Impact of sex and reproductive status on the default mode network in early midlife: implications for aging of memory circuitry and function.

Alterations to the resting-state default mode network (rsDMN) are early indicators of memory decline and Alzheimer's disease (AD). Brain regions shared by the rsDMN and memory circuitry are highly sexually dimorphic. However, data are limited regarding the impact of sex and reproductive status on rsDMN connectivity and memory circuitry and function. In the current investigation, rsDMN connectivity was assessed in 180 early midlife adults aged 45 to 55 by sex and reproductive status (87 women; 93 men). Associations between left and right hippocampal connectivity of rsDMN and verbal memory encoding circuitry were examined using linear mixed models, controlled for age and parental socioeconomic status, testing interactions by sex and reproductive status. Relative to men, women exhibited greater rsDMN connectivity between the left and right hippocampus. In relation to rsDMN-memory encoding connectivity, sex differences were revealed across the menopausal transition, such that only postmenopausal women exhibited loss of the ability to decrease rsDMN left-right hippocampal connectivity during memory encoding associated with poorer memory performance. Results demonstrate that sex and reproductive status play an important role in aging of the rsDMN and interactions with memory circuitry/function. This suggests the critical importance of sex and reproductive status when studying early midlife indicators of memory decline and AD risk.

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later.

Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

BACKGROUND: Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines. METHODS: Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones. RESULTS: Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer. CONCLUSIONS: HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

Moderate Colitis Not Requiring Intravenous Steroids Is Associated with Improved Survival in Stage IV Melanoma after Anti-CTLA4 Monotherapy, But Not Combination Therapy.

BACKGROUND: For patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making. MATERIALS AND METHODS: Patients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS). RESULTS: In total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS. CONCLUSION: This single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.

Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study.

BACKGROUND: Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African. OBJECTIVES: To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups. METHODS: Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal. RESULTS: In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50-57% vs. 20%, 95% CI 13-28%; adjusted P < 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7-20·3 vs. 5·4 months, 95% CI 4·5-7·0; adjusted P < 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48-6·81; adjusted P < 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46-0·74; adjusted P < 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes. CONCLUSIONS: Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.

Compliance with sentinel lymph node biopsy guidelines for invasive melanomas treated with Mohs micrographic surgery.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has not been studied for invasive melanomas treated with Mohs micrographic surgery using frozen-section MART-1 immunohistochemical stains (MMS-IHC). The primary objective of this study was to assess the accuracy and compliance with National Comprehensive Cancer Network (NCCN) guidelines for SLNB in a cohort of patients who had invasive melanoma treated with MMS-IHC. METHODS: This retrospective cohort study included all patients who had primary, invasive, cutaneous melanomas treated with MMS-IHC at a single academic center between March 2006 and April 2018. The primary outcomes were the rates of documenting discussion and performing SLNB in patients who were eligible based on NCCN guidelines. Secondary outcomes were the rate of identifying the sentinel lymph node and the percentage of positive lymph nodes. RESULTS: In total, 667 primary, invasive, cutaneous melanomas (American Joint Committee on Cancer T1a-T4b) were treated with MMS-IHC. The median patient age was 69 years (range, 25-101 years). Ninety-two percent of tumors were located on specialty sites (head and/or neck, hands and/or feet, pretibial leg). Discussion of SLNB was documented for 162 of 176 (92%) SLNB-eligible patients, including 127 of 127 (100%) who had melanomas with a Breslow depth >1 mm. SLNB was performed in 109 of 176 (62%) SLNB-eligible patients, including 102 of 158 melanomas (65%) that met NCCN criteria to discuss and offer SLNB and 7 of 18 melanomas (39%) that met criteria to discuss and consider SLNB. The sentinel lymph node was successfully identified in 98 of 109 patients (90%) and was positive in 6 of those 98 patients (6%). CONCLUSIONS: Combining SLNB and MMS-IHC allows full pathologic staging and confirmation of clear microscopic margins before reconstruction of specialty site invasive melanomas. SLNB can be performed accurately and in compliance with consensus guidelines in patients with melanoma using MMS-IHC.

Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis.

BACKGROUND: Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown. METHODS: Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined. RESULTS: Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028). CONCLUSIONS: Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.

Clinical Outcomes of Patients with Metastatic Cancer Receiving Immune Checkpoint Inhibitors in the Inpatient Setting.

