Carpal Tunnel Syndrome Associated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic approach to diverse malignancies, leading to substantial enhancements in patient prognosis. However, along with their benefits, ICIs also increase the incidence of immune-related adverse events (irAEs). In the present paper, we highlight four cases of carpal tunnel syndrome (CTS) as an uncommon manifestation of toxicity induced by ICIs. Although diagnosed with different malignancies, the patients were undergoing ICI therapy when they developed CTS-consistent side effects accompanied by severe neuropathy. Prompt treatment with corticosteroids, intravenous immunoglobulins, or methotrexate resulted in complete symptomatic relief for all patients. This article therefore emphasizes the importance of recognizing and managing rare adverse events associated with ICI use to ensure optimal patient care.

Unexpected Adverse Events of Immune Checkpoint Inhibitors.

The introduction of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment standards and significantly enhanced patient prognoses. However, the utilization of these groundbreaking therapies has led to the observation and reporting of various types of adverse events, commonly known as immune-related adverse events (irAEs). In the following article, we present four patients who encountered uncommon toxicities induced by ICIs. The first patient was a 59-year-old female diagnosed with stage 4 lung adenocarcinoma. She received immunotherapy (pembrolizumab) together with chemotherapy and subsequently developed autonomic neuropathy (AN). The next two patients also received chemo-immunotherapy (pembrolizumab) and were both 63-year-old males with stage 4 lung adenocarcinoma. One of the two experienced palmoplantar keratoderma, while the other presented with Reiter's syndrome (urethritis, conjunctivitis and arthritis). The 4th patient, an 80-year-old male with stage 4 squamous cell carcinoma of the lung, received chemo-immunotherapy (pembrolizumab) and developed myasthenia gravis.

Osimertinib in advanced EGFR-mutant lung adenocarcinoma with asymptomatic brain metastases: an open-label, 3-arm, phase II pilot study.

BACKGROUND: Osimertinib is selective for both epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) sensitizing and Thr790Met mutations. While intracranial activity of osimertinib is documented in larger trials, a prospective study focusing exclusively on patients with asymptomatic brain metastases has not been reported. METHODS: In this nonrandomized, phase II, open-label, 3-arm prospective proof-of-concept pilot study, 48 patients with metastatic EGFR-mutant lung adenocarcinoma (LUAD) received osimertinib 80 mg daily. Patients were either treatment naive (arm A = 20) or previously treated with an EGFR-TKI and Thr790Met positive (arm B = 18) or negative (arm C = 10). In cases of isolated intracranial progression, osimertinib dose was escalated (160 mg). The primary endpoints were intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). The secondary endpoint was intracranial progression-free survival (iPFS). This study is registered at Clinicaltrials.gov, NCT02736513. RESULTS: The iORRs were 84.2%, 66.7%, and 50% and the iDCRs were 94.7%, 94.4%, and 80% in arms A, B, and C, respectively. The median iPFS was 11.8 months (95% CI 7.7 to NA), 7.6 months (95% CI 5.3 to NA), and 6.3 months (95% CI 3.9 to NA) in arms A, B, and C, respectively. Following dose escalation, pooled iORR was 54% (arm A = 5, arm B = 4, arm C = 2). Adverse events were similar to those in previously published literature. CONCLUSION: Osimertinib demonstrated high efficacy on brain metastases. All trial arms displayed a significant decrease in the number and diameter of target lesions. These findings indicate that osimertinib is effective for Thr790Met-positive and -negative LUAD patients with asymptomatic brain metastases. Therefore, osimertinib should be considered a viable option for EGFR-mutant patients with brain involvement regardless of their Thr790Met mutation status.

Bevacizumab for stereotactic radiosurgery-induced radiation necrosis in patients with non-small cell lung cancer treated with immune check-point inhibitors.

