Potential application mechanism of traditional Chinese medicine in treating immune checkpoint inhibitor-induced colitis.

Cancer ranks among the foremost causes of mortality worldwide, posing a significant threat to human lives. The advent of tumor immunotherapy has substantially transformed the therapeutic landscape for numerous advanced malignancies, notably non-small cell lung cancer and melanoma. However, as immune checkpoint inhibitors (ICIs) are increasingly applied in clinical settings, a spectrum of undesired reactions, termed immune-related adverse events (irAEs), has emerged. These adverse reactions are associated with immunotherapy and can result in varying degrees of harm to the human body. Among these reactions, Immune checkpoint inhibitor-induced colitis (ICIIC) stands out as one of the most prevalent clinical adverse events. In contemporary times, traditional Chinese medicine (TCM) has demonstrated remarkable efficacy in addressing various maladies. Consequently, investigating the potential application and mechanisms of Chinese medicine in countering immune checkpoint inhibitor-induced colitis assumes significant importance in the treatment of this condition.

Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer: An In-depth chronotherapeutic study.

INTRODUCTION: Recent retrospective studies suggest potential large patient's benefit through proper timing of immune checkpoint blockers (ICB). The association between ICB treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex. METHODS: A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied. RESULTS: 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 [1.17-2.1], p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p = 0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p = 0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1-3 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was equal to 4.8 ([2.3-10.1], p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4). CONCLUSIONS: Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.

Characteristics of Ocular Inflammatory Side Effects Associated with Immune Checkpoint Inhibitors in a Northern California Population.

PURPOSE: To characterize the ocular inflammatory side effects associated with immune checkpoint inhibitor (CPI) treatment in a Northern California population. DESIGN: Retrospective case series. PARTICIPANTS: Patients receiving CPI within an integrated healthcare delivery system. METHODS: All patients within Kaiser Permanente Northern California receiving CPI between January 1, 2012 and November 1, 2018 were identified. Medical records of those seen in the ophthalmology clinic at least once were retrospectively reviewed. MAIN OUTCOME MEASURES: Type and duration of ocular inflammation, indication for and exposure to CPI, time from exposure to diagnosis of ocular inflammation. RESULTS: 31 cases of ocular inflammation were identified in 5061 patients (0.61%) receiving CPI. Mean ± SD age was 67 ± 11.9 (range 38-89). Mean time from exposure to diagnosis was 6.8 ± 5.5 months (range 0.5-17). 87% of cases were bilateral, and 43% of cases were chronic. Average ophthalmology follow-up was 16 ± 18 months (range 0-71). 16/31 (52%) had anterior uveitis, 7/31 (23%) had serous retinal detachment or panuveitis resembling Vogt-Koyanagi-Harada syndrome, 4/31 (13%) had papillitis, and 6/31 (19%) had diplopia or ocular motility defect. There was one case each (3.2%) of melanoma associated retinopathy, corneal edema, granulomatous lacrimal gland enlargement, and choroidal neovascularization. CONCLUSIONS: Ocular inflammation is a rare immune associated side effect of CPI treatment, the most common manifestation of which is anterior uveitis.

The Combined Effect of Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors on Thyroid Function.

