations of neural MS can be variable, including rare ones like spinal cord compression.Timely recognition of MS is paramount, as it is potentially curable.

Assessment of common risk factors and validation of the Gail model for breast cancer: A hospital-based study from Western India.

OBJECTIVE: Modified Gail Model is a noninvasive, easy to implement risk estimation tool for absolute breast cancer risk. It was developed with data collected from non African American females and further modified for African-American, the Hispanic, and Native American populations. The use of this model for population outside the US and European country is not yet validated. We evaluated the prevalent risk factors and the effectiveness of the Gail model for risk assessment in our local Indian population. MATERIALS AND METHODS: A retrospective analysis of a prospectively maintained database was conducted on patients treated between 2008 and 2013. Six hundred and fifty patients were included in each group. Six questions were taken as per the breast cancer risk assessment tool calculator. A value of over 1.67% was taken as a high risk for breast cancer development. RESULTS: The mean age of the participant was 50 ± 21.3 years in cases and 41 ± 16.4 years in controls. Age and age at first childbirth >30 years were found to be significant and associated with increased risk of breast carcinoma, but the age at menarche, family history, previous breast biopsy, and atypical hyperplasia was no significant. The Gail model was assessed, and sensitivity was 10.30% and 96.30% specificity for our population. Positive and negative predictive values were 73.62% and 51.77%. CONCLUSION: Our study concluded that the Gail model is not an appropriate risk assessment tool for the population in its present form. For the future application of this model, we need to perform a bigger study with a higher sample size representing a maximum number of local variabilities in the Indian population.

A Tale of Immune-Related Adverse Events With Sequential Trials of Checkpoint Inhibitors in a Patient With Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitor (CPI) therapy is approved for the treatment of many cancers. As its use becomes more prevalent, sequential trials with different CPIs as monotherapy or combination therapy will become more common. It is thought that the increased cumulative dose of CPIs over multiple trials increases the risk of immune-related adverse events (irAEs). However, it is not known if using one CPI combination increases the risk of developing irAEs during the subsequent trial of a different CPI combination. Here, we present a patient with multiple episodes of high-grade irAEs over the course of sequential trials of combination CPIs. A 65-year-old female patient with metastatic renal cell cancer received two trials of combination CPIs. During the first trial with durvalumab and tremelimumab, she had CPI-induced grade 2 skin rashes and primary hypothyroidism with a mild elevation in lipase, normal antithyroid antibody profile, and normal blood glucose. Due to progression after the first trial, her regimen was changed to ipilimumab and nivolumab combination therapy. She subsequently presented to the emergency room with diabetic ketoacidosis on the sixth week following treatment initiation and was diagnosed with new-onset insulin-dependent type 1 diabetes mellitus (DM) with a negative antibody profile for DM. Immune CPIs cause irAEs by increasing immune activity against self-antigens. Sequential trials of CPIs may increase the risk of irAEs by increasing the cumulative CPI dose, or by organ injury inflicted by the first set of CPIs which is tipped "over the edge" by subsequent trials. We believe that the latter mechanism could be responsible for our case. Sequential CPI therapy should be planned carefully with increased surveillance for the early diagnosis and treatment of irAEs.