BACKGROUND: Bevacizumab was shown to be effective in the treatment of brain radiation necrosis (RN) attributed to the use of stereotactic radiosurgery (SRS). Data on its efficacy and safety in non-small cell lung cancer (NSCLC) patients treated with immune check-point inhibitors (ICI) is lacking. METHODS: A multi-center retrospective analysis of all consecutive patients with NSCLC treated with ICI, who received bevacizumab for post-SRS RN between April 2017 and June 2020. Improvement in RN-associated symptoms, RN radiological improvement, and decrease in corticosteroid dose following bevacizumab initiation were assessed. RESULTS: Thirteen patients were identified. The median time from diagnosis of RN to initiation of bevacizumab was 3 months (range 1.1-7.8 months), and the median number of bevacizumab cycles before assessment was 2 (range, 1-5). Patients continued ICI during treatment with bevacizumab. Improvement in RN-associated symptoms was observed in 11 patients (85%). In ten patients (77%) the daily dose of dexamethasone was decreased. Radiological improvement of RN occurred in all 11 cases available for radiological assessment (100%). Treatment was withheld in two patients for grade 3-4 toxicity. At a median follow up of 11.9 months (range 2.0-35.4 months), one patient experienced a recurrent episode of RN; the estimated median survival since RN diagnosis was 21.9 months (95% CI 3.8-40.2 months). CONCLUSION: Treatment with bevacizumab appears to be safe and effective for the treatment of SRS-induced RN in patients with NSCLC treated with ICI. This is the first series to report on the use of bevacizumab in this clinical scenario.

The impact of osimertinib' line on clonal evolution in EGFRm NSCLC through NGS-based liquid biopsy and overcoming strategies for resistance.

BACKGROUND: Resistance mechanisms following 1st line therapy with osimertinib in EGFR + NSCLC have become focus of investigation. This retrospective study aims to deepen the understanding and clarify possible mechanisms of osimertinib 1st line resistance in comparison to the 2nd line by examining NGS results of 30 patients who developed resistance to osimertinib. Furthermore, we followed clinical outcomes of select patients who received combined therapy following EGFR resistance, a novel strategy not yet widely tested. METHODS: Liquid biopsy technique (Guardant360) was used to monitor tumor dynamics in patients who were treated with osimertinib as 1st-line therapy (Group A, N = 15) and patients who received osimertinib as 2nd-line therapy (Group B, N = 15). RESULTS: At the time of progression under osimertinib all but one patient preserved the primary EGFR mutation. While the C797S mutation was relatively common in the 2nd-line osimertinib setting (5/15), it did not develop in group A patients. TP53 was the most common detected mutation among all patients accounting for 11/15 in group A (73.33 %) and 10/15 in group B (66.67 %). In group A MET amplification was found in 3/15 patients (20 %) whereas MET mutation appeared in only one patient from group B. The outcomes of different treatment approaches post osimertinib resistance is reported including chemotherapy with/without osimertinib for maintaining control of brain metastases, drug combination such as osimertinib with crizotinib, chemo-immunotherapy and others. Overall survival in this cohort ranged from 12 to80 months. CONCLUSIONS: Mechanisms of resistance to osimertinib as 1st-line therapy differ from those which develop in the 2nd-line setting and commonly include MET amplification. C797S is not a main resistance mechanism in the 1st-line setting, whereas it is more common in the 2nd-line setting. Combined therapy was effective and well tolerated, making it an acceptable choice in patients for whom there is a reasonable rationale for such treatment, however this approach deserves further investigation.

Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases.

BACKGROUND: Osimertinib is a selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with increased penetration across the blood-brain barrier compared with previous EGFR-TKIs, and thus, a 52% reduction in the risk of intracranial disease progression is seen when it is used as a first line of therapy compared with gefitinib and erlotinib. It is also efficient as second-line therapy for patients who developed the T790M resistance mutation following treatment with previous generation TKIs. Here, we report 11 patients who were treated by an increasing dose of osimertinib from 80 mg to 160 mg QD orally following intracranial progression in either first- or second-line setting. METHODS: This is a subcohort analysis from a larger nonrandomized, phase 2, open-label trial, evaluating the efficacy of osimertinib dose escalation from 80 mg to 160 mg in EGFR-mutated advanced non-small-cell lung cancer (NSCLC) patients with intracranial progression in either first- (arm A) or second-line setting (arm B for T790M+ and C for T790M-). RESULTS: Eleven patients, 5 in arm A, 4 in arm B, and 2 in arm C were reported in this study. The mPFS of osimertinib before dose escalation was 11.4 ± 8.9 (6.6-30.7) months for arm A, 8.7 ± 1.8 (6.3-11.2) for arm B, and 14.5 ± 7.8 (6.7-22.3) for arm C. Intracranial response rate to dose escalation was 54% (6 of 11) with 2 of 11 having intracranial stability. Median iPFS was 4.3 ± 7.4 (0.7-25.5) months; 3.8 ± 6.4 (1.8-18.9), 5.6 ± 9.7 (0.7-25.5), and 7.0 ± 2.7 (4.3-9.6) for arms A/B/C, respectively. Dose escalation was well tolerated with diarrhea and paronychia as the main dose-limiting symptoms. CONCLUSIONS: Osimertinib 160 mg is feasible and may offer a therapeutic alternative for patients with isolated intracranial progression on osimertinib standard (80 mg) dose. Further studies on CNS osimertinib pharmacokinetics are needed to test this hypothesis.

