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.

Statin use improves the efficacy of nivolumab in patients with advanced renal cell carcinoma.

BACKGROUND: Statins are widely used in an ageing population, including subjects with solid malignancies. However, no conclusive evidence is currently available on their potential influence on patients' outcome. We aimed to assess whether statin exposure affects the survival of patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab. PATIENTS AND METHODS: Medical records of patients with documented mRCC treated with second- or third-line nivolumab were reviewed at ten institutions from Italy, Spain and the USA. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit. Univariate and multivariate analyses were used to explore the association of variables of interest with survival. RESULTS: A total of 219 patients with mRCC receiving nivolumab between January 2016 and September 2021 were eligible for inclusion in this study; 59 (27%) were statin users. The median OS (34.4 versus 18.6 months, p = 0.017) and PFS (11.7 versus 4.6 months, p = 0.013) resulted apparently longer in statin users. Stratified by age, longer median OS and PFS were associated with statin exposure in both patients aged ≥70 y (median OS: 21.4 versus 10.1 months, p = 0.047; median PFS: 16.4 versus 4.6 months, p = 0.022) and <70 y (median OS: 34.4 versus 21.4 months, p = 0.043; median PFS: 10.3 versus 4.6 months, p = 0.042). Overall clinical benefit resulted higher in statin users than non-users (71% versus 54%, p = 0.030). CONCLUSIONS: Our study suggests a prognostic impact of statin use in patients receiving nivolumab for mRCC.

Concomitant Proton Pump Inhibitors and Outcome of Patients Treated with Nivolumab Alone or Plus Ipilimumab for Advanced Renal Cell Carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent the standard of care as first- or second-line treatment in patients with renal cell carcinoma (RCC). Proton pump inhibitors (PPIs) are among the most prescribed drugs worldwide and are known to affect gut microbiota, which is gaining interest in its association with outcomes for patients on ICIs. OBJECTIVE: The aim of this study was to evaluate the impact of PPIs on outcomes in RCC patients receiving immunotherapy. PATIENTS AND METHODS: We retrospectively collected data from patients with metastatic RCC who received the combination of ipilimumab and nivolumab for first-line treatment (Cohort 1) or single-agent nivolumab for second-line or third-line treatment (Cohort 2) from five international centers with expertise in the treatment of RCC. Data about clinicopathological characteristics, PPI use, and outcome on ICIs were collected. Endpoints of the study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Two hundred and eighteen patients (71% male, median age 61 years) were included in the analysis, 62 in Cohort 1 (including 25 patients receiving PPIs) and 156 in Cohort 2 (including 88 patients receiving PPIs), and were followed up for a median of 42 months. In Cohort 1, no difference was observed in ORR (48% vs 57%; p = 0.203), PFS (12.2 vs 8.5 months; p = 0.928), or OS (not reached [NR] vs 27.3 months; p = 0.84). In Cohort 2, no difference was observed in ORR (32% vs 28%; p = 0.538), PFS (6.7 vs 9.0 months; p = 0.799), or OS (16.0 vs 26.0 months; p = 0.324). CONCLUSIONS: In patients with RCC, concomitant PPI use did not seem to affect survival outcomes on ICIs, either as combination therapy or monotherapy.

Combination Therapy With Bortezomib in Renal Medullary Carcinoma: A Case Series.

BACKGROUND: Renal medullary carcinoma (RMC) is a very rare, aggressive neoplasm occurring almost exclusively in adolescents and young adults with sickle cell trait. Given the rare nature of this tumor, accounting for less than 0.5% of all renal carcinomas, most of the published data on therapies is from case reports and small case series, and current treatments are insufficient, with most patients succumbing to their disease in months. We report our experience with a cytotoxic chemotherapy regimen consisting of platinum-based therapy, doxorubicin, and bortezomib. METHODS: Three patients with metastatic RMC at a single institution were treated off-label with a perioperative chemotherapy regimen for 4 cycles of 2 alternating regimens: regimen A consisting of cisplatin, doxorubicin, and bortezomib; regimen B consisting of carboplatin, paclitaxel, and gemcitabine. A radical nephrectomy was performed on all patients. Surveillance imaging was performed on all patients to assess response and disease burden. Patients received up to 12 months of maintenance therapy with everolimus. RESULTS: Three African American patients - 2 males and 1 female aged 14, 28, and 31 - with sickle cell trait and metastatic disease were treated with this regimen. The median follow-up was 18 months. All had resection of the primary tumor - 2 patients after receiving neoadjuvant therapy, and one patient underwent resection prior to referral. All 3 patients achieved complete responses based on imaging, 2 of which lasted for 12 months, and another is still in remission over 7 years after diagnosis. CONCLUSIONS: This regimen of alternating cycles of platinum-based chemotherapy with bortezomib appeared to be active against RMC and was generally well-tolerated. Given the extremely rare nature of this disease and dismal prognosis, new treatment modalities should be pursued, and whenever possible, patients should be enrolled in a clinical trial. We propose that a multiinstitution clinical trial of this regiment may be warranted.