Background: Recent successes with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of solid malignancies have paved the way for a new era of combined therapy. A common side effect seen with each of these classes of treatment is thyroid dysfunction, with rates estimated at 30-40% for TKI and 10-20% for ICI. However, little is known about the effect of combined ICI+TKI therapy on thyroid function. Therefore, this study evaluated the incidence, clinical features, and risk factors for developing thyroid abnormalities during ICI+TKI therapy and the relationship to cancer outcomes. Methods: We conducted a retrospective cohort study of patients treated with combination ICI+TKI cancer therapy at City of Hope Comprehensive Cancer Center from 2017 to 2023 who had pretreatment normal thyrotropin (TSH) levels. Primary analyses assessed the frequency, timing, and severity of thyroid function test abnormalities during ICI+TKI cancer therapy, and the requirement for thyroid hormone replacement. Secondary analyses evaluated risk factors for the development of thyroid dysfunction, including sex and drug regimen, and the association with cancer progression-free survival or overall survival. Univariable and multivariable models were used. Results: There were 106 patients who received ICI+TKI therapy with a median age of 63.5 years and a median follow-up of 12.8 months (interquartile range [IQR] 5.9-20.9). Notably, 63.2% (67/106) developed thyroid function abnormalities during ICI+TKI therapy, including 11 (10.4%) with hyperthyroidism, 42 (39.6%) with subclinical hypothyroidism (SCHypo), and 14 (13.2%) with overt hypothyroidism. The onset of thyroid dysfunction occurred at a median of 7 weeks (IQR 3.1-9.0) after start of ICI+TKI treatment for hyperthyroidism, 8.0 weeks (IQR 3.0-19.0) for SCHypo, and 8.1 weeks (IQR 5.9-9.1) for overt or worsening hypothyroidism. Hyperthyroidism resolved to hypothyroidism or normal TSH without intervention in all subjects, suggesting thyroiditis, and hypothyroidism was readily treated with thyroid hormone replacement. Conclusions: Thyroid dysfunction is a frequent adverse event in individuals treated with combination ICI+TKI therapy, with our data suggesting a rapid onset and higher incidence than previously seen with ICI or TKI therapy alone. Therefore, close monitoring of thyroid function during initial therapy and multidisciplinary care with endocrinology are recommended to facilitate early detection and initiation of thyroid hormone replacement in these patients.

Immunoneoadjuvant therapy with immune checkpoint inhibitors of gastric cancer: an emerging exemplification : Immunoneoadjuvant therapy of gastric cancer.

Advances in immune checkpoint inhibitors (ICIs) have enabled more effective treatment for individuals with various types of solid tumors. Given the improved survival benefit and acceptable safety profile of ICIs in advanced gastric cancer, there is plenty of interest in the use of ICIs in the neoadjuvant setting with curative intent. Theoretically, immunoneoadjuvant with ICIs could boost the levels of endogenous tumor antigen present in the tumor to enhance T-cell priming and further enhance systemic immunity. This systemic immune response may improve the detection and elimination of the disseminated micrometastatic tumors beyond the resected tumor, which are sources of postsurgical relapse. Numerous clinical studies have begun to explore the application of ICIs in neoadjuvant treatment of gastric cancer. This article reviews the progress in the use of ICI monotherapy and in combination with alternative therapies for the treatment of gastric cancer to aid in the development of gastric cancer immunoneoadjuvant therapy and improve the overall therapeutic benefit.

Association of Geriatric Nutritional Risk Index With Immune Checkpoint Inhibitor Treatment Duration and Adverse Events in Lung Cancer.

BACKGROUND/AIM: Compared to conventional cytotoxic anticancer agent-based therapy, treatment with immune checkpoint inhibitors (ICI) significantly prolongs overall survival. The Geriatric Nutritional Risk Index (GNRI) has been used as a new prognostic indicator in cancer. As nutritional status is associated with prognosis and indicates treatment response, we investigated the effect of the pretreatment GNRI on the (1) occurrence of ICI-induced immune-related adverse events (ir-AE) and (2) association with time to treatment failure (TTF) in ICI monotherapy for lung cancer. PATIENTS AND METHODS: In this study, 127 patients with lung cancer who were treated with ICI monotherapy were retrospectively enrolled. Based on a cutoff value of 92 for the GNRI, we investigated intergroup differences in the occurrence of adverse events and their association with TTF in the High-GNRI (≥92) and Low-GNRI (<92) groups. For intergroup comparisons, we used the Student's t-test, Welch's t-test, Fisher's direct probability test, and Mann-Whitney's U-test, and factors with p<0.05 in the intergroup comparison were extracted as explanatory variables. RESULTS: Based on the pretreatment GNRI, the median TTF was 5.1 months (95%CI=2.4-7.9 months) in the High-GNRI group and 2.3 months (95%CI=1.6-3.1 months) in the Low-GNRI group, with the High-GNRI group having a significantly longer TTF (p<0.01). The incidence of skin rash (p=0.0129) and pruritus (p<0.01) was significantly higher in the High-GNRI group. CONCLUSION: Pretreatment GNRI influences the continuation of ICI monotherapy. The High-GNRI group demonstrated a significantly higher frequency of skin lesions, which may have influenced the prolongation of TTF.

Evaluation of mycophenolic acid exposure in a patient with immune-related hepatotoxicity caused by nivolumab and ipilimumab therapy for malignant melanoma: a case report.