The autonomic phenotype of rumination.

Recent studies suggest that ruminative thoughts may be mediators of the prolonged physiological effects of stress. We hypothesized that autonomic dysregulation plays a role in the relation between rumination and health. Rumination was induced by an anger-recall task in 45 healthy subjects. Heart rate variability (HRV), baroreflex sensitivity (BRS), and baroreflex effectiveness index (BEI) change scores were evaluated to obtain the autonomic phenotype of rumination. Personality traits and endothelial activation were examined for their relation to autonomic responses during rumination. Degree of endothelial activation was assessed by circulating soluble intercellular adhesion molecule-1 (sICAM-1). Vagal withdrawal during rumination was greater for women than men. Larger decreases in the high frequency component of HRV were associated with higher levels of anger-in, depression, and sICAM-1 levels. BRS reactivity was negatively related to trait anxiety. BEI reactivity was positively related to anger-in, hostility, anxiety, and depression. Lower BEI and BRS recovery were associated with lower social desirability and higher anger-out, anxiety, and depression. Findings suggest that the autonomic dysregulation that characterizes rumination plays a role in the relationships between personality and cardiovascular health.

Metabolic predictors of inflammation, adhesion, and coagulability in healthy younger-aged adults.

Elevated levels of inflammatory biomarkers are associated with the pathophysiology of cardiovascular diseases and are predictors of cardiovascular events. The objective of this study was to determine the unique contributions of metabolic factors as predictors of inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)), adhesion (soluble intercellular adhesion molecule-1 (sICAM-1)), and coagulation (D-dimer) in healthy younger-aged adults. Participants were 83 women and 92 men (mean age 30.04 years, s.d. +/- 4.8, range 22-39) of normal weight to moderate obese weight (mean BMI 24.4 kg/m(2), s.d. +/- 3.35, range 17-32). The primary data analytical approaches included Pearson correlation and multiple linear regression. Circulating levels of CRP, IL-6, sICAM-1, and D-dimer were determined in plasma. Higher levels of CRP were independently associated with higher BMI, a greater waist-to-hip ratio, female gender, and higher triglycerides (P < 0.001). Higher IL-6 levels were independently associated with a greater waist-to-hip ratio (P < 0.01). Higher levels of sICAM-1 were independently associated with higher BMI, higher triglycerides, and lower insulin resistance (P < 0.001). Higher D-dimer levels were independently associated with higher BMI and being female (P < 0.001). Having a higher BMI was most consistently associated with elevated biomarkers of inflammation, adhesion, and coagulation in this sample of healthy younger-aged adults, although female gender, insulin resistance, and lipid levels were also related to the biomarkers. The findings provide insight into the adverse cardiovascular risk associated with elevated body weight in younger adults.

How family history and risk factors for hypertension relate to ambulatory blood pressure in healthy adults.