Timing of steroid initiation and response rates to immune checkpoint inhibitors in metastatic cancer.

BACKGROUND: Corticosteroids (CS) are the mainstay of immune-related adverse effect (irAE) management, as well as for other indications in cancer treatment. Previous studies evaluating whether CS affect immune checkpoint inhibitor (CPI) efficacy compared patients receiving CS versus no CS. However, there is a paucity of clinical data evaluating the timing of concomitant CS and CPI efficacy. METHODS: We retrospectively collected data from patients who received CS during CPI treatment at a single institution. Patients were in two cohorts based on timing of initiation of CS (≥2 months vs <2 months after initiating CPI). Patient characteristics, irAEs, cancer type, treatment type, treatment response/progression per RECIST V.1.1, and survival data were collected. Kaplan-Meier and Cox proportional hazard regression methods estimated HRs for the primary endpoint of progression-free survival (PFS) along with overall survival (OS). RESULTS: We identified 247 patients with metastatic cancer who received CS concurrently with CPIs. The median time on CS was 1.8 months. After adjusting for treatment type, tumor type, brain metastases, and irAEs, those treated with CS ≥2 months after starting CPI had a statistically significant longer PFS (HR=0.30, p<0.001), and OS (HR 0.34, p<0.0001) than those who received CS <2 months after starting CPI. Objective response rate (ORR) for patients on CS ≥2 months was 39.8%, versus ORR for patients <2 months was 14.7% (p value =<0.001) CONCLUSION: Our results suggest that early use of CS during CPI treatment significantly hinders CPI efficacy. This data needs to be validated prospectively. Future studies should focus on the immune mechanisms by which CSs affect T-cell function early in the CPI treatment course.

Multivariate mortality analyses in COVID-19: Comparing patients with cancer and patients without cancer in Louisiana.

BACKGROUND: This is the largest and only multivariate study evaluating the difference in mortality from coronavirus disease 2019 (COVID-19) between patients with cancer and patients without cancer in the United States. The objective was to assess COVID-19 mortality rates in patients with cancer versus patients without cancer and uncover possible statistically significant characteristics contributing to mortality. METHODS: This retrospective study analyzed patients with cancer and patients without cancer who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from March 1 through April 30, 2020. This was a multicenter study in the state of Louisiana throughout the Ochsner Health System in both tertiary and nontertiary centers. Patients older than 18 years were eligible. Three hundred twelve patients with cancer were compared with 4833 patients without cancer. RESULTS: Mortality was found to be higher in the cancer group. Patients of advanced age with cancer had a significant increase in mortality (odds ratio [OR], 5.96; P < .001). Other significant risk factors for increased mortality were male sex (OR, 2.15), a history of chronic kidney disease (OR, 3.84), and obesity (OR, 1.30). In hospitalized patients with cancer, adverse vital signs on admission, decreased absolute lymphocyte counts, thrombocytopenia, elevated creatinine, lactic acidosis, and elevated procalcitonin all seemed to increase the risk of death. Among patients with cancer, active or progressive disease (P < .001) and recent therapy (OR, 2.34; 95% confidence interval, 1.08-5.08) were shown to increase mortality. CONCLUSIONS: Patients with cancer have increased mortality in the setting of infection with SARS-CoV-2 in comparison with patients without cancer. Patients with cancer who are 65 years of age or older and those with certain comorbidities have the greatest risk of death. Recent cancer-directed therapy and disease status also seem to play roles in mortality. LAY SUMMARY: This is the largest study of patients with cancer versus patients without cancer to date and is the first multivariate analysis study comparing these 2 patient populations. This study confirms the hypothesis that patients with cancer are at increased risk for mortality and that there are multiple characteristics posing the potential to risk-stratify these patients in the setting of a future outbreak.

Primary colon adenocarcinoma with choriocarcinoma differentiation: a case report and review of the literature.