BACKGROUND: Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice. CASE PRESENTATION: We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure. CONCLUSION: Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.

Integrating Baseline Nutritional and Inflammatory Parameters with Post-Treatment EBV DNA Level to Predict Outcomes of Patients with De Novo Metastatic Nasopharyngeal Carcinoma Receiving Chemotherapy Combination PD-1 Inhibitor.

OBJECTIVES: To develop and validate a prognostic nomogram based on baseline nutritional and inflammatory parameters for risk stratification in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC) receiving chemotherapy combination programmed death-1 (PD-1) inhibitor. METHODS: This retrospective study analyzed 131 patients with dmNPC (88 and 43 in the training and validation cohorts, respectively) between March 2017 and November 2020. All these patients received chemotherapy combined with PD-1 inhibitor treatment. We identified independent risk factors using univariate and multivariate Cox regression analyses and established a nomogram to predict the progression-free survival (PFS). The predictive accuracy of the nomogram was evaluated and independently validated. RESULTS: Baseline nutritional risk index (NRI), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), uric acid (UA), and post-treatment Epstein-Barr virus (EBV) DNA were used to develop a nomogram that could divide patients into favorable- and unfavorable-prognosis groups. The median PFS (mPFS) was significantly longer in the favorable-prognosis group compared to the unfavorable-prognosis group (35.10 months [95% CI: 27.36-42.84] vs. 7.23 months [95% CI: 6.50-7.97]; p = 0.001). All results were confirmed in the validation cohort. CONCLUSIONS: The proposed model improved the prognostic risk stratification for patients with dmNPC undergoing chemotherapy combined with PD-1 inhibitor treatment.

Systematic vitamin D supplementation is associated with improved outcomes and reduced thyroid adverse events in patients with cancer treated with immune checkpoint inhibitors: results from the prospective PROVIDENCE study.

BACKGROUND: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs). METHODS: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion. RESULTS: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85). CONCLUSION: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs.

Case Report: Imaging immune checkpoint inhibitor-induced yin-yang effects in the brain.

Background: Treatment with immune checkpoint inhibitors (ICI) can induce durable responses in cancer patients, but it is commonly associated with serious immune-related side effects. Both effects are suggested to be mediated by CD8+ T-cell infiltration. Whole body CD8+ T-cell distribution can be visualized by PET imaging of a 89Zr-labeled anti-humanCD8a minibody, currently investigated in a phase 2b trial. Main body: An adult patient diagnosed with metastatic melanoma developed ICI-related hypophysitis after two courses of combined immunotherapy (ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) at 3 weeks interval). On a [89Zr]Zr-crefmirlimab berdoxam PET/CT scan, made 8 days before clinical symptoms occurred, increased CD8+ T-cell infiltration in the pituitary gland was detected. Simultaneously, tracer uptake in a cerebral metastasis was increased, indicating ICI-induced tumor infiltration by CD8+ T-cells. Conclusions: The observations in this case report underscore the role of CD8+ T-cell in non-tumor tissues in ICI-related toxicity. In addition, it illustrates a potential role for molecular imaging by PET/CT for investigation and monitoring of ICI-induced effects.

Incidence of diabetes mellitus in patients treated with immune checkpoint inhibitors (ICI) therapy - A comprehensive cancer center experience.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and more patients are receiving ICIs than before. Although this has improved cancer care but so has the increase in the incidence of immune-related adverse events (irAEs) including endocrinopathies. ICI-induced diabetes mellitus (DM) is a rare irAE with an approximate incidence of 1%. Due to paucity of data in literature about ICI-induced DM, we conducted a study to report the incidence and characteristics of new onset and worsening of DM in patients treated with ICIs. METHODS: We conducted a retrospective review of patients who received ICIs during 10-year period. We identified patients with newly diagnosed DM and worsening of preexisting DM. FINDINGS: Among 2,477 patients who received one or multiple ICIs, 14 patients developed new onset DM and 11 patients experienced worsening of pre-existing DM. Median time to new onset or worsening DM from ICI treatment initiation was âˆ¼ 12 weeks. Median hemoglobin A1c was 6.2% at baseline and 8.5% at the onset of ICI-induced DM. Seven patients presented with diabetes ketoacidosis (DKA), all in the new onset group. (p = 0.02) No significant difference was observed between two groups regarding personal history of autoimmune disorder or family history of DM. (p greater than 0.05) Positive autoantibodies were found in three patients [two with Glutamic Acid Decarboxylase (GAD65) antibodies and one with insulin autoantibodies (IAA)]. INTERPRETATION: The incidence of new onset and worsening DM in patients treated with ICIs was 1.01%.