BACKGROUND: Although family history is a major predictor of hypertension, other risk factors have been linked to elevated blood pressure (BP). This study explored the relationship of norepinephrine (NE), insulin resistance and lipids to family history of hypertension, and attempted to determine the combined effects of family history and these factors on BP. METHODS: A total of 220 healthy men and women, aged 22-50 years, completed two 24 h ambulatory BP sessions. Based on family history information obtained from parents, three groups were formed: subjects with two hypertensive parents, one hypertensive parent or normotensive parents. Plasma samples were obtained to derive fasting catecholamine levels, insulin, glucose and lipids. RESULTS: Individuals with two hypertensive parents had high insulin, insulin resistance and low-density lipoprotein cholesterol. Although NE was not directly linked to family history, high NE levels were associated with increased BP, after controlling for family history and body mass index. Women with two hypertensive parents and elevated NE levels had higher systolic BP and diastolic BP during waking and sleep periods. In men the combination of two hypertensive parents and high NE was related only to diastolic BP during waking. CONCLUSIONS: NE results provide evidence of sympathetic activation in the identification of individuals at risk for hypertension. Studying family history of hypertension and other risk factors in healthy individuals provides a unique opportunity to explore factors leading to elevated BP long before a diagnosis of hypertension is made.

Vascular profile, delayed recovery, inflammatory process, and ambulatory blood pressure: laboratory-to-life generalizability.

Impaired recovery and plasma concentration of intercellular adhesion molecule-1 (sICAM-1) were both highlighted as plausible and more established markers of cardiovascular disease, respectively. Hemodynamic patterns during recovery and their link with circulating levels of sICAM-1 were examined as predictors of 24-h blood pressure (ABP). Impedance cardiography measures and beat-to-beat BP were recorded in 45 healthy subjects during a 10-min baseline, four tasks, and four 10-min recovery periods. sICAM-1 levels at rest were determined by ELISA. ABP measures were obtained combining data from a work and an off day. Hierarchical regressions showed that patterns of compensatory changes in cardiac output and total peripheral resistance during recovery improved the prediction of ABP above and beyond resting and recovery BP, or reactivity hemodynamic patterns. Stress-induced recovery was essentially vascular in nature and a more vascular profile was associated with higher ABP and higher circulating levels of sICAM-1. The results suggest a link between recovery hemodynamics and cardiovascular risk.

Moods in everyday situations: effects of combinations of different arousal-related factors.

OBJECTIVE: This study examined women's mood responsiveness associated with patterns of stress hormone levels in everyday situations. METHODS: Self-reports of negative, positive, and energy dimensions of mood were obtained from 203 nurses throughout the day on a workday and on an off-work day during the luteal and follicular phases of the menstrual cycle. Individual differences in daytime norepinephrine and cortisol were assessed. RESULTS: Patterns of norepinephrine and cortisol levels were associated with ratings of the following moods: tired, sad, and happy. Phase of the menstrual cycle and the day factor (workday, off-work day) modified the association of mood ratings and stress hormone patterns. CONCLUSION: The experience of negative mood is associated with both hypoarousal and hyperarousal conditions. A homeostatic arousal-related concept of mood regulation is discussed.

Baroreflex mechanisms in major depression.

BACKGROUND: Recent studies have shown that depressive disorder is associated with impaired baroreceptor or baroreflex sensitivity, which is proposed to be a predisposing factor for sudden death in patients with manifest cardiac disease. These studies have not evaluated the afferent and efferent components of the cardiac baroreflex loop or other baroreflex mechanisms that regulate target processes (cardiac metabolism and blood pressure variability) related to the impairment. The objective of this study was to gain more insight into autonomic functioning in depressive disorder to more fully examine the potential basis for increased cardiac mortality. METHODS: The subjects were 28 women and men with unipolar major depression who were taking antidepressant medications and who were in partial remission and free of cardiovascular or other serious disease, and 28 healthy control subjects matched for sex, age, and ethnicity. The two samples were compared for negative affective dispositions (anger expression, hostility, defensiveness, anxiety), spontaneous (closed-loop) baroreflex activity, heart rate, heart rate variability, systolic blood pressure, and heart rate-systolic blood pressure double product under resting conditions. RESULTS: Depressed patients showed a general disposition to anger suppression coupled with higher hostility and anxiety, and lower defensiveness. The patients showed higher general sympathetic activity (high levels of blood pressure, low-frequency heart rate variability) and lower parasympathetic-related activity (high heart rate and reduced high frequency heart rate variability) with affected cardiac metabolism estimated by the double product. Depressed patients had lower baroreflex sensitivity related to a higher gain of the afferent component of the baroreflex without respective gain adjustment of its efferent component (reflex gain 'de-afferentation'). It was coupled with a compensatory higher number of effective baroreflex reactions (reflex gating 're-afferentation'). Antidepressant agents and depressed mood had additional independent effects on baroreflex sensitivity through the efferent component of the cardiac baroreflex loop. CONCLUSIONS: The data indicate that different baroreflex components and mechanisms may be impaired in patients with depression and may contribute to their increased cardiac risk.