BACKGROUND: Choriocarcinoma is an aggressive malignancy of trophoblastic tissue, typically of gestational etiology. Sporadic, nongestational cases are rarely found outside of the gonads. There are only 31 cases of primary choriocarcinoma of the colon reported in the literature. As a consequence of their rarity and aggressive nature, timely diagnosis and effective treatment have proved challenging, and prognosis is very poor. For that reason, we present a rare case with prolonged survival in the youngest reported patient . CASE PRESENTATION: A 26-year-old Caucasian woman presented with abdominal cramping and rectal and vaginal bleeding. Elevated serum human chorionic gonadotropin and an 8-cm right-sided mass seen on ultrasound suggested ectopic pregnancy. The patient was treated with methotrexate; however, her symptoms persisted, and her human chorionic gonadotropin levels continued to rise. Further workup showed a large mass of the sigmoid colon with multiple hepatic lesions suggestive of metastases. Preliminary pathology showed adenocarcinoma. Despite surgical resection and initiation of FOLFOX chemotherapy (folinic acid, fluorouracil, oxaliplatin), the patient had significant clinical deterioration, and her human chorionic gonadotropin increased exponentially. Further pathological review showed two distinct phenotypes: adenocarcinoma merging with choriocarcinoma. The result of evaluation of the metastatic lesions was also positive for choriocarcinoma. Treatment was promptly changed to a choriocarcinoma-targeting chemotherapy regimen of EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), resulting in rapid and dramatic response. The patient had mild progression after 1 year and was switched back to FOLFOX with bevacizumab. After five cycles, scans showed further progression, and the patient was started on third-line therapy with FOLFIRI (folinic acid, fluorouracil, irinotecan) and bevacizumab. Eighteen months after her diagnosis, the patient was alive and maintaining an overall response. CONCLUSIONS: Our patient achieved a marked response and prolonged survival. Although a comprehensive review of the literature showed that survival with these tumors has improved over the past 10 years, prognosis remains poor. Currently, there is no established algorithm for the management of these rare tumors, but both the literature and our patient's case indicate that a choriocarcinoma-targeted regimen is critical for survival. Further evaluation of these rare tumors is warranted in order to identify pathological patterns that may help in the diagnosis, management, and survival of these malignancies.

Impact of Biopsy Technique on Clinically Important Outcomes for Cutaneous Melanoma: A Systematic Review and Meta-analysis.

We performed a systematic review and meta-analysis to examine the relationship between the type of biopsy technique employed in the diagnosis of cutaneous melanoma and 4 clinically important outcomes: melanoma-specific mortality, all-cause mortality, Breslow tumor depth, or melanoma recurrence. Our database was obtained by searching PubMed, Ovid MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Library from inception until December 6, 2019. Studies were identified that compared biopsy techniques used to diagnose cutaneous melanoma with any of our study outcomes. We included 7 observational studies for our meta-analysis after screening 3231 titles and abstracts. Pooled data identified a significantly higher all-cause mortality in the punch biopsy group (risk ratio [RR], 1.520; P=.02). A higher, but nonsignificant, rate of melanoma-specific mortality (RR, 1.96; P=.22) and melanoma recurrence (RR, 1.20; P=.186) was also found for the punch biopsy group. Breslow tumor thickness was not significantly lower for punch incision (standardized mean difference, -0.42; P=.27). We found limited evidence for differences in clinically important outcomes across the spectrum of the most common methods employed in clinical practice for the initial diagnosis of cutaneous melanoma. A small, but significant, increase (P=.02) in all-cause mortality with punch biopsies was not seen for the other outcomes and was most likely due to small sample sizes and demographic differences in the included studies and unlikely represents a clinically important outcome. Our findings support the use of existing clinical practice guidelines for evaluating pigmented lesions suspicious for cutaneous melanoma.

Recurrent epistaxis leading to diagnosis of primary sinonasal melanoma.

A 48-year-old man presented to urgent care with recurrent epistaxis over 6 months. Initially, nosebleeds were controlled with packing or cautery. Ultimately, he was referred to ear, nose and throat department and underwent nasal endoscopy which revealed polypoid tissue. A biopsy of the polyp showed non-specific inflammation with no evidence of malignancy. Follow-up maxillofacial CT revealed a large mass lesion in the right maxillary sinus, right nasal fossa, much of the ethmoids and right sphenoid, with destruction of adjacent bony structures. MRI revealed a mass in the right nasal cavity with extension into the ethmoid and anterior sphenoid sinus, anterior cranial fossa and medial orbits. Staging CT discovered metastatic disease in the adrenal glands and lymphadenopathy in the neck. The patient underwent endoscopic sinus surgery with debulking and tissue diagnosis of malignant melanoma. He completed radiation therapy to sinus and was subsequently enrolled in a clinical trial. Most recent imaging revealed complete metabolic response on positron emission tomography.