Vitamin D Status Is Associated With Immune Checkpoint Inhibitor Efficacy and Immune-related Adverse Event Severity in Lung Cancer Patients: A Prospective Cohort Study.

Vitamin D (VitD) is potentially immunomodulatory, so here we aimed to explore the relationships between serum VitD levels, immune checkpoint inhibitor (ICI) efficacy, and immune-related adverse events (irAEs). Serum 25-hydroxyvitamin D [25(OH)D] levels were quantified before and after ICI treatment in prospectively enrolled patients with advanced lung cancers. Of 77 enrolled patients, 29 developed 42 irAEs. Baseline 25(OH)D levels of partial response (PRs) patients were significantly higher than non-PR patients (19.39±7.16 vs. 16.28±5.99 ng/mL, P =0.04). The area under the curve of 25(OH)D >15.73 ng/mL to identify PR was 0.63 (95% CI, 0.51-0.76, P =0.047), and baseline 25(OH)D levels >15.73 ng/mL (odds ratio: 2.93, 95% CI, 1.10-7.79, P =0.03) and prior targeted therapy (odds ratio: 0.30, 95% CI, 0.10-0.92, P =0.04) were independent predictors of PR as best efficacy by multivariable logistic regression. With respect to irAEs, baseline 25(OH)D levels were higher in grade 1 irAE patients than in grade 2/3/4 irAE patients (20.07±8.64 vs. 15.22±2.30 ng/mL, P =0.02). However, the area under the curve was only 0.56 (95% CI, 0.42-0.70, P =0.39) for a baseline 25(OH)D of 20.99 ng/mL for predicting irAE occurrence. There was a direct monotonic relationship and U-shaped relationship between baseline 25(OH)D levels and ICI efficacy and irAE occurrence, respectively. Overall survival was significantly different between VitD sufficient, insufficient, and deficient patients (log-rank P =0.01), which remained after adjustment in Cox proportional hazards regression models. Baseline 25(OH)D levels seem to be associated with ICI efficacy and prognosis, it might be helpful to assess the baseline VitD status, and supplementation with VitD might bring some benefit to enhance ICI efficacy and reduce moderate-severe irAEs.

Risk Factors for Immune Checkpoint Inhibitor Immunotherapy Toxicity Among Older Adults with Cancer.

OBJECTIVES: Immune checkpoint inhibitor immunotherapy (IO) is revolutionizing cancer care but can lead to significant toxicity. This study seeks to describe potential risk factors for immune-related adverse events (irAEs) specifically among older adults. MATERIALS AND METHODS: This was a retrospective study at a single academic comprehensive cancer center based on chart review data abstracted by physicians. For patients aged ≥70 years, frequency, type, and grade of irAEs and their association with baseline patient demographics, comorbidities, mobility, and functional status were characterized using bivariate analysis. Based on those results, multivariable logistic regressions were constructed to model the association between these characteristics with any grade and grade 3 or higher irAEs. RESULTS: Data were analyzed for 238 patients aged ≥70 years who received IO for mostly (≥90%) advanced cancer between 2011 and 2018. Thirty-nine percent of older adults experienced an irAE and 13% experienced one that was grade 3 or higher. In the multivariable analysis, depression was associated with an increased incidence of any grade irAE, while decreased life-space mobility was associated with an increased incidence of grade ≥3 irAEs. CONCLUSION: Most characteristics of special interest among older adults, include fall risk, weight loss, cognitive limitations, and hearing loss, were not associated with irAEs in our study. However, decreased life-space mobility and depression are potential risk factors for IO toxicity among older adults with advanced cancer. Interventions designed to evaluate and mitigate modifiable risk factors for treatment-related toxicity are needed, and the results of this study may be useful for guiding those efforts.

Outcomes of responders to PD-1/PD-L1 inhibitors who discontinue therapy after sustained disease control.

