Routine Screening for Central and Primary Adrenal Insufficiency during Immune-Checkpoint Inhibitor Therapy: An Endocrinology Perspective for Oncologists.

BACKGROUND: Immune checkpoint inhibitor (ICI)-associated hypothalamic-pituitary-adrenal axis disruption can lead to hypocortisolism. This is a life-threatening but difficult to diagnose condition, due to its non-specific symptoms that overlap with symptoms of malignancy. Currently, there is no consensus on how to best screen asymptomatic patients on ICI therapy for hypophysitis with serum cortisol. METHODS: A retrospective chart review of patients treated with ICI in a tertiary care centre was conducted to assess the rate of screening with cortisol and whether this had an impact on diagnosis of ICI-hypophysitis in the preclinical stage. Patients were identified as having hypophysitis with an adrenocorticotropin hormone (ACTH) deficiency based on chart review of patients with cortisol values ≤ 140 nmol/L (≤5 mcg/dL). We also assessed what proportion of cortisol values were drawn at the correct time for interpretation (between 6 AM and 10 AM). RESULTS: Two hundred and sixty-five patients had 1301 cortisol levels drawn, only 40% of which were drawn correctly (between 6 and 10 AM). Twenty-two cases of hypophysitis manifesting with ACTH deficiency were identified. Eight of these patients were being screened with cortisol following treatment and were detected in the outpatient setting. The remaining 14 patients were not screened and were diagnosed when symptomatic, after an emergency room visit or hospital admission. Sixty percent of the cortisol tests were uninterpretable as they were not drawn within the appropriate time window. CONCLUSION: Measuring morning serum cortisol in asymptomatic patients on ICI therapy is a fast and inexpensive way to screen for hypophysitis and should become the standard of care. Random serum cortisol measurement has no clinical value. Education needs to be provided on when to correctly perform the test and how to interpret it and we provide an algorithm for this purpose. The adoption and validation of such an algorithm as part of routine practice could significantly reduce morbidity and mortality in patients, especially as ICI therapy is becoming increasingly commonplace.

A Contemporary Report of Clinical Outcomes in Patients with Melanoma Brain Metastases.

Background: Brain metastases are observed in more than 40% of all patients with stage 4 melanoma. In recent years, more extensive use of stereotactic radiation (STRT) and the advent of immune checkpoint inhibitors have positively impacted outcomes in patients with metastatic melanoma.brain metastases. Here, we examined real world clinical outcomes of patients presenting with melanoma brain metastases (MBMs). Methods: This retrospective review evaluated MBMs patients treated at The Ottawa Hospital from April 2000 to July 2017. Clinical, radiologic, pathologic and treatment information were gathered from the electronic medical records. The primary outcome was overall survival. The proportional Cox regression model was employed for survival data, while the Fisher's exact and Mann-Whitney U tests analyzed the relationship between categorical and continuous data, respectively. Results: This retrospective study included 276 patients. Brain metastases were detected symptomatically in 191 patients (69.2%); the rates of detection by routine screening were 4.6% in the pre-2012 era and 11.7% in the contemporary era (p = 0.029). Median survival was three months. Predictors of overall survival were age, higher lactate dehydrogenase (LDH) values, multiple brain lesions, more extensive extracranial disease, neurological symptoms, infratentorial lesions and treatment type. Multivariable analysis demonstrated that stereotactic radiotherapy (STRT) was associated with a hazard ratio of 0.401 (p < 0.001) for survival; likewise, immune checkpoint inhibitor therapy was associated with a hazard ratio of 0.375 (p < 0.001). Conclusion: The findings from this study as "real world" data are consistent with results of pivotal clinical trials in MBMs patients and support contemporary locoregional and immunotherapy practices.

Imaging Intensity and Survival Outcomes in High-Risk Resected Melanoma Treated by Systemic Therapy at Recurrence.