Ambulatory blood pressure and family history of hypertension in healthy men and women.

BACKGROUND: Family history of hypertension is a primary predictor of high blood pressure (BP). This study attempted to determine whether there is a gradual increase in BP between individuals with two hypertensive parents, one hypertensive parent, and normotensive parents and whether this increase is apparent with both ambulatory and casual BP assessments in men as well as in women. METHODS: A total of 220 healthy men and women, aged 22 to 50 years, completed two 24-h ambulatory BP sessions (one work day and one off work day). Based on family history information obtained from parents, three groups were formed: subjects with two hypertensive parents, one hypertensive parent, and normotensive parents. Work and off work days did not differ; analyses were based on mean values of the 2 days. RESULTS: Men with two hypertensive parents had higher daytime and night-time ambulatory BP than men with normotensive parents. Those with one hypertensive parent had intermediate BP levels. Ambulatory BP was not associated with family history in women. Also, men with one or two hypertensive parents had higher ambulatory BP than women with hypertensive parents, whereas offspring of normotensive parents exhibited no sex differences in BP. CONCLUSIONS: Elevated systolic and diastolic BP throughout the day and night seems to characterize men with two hypertensive parents. In evaluating the relationship between family history of hypertension and BP, it is important to use ambulatory BP measures, differentiate between individuals with one and with two hypertensive parents, and focus on gender differences in BP.

Hemodynamic profile, compensation deficit, and ambulatory blood pressure.

This study hypothesized that physiologically grounded patterns of hemodynamic profile and compensation deficit would be superior to traditional blood pressure reactivity in the prediction of daily-life blood pressure. Impedance cardiography-derived measures and beat-to-beat blood pressure were monitored continuously in 45 subjects during baseline and four tasks. Ambulatory blood pressure measures were obtained combining data from one work day and one off day. The mediating effects of gender and family history of hypertension were considered. Only gender was significantly associated with hemodynamic profile. Regression analysis indicated that typical reactivity measures failed to predict everyday life blood pressure. After controlling for gender and baseline blood pressure, hemodynamic patterns during specific tasks proved to be strong predictors, overcoming limitations of previous reactivity models in predicting real-life blood pressure.

Moods in everyday situations: effects of menstrual cycle, work, and stress hormones.

OBJECTIVE: This study examined women's mood responsiveness on work and off days during different phases of the menstrual cycle. METHODS: Self-reports of negative, positive, and energy dimensions of mood were obtained throughout the day on two work and two off days during the luteal and follicular phases of the menstrual cycle in 203 women nurses. Individual differences in daytime and nighttime epinephrine, norepinephrine, and cortisol were assessed. RESULTS: High daytime norepinephrine, epinephrine, and cortisol levels were associated with higher ratings of stress and tired, and with lower ratings of happy. The phase of the menstrual cycle and the day factor (workday, off day) were also associated with mood differences, and the direction of the effects depended on hormone levels and hormone sampling period. CONCLUSION: The experience of moods is affected by the arousal-related interaction of hormone levels with the phase of the menstrual cycle and occupational stress.

Ambulatory blood pressure and the brain: a 5-year follow-up.