BACKGROUND: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are widely used in the treatment of metastatic malignancies. Judiciously balancing disease control (DC) against development of immune-related adverse events (irAE) remains a crucial aspect of treatment. The effect of treatment discontinuation after sustained disease control (SDC) is unknown. The purpose of this analysis was to evaluate outcomes of responders to ICI who discontinue treatment after a minimum of 12 months (SDC). METHODS: We retrospectively reviewed the database of the University of New Mexico Comprehensive Cancer Center (UNMCCC) between 2014 and 2021 and identified patients who had received ICI. Patients with metastatic solid tumors who had stopped ICI therapy after achieving SDC [stable disease, partial response, complete response (SD, PR, CR)] were selected and outcomes reviewed from their electronic health records. RESULTS: We identified 204 patients who were treated with ICI for various solid cancers. Forty-four patients (21.6%) met the criteria, of whom 35 with follow-up data were included in the final analysis; including 11 melanoma, 5 non-small cell lung, 4 head & neck, 8 renal, 4 urothelial, 1 anal, 1 Merkel cell carcinoma, and 1 liposarcoma. Patients were divided into two groups: those who stopped ICI due to an irAE [irAE group, n = 14, median treatment time (MTT), 16.6 mo] and those who stopped due to other reasons (eg completion of 2 years of therapy, n = 20, non-cancer related surgery, n = 1) (non-irAE group, n = 21, MTT, 23.7 mo). Among the irAE group, the most common irAE included pneumonitis, rash, transaminitis, and fatigue. As of data cutoff date, 9 of 14 (64%) patients continued to show SDC. Only 5 of 14 (36%) patients in this group experienced progression of disease (PD), with 1 of 2 patients achieving DC (median follow-up of 19.2 mo after last dose of treatment, range 3-50.2 mo). Among the non-irAE group, 13 of 21 (62%) continued to have SDC. Eight of 21 (38%) experienced PD after stopping treatment, 7 of whom received ICI rechallenge, with 2 of 7 achieving DC (median follow-up of 22.2 mo, range 3.6-54.8 mo). At a median follow-up of 21.3 mo from stopping ICI therapy (range, 3-54.8 mo), 10 patients (71%) from the irAE group and 13 (61.9%) from the non-irAE group are in DC and have not experienced PD. CONCLUSIONS: We demonstrate that 22 (66%) patients experienced SDC, regardless of cancer type or development of irAE. After including patients who were re-challenged with ICI due to PD, 25 (71%) remain in DC. Future prospective malignancy-specific trials are warranted to evaluate optimal treatment duration.

Immune checkpoint inhibitor-induced vitiligo in cancer patients: characterization and management.

This study highlights the range of non-melanoma cancers where ICI-induced vitiligo can be present and challenges the exclusivity of this phenomenon to melanoma. We believe our manuscript will encourage awareness in our colleagues and stimulate interest in further studies to elucidate the mechanisms of ICI-induced vitiligo in both melanoma and non-melanoma cancers, and to understand whether this phenomenon holds the same positive prognostic value in both cancer groups. This is a retrospective cohort study from a single-institution's electronic medical record for cancer patients treated with ICIs who subsequently developed vitiligo. We identified 151 patients with ICI-induced vitiligo, 19 (12.6%) non-melanoma and 132 (77.4%) melanoma patients. Time to onset of vitiligo was nearly doubled in the non-melanoma cohort, however, this is confounded by possible delayed diagnosis or under reporting of this asymptomatic condition in patients who do not regularly receive skin exams. The majority of patients had a stable course of vitiligo with 91.4% receiving no treatment in this largely Caucasian cohort. Two patients with non-melanoma cancers and Fitzpatrick type IV or above skin received treatment with narrowband ultraviolet B light therapy and topical steroids with near-complete response. This study highlights the occurrence of ICI-induced vitiligo in a variety of non-melanoma cancers, where skin of color patients will be more prevalent and the need for treatment will potentially be more urgent. Further study is needed to elucidate the mechanism of ICI-induced vitiligo and determine if non-melanoma cancers have the same association between vitiligo and increased tumor response.