BACKGROUND: Intensive imaging in melanoma remains controversial because its survival impact is unknown. We investigated the impact of imaging intensity on the rates of asymptomatic surveillance-detected recurrence (ASDR) and subsequent treatment outcomes in patients with access to immune checkpoint inhibitors (ICIs) and targeted therapy (TT). METHODS: Patients with resected malignant melanoma undergoing imaging surveillance at a single center between 2006 and 2016 were identified. Surveillance and recurrence characteristics (imaging, symptom, treatment, and survival data) were retrospectively collected. Univariate (t test, Chi square test) and multivariate Cox regression analyses were conducted. RESULTS: Of 353 high-risk melanoma patients (stage IIB, 24%; IIC, 19%; IIIA, 27%; IIIB, 16%; IIIC, 14%), 71 (45%) had ASDR and 88 (55%) had symptomatic recurrence (SR). Shorter imaging intervals identified more ASDR (57%, 0-6 months; 34%, 6-12 months; 33%, > 12 months; p = 0.03). ASDR had better prognostic factors than SR [fewer than three metastatic sites (43 vs. 21%, p = 0.003), normal lactate dehydrogenase (LDH; 53 vs. 38%, p = 0.09), brain metastases (11 vs. 40%, p < 0.001)] and received more systemic treatment (72 vs. 49%, p = 0.003; ICIs 55 vs. 31%, p = 0.002; TT 8 vs. 13%, p = 0.41). ASDR had better survival outcomes on ICI treatment (2-year OS, 56 vs. 31%, p < 0.001). Median OS from surveillance start was 39.6 vs. 22.8 months (p < 0.001). ASDR was independently associated with survival (hazard ratio 0.47, 95% confidence interval 0.29-0.78, p = 0.003), adjusting for stage, sex, age, disease burden, LDH, era of recurrence, brain metastases, and ICI/TT treatment. CONCLUSIONS: These real-world data support further study on intensified imaging surveillance protocols for high-risk resected melanoma, as ASDR was associated with superior survival outcomes from ICI therapy.

Correction to: Imaging Intensity and Survival Outcomes in High-Risk Resected Melanoma Treated by Systemic Therapy at Recurrence.

In the original article, the survival curves are missing in Fig. 1c, d.

Early and Late Complications of Percutaneous Core Needle Biopsy of Retroperitoneal Tumors at Two Tertiary Sarcoma Centers.

BACKGROUND: Concern persists regarding percutaneous core needle biopsy (CNB) of a potentially malignant lesion of the retroperitoneum due to the perceived risk of immediate complications and adverse oncologic outcomes, including needle tract seeding (NTS). OBJECTIVE: The aim of this study was to evaluate the incidence of (1) early complications and (2) NTS following CNB of suspected retroperitoneal sarcoma (RPS). METHODS: Patients who underwent CNB of an RP mass with pre-biopsy suspicion of sarcoma were identified from a prospective database at two centers: (1) Princess Margaret Cancer Centre/Mount Sinai Hospital, Toronto (2009-2015); and (2) The Ottawa Hospital (1999-2015). Early complications, including bleeding, pain, infection, and organ injury, were recorded. Instances of NTS were identified from long-term follow-up of patients who underwent resection of primary RPS at these two centers after initial CNB (1996-2013). RESULTS: Of 358 percutaneous CNBs of suspected RPS performed over the study period, 7 (2.0%) resulted in minor bleeding with no transfusion, 3 (0.8%) resulted in significant pain, 1 (0.3%) resulted in unplanned admission to hospital for observation, and 1 (0.3%) resulted in a pneumothorax. There were no infections. In 203 patients who underwent resection of RPS following CNB, crude cumulative local recurrence was 24% at 5 years. At a median follow-up of 44 months, there was one case of NTS (approximately 0.5%). CONCLUSION: This large bi-institutional experience with CNB of an RP mass demonstrates that both the early complication rate and the incidence of NTS are very low. Physicians and patients can be reassured that the benefits of CNB in diagnosing sarcoma and determining its histologic subtype and grade far outweigh the risks.

Chronic Hepatitis C Virus Infection Impairs M1 Macrophage Differentiation and Contributes to CD8+ T-Cell Dysfunction.

Chronic hepatitis C virus (HCV) infection causes generalized CD8+ T cell impairment, not limited to HCV-specific CD8+ T-cells. Liver-infiltrating monocyte-derived macrophages (MDMs) contribute to the local micro-environment and can interact with and influence cells routinely trafficking through the liver, including CD8+ T-cells. MDMs can be polarized into M1 (classically activated) and M2a, M2b, and M2c (alternatively activated) phenotypes that perform pro- and anti-inflammatory functions, respectively. The impact of chronic HCV infection on MDM subset functions is not known. Our results show that M1 cells generated from chronic HCV patients acquire M2 characteristics, such as increased CD86 expression and IL-10 secretion, compared to uninfected controls. In contrast, M2 subsets from HCV-infected individuals acquired M1-like features by secreting more IL-12 and IFN-γ. The severity of liver disease was also associated with altered macrophage subset differentiation. In co-cultures with autologous CD8+ T-cells from controls, M1 macrophages alone significantly increased CD8+ T cell IFN-γ expression in a cytokine-independent and cell-contact-dependent manner. However, M1 macrophages from HCV-infected individuals significantly decreased IFN-γ expression in CD8+ T-cells. Therefore, altered M1 macrophage differentiation in chronic HCV infection may contribute to observed CD8+ T-cell dysfunction. Understanding the immunological perturbations in chronic HCV infection will lead to the identification of therapeutic targets to restore immune function in HCV+ individuals, and aid in the mitigation of associated negative clinical outcomes.