OBJECTIVE: To determine if initial values of casual and ambulatory systolic blood pressure (SBP) predict white matter hyperintensities, insular subcortex hyperintensities, and brain atrophy 5 years later in a group of healthy elderly individuals. METHODS: The authors studied 155 healthy men and women, aged 55 to 79 years. Two 24-hour ambulatory blood pressure (BP) sessions assessed BP level and variability during waking and sleep. Hyperintensities and total brain volume were quantified by MRI. Procedures were repeated 5 years later in 78% (121) of subjects. RESULTS: Hyperintensities and brain atrophy increased over time, with greater increases among older subjects. The presence of increased BP level and variability initially and again 5 years later had negative consequences for the brain. Independent of age, the greater the initial SBP, the greater the likelihood that individuals would have severe white matter hyperintensities after 5 years. Also, elevated casual SBP was associated with severe insular subcortex hyperintensities and greater SBP sleep variability with increased brain atrophy. CONCLUSIONS: Among healthy elderly individuals whose initial, average, casual blood pressure (BP) was relatively low (116.9/71.1 mm Hg), small increases in casual and 24-hour ambulatory BP measures were associated with greater brain atrophy and subcortical lesions after 5 years.

Relationship between daytime sleepiness and blood pressure in healthy older adults.

BACKGROUND: Some sleep disorders have been linked to hypertension, but few studies have examined the relationship between daytime sleepiness and blood pressure (BP). This study attempted to determine whether scores on a short questionnaire assessing daytime sleepiness (Epworth Sleepiness Scale [ESS]) were associated with BP and could be used to predict hypertension after 5 years in healthy older adults who had not previously been diagnosed with hypertension. METHODS: A group of 157 healthy men and women 55 to 80 years of age completed an extensive medical examination, a series of psychosocial tests, and two 24-h ambulatory BP sessions. After 5 years the procedures were repeated in 133 (85%) of the subjects. Psychosocial variables and BP were compared in subjects scoring high (score of > or = 10) and low (< 10) on the ESS. RESULTS: Compared to individuals with low ESS sores, those scoring high had increased casual and sleep BP as well as higher systolic BP levels and diastolic BP variability during waking hours, and reported higher levels of anger, depression, anxiety, and intensity of psychological symptoms as well as lower defensiveness. Individuals with high ESS scores were more likely to be diagnosed with hypertension 5 years later. Groups with high and low ESS scores did not differ significantly on any other variables. CONCLUSIONS: The ESS, a simple measure of daytime sleepiness, identified individuals at risk for hypertension. Future studies should investigate the possibility that diagnosis and treatment of daytime sleepiness could aid in BP reduction and ultimately in decreased morbidity and mortality from cardiovascular disorders.

Moods in everyday situations: effects of menstrual cycle, work, and personality.

OBJECTIVE: This study examined women's moods on work and off days during different phases of the menstrual cycle. METHOD: Self-reports of the moods angry, happy, sad, stressed, tired, and anxious were obtained on two work and two off days during the luteal and follicular phases of the menstrual cycle in 203 nurses. Individual differences in anger expression, anxiety, and hostility were assessed. RESULTS: Ratings of anxious, stressed, and tired were higher and happy and sad were lower on the workday than the off day. Menstrual cycle phase was associated with mood differences depending on the day (work, off work) and individual differences in personality traits. CONCLUSIONS: The experience of moods in everyday life is affected by overall levels of stress and phase of the menstrual cycle. The findings suggest the need to refine sociopsychobiological and clinical models of mood regulation and of risk for disease.

A 5-year follow-up of ambulatory blood pressure in healthy older adults.

BACKGROUND: This study assessed 5-year changes in ambulatory blood pressure (ABP) in healthy, older individuals and determined the extent to which it could be predicted from earlier BP measures and other cardiovascular risk factors. METHODS: A total of 162 men and women, aged 55 to 79 years, with no prior medical disorders, completed a medical examination and two 24-h ABP sessions. The procedures were repeated 5 years later in 80% (130) of these subjects. A modified hierarchical regression analysis was used to determine whether initial ABP and casual blood pressure (CBP) measures and demographic and physical examination data could predict ABP in 5 years. RESULTS: The CBP and most ABP levels during waking and sleep increased after 5 years. However, CBP remained in the normotensive range for 73% of the subjects. The ABP variability tended to decrease over time. The ABP and CBP measures accounted for at least 50% of the variance in the prediction of ABP level after 5 years. In comparison, the predictability of ABP variability was quite low, particularly during sleep (<30% of the variance accounted for). CONCLUSIONS: The ABP and CBP were good predictors of future ABP level in healthy older subjects, but ABP variability was more difficult to predict. Except for age, none of the standard cardiovascular risk factors contributed significantly to the prediction of ABP level or variability.