Immune Checkpoint Inhibitor-induced Pneumonitis: Incidence, Clinical Characteristics, and Outcomes.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the newest class of anticancer drugs. Pneumonitis is increasingly being recognized as a potential complication of these agents. METHODS: We conducted a retrospective study of patients who received ICIs at a comprehensive cancer center. We collected data on demographics, type of malignancy, type of ICI agent, incidence of pneumonitis up to 6 weeks after receiving ICI agent, clinical characteristics, and risk factors for overall survival in patients who develop pneumonitis. RESULTS: A total of 654 patients received ICIs during the study period. The most common type of cancer for which ICI was given was adenocarcinoma of the lung (29%), followed by renal cell cancer (12%) and squamous cell lung cancer (12%). Among the study patients, 41% received nivolumab and 32% received pembrolizumab. Other patients in the study received combination of ICIs or ICI plus chemotherapeutic agent, or were part of clinical trial involving ICI. Overall 42 (6.4%) patients developed pneumonitis within 6 weeks after the last dose of treatment of any ICI agent. Of these, 81% of patients had Grade ≥ 2 pneumonitis and 45% of these required hospital admission for pneumonitis, with 10% of them requiring admission to intensive care unit. Overall, patients who received pembrolizumab-containing regimen, had prior chemotherapy, or who never had cancer-related surgery had increased risk of death. CONCLUSION: Our large retrospective study shows real-life data of incidence of pneumonitis in patients who are treated with ICIs for cancer treatment. Our data indicate that the incidence of pneumonitis is overall lower than that reported previously with relatively good outcomes.

Immune checkpoint inhibitor-mediated colitis is associated with cancer overall survival.

BACKGROUND: Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event following immune checkpoint inhibitor (ICI) therapy for cancer. IMC has been associated with improved overall survival (OS) and progression-free survival (PFS), but data are limited to a single site and predominantly for melanoma patients. AIM: To determine the association of IMC with OS and PFS and identify clinical predictors of IMC. METHODS: We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age, sex, ICI class, and malignancy to a cohort of ICI users without IMC, from May 2011 to May 2020. Using univariate and multivariate logistic regression, we determined association of presence of IMC on OS, PFS, and clinical predictors of IMC. Kaplan-Meier curves were generated to compare OS and PFS between ICI users with and without IMC. RESULTS: IMC was significantly associated with a higher OS (mean 24.3 mo vs 17.7 mo, P = 0.05) but not PFS (mean 13.7 mo vs 11.9 mo, P = 0.524). IMC was significantly associated with OS greater than 12 mo [Odds ratio (OR) 2.81, 95% confidence interval (CI) 1.17-6.77]. Vitamin D supplementation was significantly associated with increased risk of IMC (OR 2.48, 95%CI 1.01-6.07). CONCLUSION: IMC was significantly associated with OS greater than 12 mo. In contrast to prior work, we found that vitamin D use may be a risk factor for IMC.

Hypercalcemia: A Review.

Importance: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

Vitamin D metabolism pathway polymorphisms are associated with efficacy and safety in patients under anti-PD-1 inhibitor therapy.

Aim: Vitamin D (VitD) signaling has been increasingly investigated for its role in stimulating the innate and adaptive immune systems and suppressing inflammatory responses. Therefore, we examined the associations between VitD-related genetic polymorphisms, plasma 25-hydroxyvitamin D (25(OH)D), and the efficacy and safety of immune checkpoint inhibitors (ICIs). Patients and methods: A total of 13 single-nucleotide polymorphisms (SNPs) in VitD metabolic pathway genes were genotyped in 343 cancer patients receiving ICI treatment using the MassARRAY platform. In 65 patients, the associations between plasma 25(OH)D levels and ICI treatment outcomes were investigated further. Results: We found that the CYP24A1 rs6068816TT and rs2296241AA genotypes were significantly higher in patients who responded to ICIs. Furthermore, patients with higher plasma 25(OH)D levels had a better treatment response. The distribution of allele and genotype frequencies showed that three SNPs (rs10877012, rs2762934, and rs8018720) differed significantly between patients who had immune-related adverse events (irAEs) and those who did not. There was no statistically significant relationship between plasma 25(OH)D levels and the risk of irAEs. Conclusion: In summary, our findings showed that genetic variations in the VitD metabolism pathway were associated with ICI treatment outcomes, and VitD supplementation may be useful in improving ICI treatment efficacy.