Going Beyond the Numerical Scoresheet: Identifying Maladaptive Narcissistic Traits in Residency Applicants.

OBJECTIVE: Certain personality traits assessed during interviews have been shown to negatively predict performance in residency. An informal needs assessment at our institution suggested that it would be particularly important to identify traits associated with maladaptive narcissism (i.e., entitlement, difficulty accepting criticism, and arrogance). The objective of this study was to evaluate an interview station designed to identify narcissistic personality traits among applicants to our general surgery residency program. DESIGN: An interview station was developed in which applicants were provided negative feedback as a simulated evaluation. Two interviewers (1 staff surgeon, 1 senior resident) interviewed 48 applicants at this station. The 48 participants were also asked to complete the Narcissism Personality Index (NPI-40), which assesses adaptive and maladaptive facets of narcissism. NPI-40 scores were compared to the interview station scoresheet, which included numerical rating scales and a subjective "red flag" system used to identify concerns related to professionalism or personality. RESULTS: Linear regression demonstrated a significant correlation between red flags on the negative feedback station and a high maladaptive proportion of narcissism on the NPI-40 (p = 0.02). The numerical interview score and the proportion of maladaptive narcissism score did not reach significance (p = 0.05). There was a high inter-rater reliability between interviewers' numerical scores (r = 0.89) and in determining red flags (σ = 0.83). CONCLUSIONS: We designed an interview station that successfully identified general surgery residency interviewees displaying high proportions of maladaptive narcissistic traits. Despite an objective scoring process, subjective opinion of interviewers was more valuable in identifying these applicants. Our findings suggest that the written comments of surgeons in interview stations designed to identify applicants with difficulty accepting negative feedback may provide valuable information that is not captured by the numerical scoring process.

Radioactive Seed Localization Versus Wire-Guided Localization for Nonpalpable Breast Cancer: A Cost and Operating Room Efficiency Analysis.

BACKGROUND: This study aimed to compare the cost and resource use between our first-year experience using breast-conserving surgery (BCS) with radioactive seed localization (RSL) and the previous-year standard practice of BCS with wire-guided localization (WGL) for patients with nonpalpable breast cancer at a large Canadian tertiary center. METHODS: For this retrospective cohort study, data for BCS cases with RSL was collected from 1 April 2015 to 31 March 2016 and for BCS cases with WGL from 1 April 2014 to 31 March 2015. RESULTS: The study compared 153 WGL patients with 194 RSL patients. The two groups had no significant demographic differences. The average cost per patient for RSL, including opportunity costs, was $250.90 versus $1130.41 for WGL. Dedicated allocated radiology appointments to RSL increased (9 per day), and fewer radiologists were required for these procedures per day. Patients were transported to the operating room more quickly for RSL procedures (120 vs. 254 min; p < 0.001). Fewer vasovagal reactions occurred after insertion of RSL versus WGL (p = 0.05). No significant differences were observed in terms of surgical time, specimen volume, positive margins, or margin reexcision rates. No significant differences in postoperative complication rates were observed. CONCLUSIONS: In this study, RSL had lower costs than WGL, allowed for more efficient use of radiology scheduling and resources, and had shorter wait times for patients on their day of surgery. In addition, RSL led to fewer vasovagal reactions at insertion. Therefore, RSL should be used instead of WGL given the reduced cost, decreased need of human resources, improved efficiency, and potential benefits to the patient experience.

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection.

BACKGROUND: Nivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer. CASE PRESENTATION: We illustrate the outcomes of a 63 year-old type I diabetic female patient who developed pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation. After downward titration of the patient's immunosuppressive medications and extensive multidisciplinary review, she was treated with nivolumab in the first-line setting. Within 1 week of administration, the patient experienced acute renal allograft rejection, renal failure and concurrent diabetic ketoacidosis due to steroid therapy. Allograft function did not return, but patient made a full clinical recovery after being placed on hemodialysis. Subsequently, the patient had clinical disease progression off therapy and required re-challenge with nivolumab on hemodialysis, resulting in ongoing clinical and radiographic response. CONCLUSIONS: This case illustrates multiple practical challenges and dangers of administering anti-PD1 immune checkpoint inhibitors to patients with solid-organ transplantation including need for titration of immunosuppressive medications, risks of allograft rejection, and treatment during hemodialysis.

Viro-immune therapy: A new strategy for treatment of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses (TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1 (PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.