BACKGROUND: As indications for immune checkpoint inhibitor (ICI) therapy have increased in recent years, so has the proportion of patients eligible for this type of therapy. However, a lack of data exists about the risks and benefits of ICI therapy in hospitalized patients, who tend to be frailer and sicker than patients enrolled in clinical trials. MATERIAL AND METHODS: We conducted a retrospective cohort study among hospitalized patients with metastatic solid tumors who received ICI therapy at a large academic cancer center over the course of 4 years. We analyzed the characteristics and outcomes of these patients and identified demographic and clinical factors that could be used to predict mortality. RESULTS: During the 4-year study period, 106 patients were treated with ICI therapy while admitted to the hospital; 70 (66%) had Eastern Cooperative Oncology Group Performance Status ≥2, which would have prevented them from enrolling in most clinical trials of ICIs. Fifty-two patients (49%) died either during admission or within 30 days of discharge; median overall survival was 1.0 month from discharge, and 16 patients (15%) were alive 6 months after discharge. Independent predictors of death following receipt of inpatient ICI included a diagnosis of non-small cell lung cancer relative to melanoma and prior treatment with two or more lines of therapy. CONCLUSION: The poor overall outcomes observed in this study may give clinicians pause when considering ICI therapy for hospitalized patients, particularly those with characteristics that are associated with a greater risk of mortality. IMPLICATIONS FOR PRACTICE: Immunotherapy strategies for patients with cancer are rapidly evolving and their use is expanding, but not all patients will develop a response, and secondary toxicity can be significant and challenging. This is especially evident in hospitalized patients, where the economic cost derived from inpatient immune checkpoint inhibitor (ICI) administration is important and the clinical benefit is sometimes unclear. The poor overall outcomes evidenced in the ICI inpatient population in this study highlight the need to better identify the patients that will respond to these therapies, which will also help to decrease the financial burden imposed by these highly priced therapies.

Temporal Trends and Outcomes Among Patients Admitted for Immune-Related Adverse Events: A Single-Center Retrospective Cohort Study from 2011 to 2018.

BACKGROUND: The aim of this study was to characterize severe immune-related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death. METHODS: Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected. RESULTS: In total, 450 admissions were classified as irAE admissions and represent the study's cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA-4 monotherapy recipients (odds ratio [OR], 2.02; p < .001) and CTLA-4 plus PD-1 combination therapy recipients (OR, 1.88; p < .001), relative to PD-1/PD-L1 monotherapy recipients, and patients with multiple toxicity had a 5-fold increase in inpatient mortality. CONCLUSION: This study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA-4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi-organ involvement is common and those patients are at highest risk of inpatient mortality. IMPLICATIONS FOR PRACTICE: The number of patients admitted to Massachusetts General Hospital for immune-related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.

Liver biopsy findings in patients on immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) can induce a durable response against a wide range of malignancies but cause immune related adverse events. The purpose of this study was to evaluate whether the pattern of inflammation in a liver biopsy in patients on ICIs is likely to be related to ICIs or other causes, and whether the pattern correlates with LFT abnormalities, imaging findings, and responsiveness to steroids. Cancer patients on ICIs who underwent liver biopsy were identified. Clinical data were obtained from electronic records. Liver biopsies were recorded as hepatitic, cholangitic, mixed, steatotic, or as mild nonspecific changes. In total, 28 liver biopsies had a predominantly hepatitic pattern of inflammation, including 11 biopsies with granulomas and 10 with endothelialitis. Eight biopsies had a mixed hepatocytic and cholangitic pattern of injury, including 6 with granulomas and 4 with endothelialitis. Sixteen patients had a predominantly cholangitic pattern, with portal-based inflammation. Three patients had a pattern resembling fatty liver, and five had mild nonspecific changes. The three most common histologic patterns correlated with the pattern of LFT abnormalities. The majority of patients with a cholangitic pattern had competing causes for elevated LFTs, including disease progression or concomitant chemotherapy. The cholangitic pattern was more likely to have bile duct dilatation or narrowing on liver imaging. The pattern of inflammation, degree of lobular injury, or presence of granulomas or endothelialitis did not predict response to steroids or the need for secondary immunosuppression. In this retrospective study, the pattern of inflammation did not predict the need for steroids, the length of time that steroids is required, or the need for secondary immunosuppression. A cholangitic pattern was seen when the pattern of LFTs was cholestatic, and was associated with imaging abnormalities of the bile duct, but a similar pattern was seen in bile duct obstruction and other drug reactions.

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum.

Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined. ANN NEUROL 2020;87:659-669.

Systematic review and meta-analysis of local recurrence rates of head and neck cutaneous melanomas after wide local excision, Mohs micrographic surgery, or staged excision.

BACKGROUND: Prospective trials have not compared the local recurrence rates of different excision techniques for cutaneous melanomas on the head and neck. OBJECTIVE: To determine local recurrence rates of cutaneous head and neck melanoma after wide local excision (WLE), Mohs micrographic surgery (MMS), or staged excision. METHODS: A systematic review of PubMed, EMBASE, and Web of Science identified all English case series, cohort studies, and randomized controlled trials that reported local recurrence rates after surgery for cutaneous head and neck melanoma. A meta-analysis utilizing a random effects model calculated weighted local recurrence rates and confidence intervals (CI) for each surgical technique and for subgroups of MMS and staged excision. RESULTS: Among 100 manuscripts with 13,998 head and neck cutaneous melanomas, 51.0% (7138) of melanomas were treated by WLE, 34.5% (4826) by MMS, and 14.5% (2034) by staged excision. Local recurrence rates were lowest for MMS (0.61%; 95% CI, 0.1%-1.4%), followed by staged excision (1.8%; 95% CI, 1.0%-2.9%) and WLE (7.8%; 95% CI, 6.4%-9.3%). LIMITATIONS: Definitions of local recurrence varied. Surgical techniques included varying proportions of invasive melanomas. Studies had heterogeneity. CONCLUSION: Systematic review and meta-analysis show lower local recurrence rates for cutaneous head and neck melanoma after treatment with MMS or staged excision compared to WLE.

Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.

AIMS: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented. METHODS AND RESULTS: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE. CONCLUSION: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.

Neurologic complications of melanoma.

Neurologic complications are common in patients with melanoma and are often associated with a poor prognosis. In an era with new, effective treatments, patients are living longer, and this has resulted in an increase in complications of both the disease and the therapy. A multidisciplinary approach to neurologic complications in patients with melanoma, with involvement from medical oncology, neuro-oncology, radiation oncology, and often neurosurgery, is necessary. In this review, neurologic complications of melanoma, including clinical implications and treatment strategies, are described.

The Evolution of Adjuvant Therapy for Melanoma.

PURPOSE OF REVIEW: The past decade has been a time of remarkable advancement in the field of adjuvant therapy for patients with resected high-risk melanoma. Here, we review the data for adjuvant melanoma and raise questions about the best choice of therapy for an individual patient. RECENT FINDINGS: There have been several new adjuvant approvals including immunotherapy and targeted therapy approaches. Nivolumab is approved for patients with nodal involvement or metastatic disease after resection. Pembrolizumab is approved for patients with nodal involvement after resection. In addition, the combination of dabrafenib and trametinib is approved in patients' nodal involvement after resection whose tumors harbor BRAFV600E/K mutations. New therapeutic opportunities have provided promising options for patients with high-risk disease. These advances have significantly challenged the previous standard-of-care for this population of patients. Data is still forthcoming regarding durability of benefit and safety of these new treatments.

Predictability matters: role of the hippocampus and prefrontal cortex in disambiguation of overlapping sequences.

Previous research has demonstrated that areas in the medial temporal lobe and prefrontal cortex (PFC) show increased activation during retrieval of overlapping sequences. In this study, we designed a task in which degree of overlap varied between conditions in order to parse out the contributions of hippocampal and prefrontal subregions as overlap between associations increased. In the task, participants learned sequential associations consisting of a picture frame, a face within the picture frame, and an outdoor scene. The control condition consisted of a single frame-face-scene sequence. In the low overlap condition, each frame was paired with two faces and two scenes. In the high overlap condition, each frame was paired with four faces and four scenes. In all conditions the correct scene was chosen among four possible scenes and was dependent on the frame and face that preceded the choice point. One day after training, participants were tested on the retrieval of learned sequences during fMRI scanning. Results showed that the middle and posterior hippocampus (HC) was active at times when participants acquired information that increased predictability of the correct response in the overlapping sequences. Activation of dorsolateral PFC occurred at time points when the participant was able to ascertain which set of sequences the correct response belonged to. The ventrolateral PFC was active when inhibition was required, either of irrelevant stimuli or incorrect responses. These results indicate that areas of lateral PFC work in concert with the HC to disambiguate between overlapping sequences and that sequence predictability is key to when specific brain regions become active.

High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma.

BACKGROUND: It remains unclear whether high doses of glucocorticoids have a negative impact on the efficacy of checkpoint inhibitors. To control for the potential association between immune-related adverse events (irAEs) and improved survival, this study examined a unique cohort of patients who had the same irAE treated with varying glucocorticoid doses. METHODS: In total, 98 patients with melanoma who had ipilimumab-induced hypophysitis were identified retrospectively in the Partners Healthcare system using an automated electronic medical record query tool. Patients with melanoma who received ipilimumab at Massachusetts General Hospital without developing hypophysitis were listed in an actively maintained institutional patient database. Glucocorticoid doses for patients with hypophysitis were categorized as low dose (LD) or high dose (HD). Survival analyses were performed for patients who received ipilimumab monotherapy. RESULTS: Both overall survival (OS) and the time to treatment failure were significantly longer in the LD group compared with the HD group (hazard ratio, 0.24; P = .002 and 0.28, P = .001, respectively). Median OS and the time to treatment failure were not reached in the LD group and were 23.3 and 14.5 months, respectively, in the HD group. All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months; P = .0003). This advantage was maintained in the HD group versus the nonhypophysitis group (P = .02). Radiologic and endocrinologic outcomes and symptom resolution did not differ in the LD group versus the HD group. CONCLUSIONS: Among patients with melanoma who had ipilimumab-induced hypophysitis, those who received higher doses of glucocorticoids had reduced survival. This is the first study to demonstrate a potential negative effect of high glucocorticoid doses on the efficacy of checkpoint inhibitors after an irAE. These findings have potential implications for the management of other irAEs.