Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study.

BACKGROUND: The dependence of the adaptive immune system on circadian rhythm is an emerging field of study with potential therapeutic implications. We aimed to determine whether specific time-of-day patterns of immune checkpoint inhibitor infusions might alter melanoma treatment efficacy. METHODS: Melanoma Outcomes Following Immunotherapy (MEMOIR) is a longitudinal study of all patients with melanoma who received ipilimumab, nivolumab, or pembrolizumab, or a combination of these at a single tertiary cancer centre (Winship Cancer Institute of Emory University, Atlanta, GA, USA). For this analysis, we collected deidentified participant-level data from the MEMOIR database for adults (age ≥18 years) diagnosed with stage IV melanoma between 2012 and 2020. Those who received fewer than four infusions were excluded. Standard of care doses were used, with modifications at the treating physicians' discretion. The primary outcome was overall survival, defined as death from any cause and indexed from date of first infusion of immune checkpoint inhibitor. We calculated the association between overall survival and proportion of infusions of immune checkpoint inhibitors received after 1630 h (a composite time cutoff derived from seminal studies of the immune-circadian rhythm to represent onset of evening) using Cox regression and propensity score-matching on age, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy. Treatment-related adverse events that led to change or discontinuation of immune checkpoint inhibitors were also assessed. FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 481 patients with melanoma received treatment with immune checkpoint inhibitors at the study centre, of whom 299 had stage IV disease and were included in this study; median follow-up was 27 months (IQR 14 to 47). In the complete unmatched sample, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR 51 to 72). Every additional 20% of infusions of immune checkpoint inhibitors received after 1630 h (among all infusions received by a patient) conferred an overall survival hazard ratio (HR) of 1·31 (95% CI 1·00 to 1·71; p=0·046). A propensity score-matched analysis of patients who did (n=73) and did not (n=73) receive at least 20% of their infusions of immune checkpoint inhibitors after 1630 h (54 [37%] of 146 patients were women and 92 [63%] were men, with a median age of 58 years [IQR 48 to 68]) showed that having at least 20% of infusions in the evening was associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [1·04 to 4·00; p=0·038]). This result remained robust to multivariable proportional hazards adjustment with (HR 1·80 [1·08 to 2·98; p=0·023]) and without (2·16 [1·10 to 4·25; p=0·025]) inclusion of the complete unmatched study sample. The most common adverse events were colitis (54 [18%] of 299 patients), hepatitis (27 [9%]), and hypophysitis (15 [5%]), and there were no treatment-related deaths. INTERPRETATION: Our findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening than if stimulated in the daytime. Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma. FUNDING: National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute.

Patient preferences regarding incidental genomic findings discovered during tumor profiling.

BACKGROUND: During the process of tumor profiling, there is the potential to detect germline variants. To the authors' knowledge, there currently is no accepted standard of care for how to deal with these incidental findings. The goal of the current study was to assess disclosure preferences among patients with cancer regarding incidental genomic variants that may be discovered during tumor profiling. METHODS: A 45-item questionnaire was administered to 413 patients in ambulatory oncology clinics. The survey captured demographic and disease variables and personal and family history, and presented case scenarios for different types of incidental germline variants that could theoretically be detected during genomic analysis of a patient's tumor. RESULTS: The possibility of discovering non-cancer-related, germline variants did not deter patients from tumor profiling: 77% wanted to be informed concerning variants that could increase their risk of a serious but preventable illness, 56% wanted to know about variants that cause a serious but unpreventable illness, and 49% wanted to know about variants of uncertain significance. The majority of patients (75%) indicated they would share hereditary information regarding predisposition to preventable diseases with family and 62% would share information concerning unpreventable diseases. The most frequent concerns about incidental findings were ability to obtain health (48%) or life (41%) insurance. Only 21% of patients were concerned about privacy of information. CONCLUSIONS: Patients with cancer appear to prefer to receive information regarding incidental germline variants, but there is substantial variability with regard to what information patients wish to learn. The authors recommend that personal preferences for the disclosure of different types of incidental findings be clarified before a tumor profiling test is ordered. Cancer 2016;122:1588-97. © 2016 American Cancer Society.

Cutaneous and Noncutaneous Adverse Effects in Patients with Advanced Melanoma Receiving Immunotherapy.

Relationships between cutaneous adverse effects (CAEs) and noncutaneous adverse effects (NCAEs) of melanoma immunotherapy may help identify patterns tied to distinct immunologic pathways. The objective of this study was to determine the associations between CAEs and NCAEs among patients with stages III-IV melanoma receiving immunotherapy and who were enrolled in a prospective cohort. Electronic medical record data were abstracted from the first immunotherapy infusion until 1 year later. CAEs were rash or itch. NCAEs were symptoms and/or laboratory abnormalities documented as immunotherapy related. NCAE onset and time to NCAE were compared between participants with and without CAEs using ORs and Wilcoxon rank sum tests. Of 34 participants, 11 (32.4%) developed no adverse effects, 7 (20.1%) developed CAEs only, 3 (8.8%) developed NCAEs only, and 13 (38.2%) developed both CAEs and NCAEs. After adjustment for age, sex, and immunotherapy regimen, CAE was associated with higher odds of NCAE development (OR = 9.72; 95% confidence interval = 1.2-76.8). Median NCAE onset was 63 days in those with CAEs and 168 days in those without CAEs (P = 0.41). Limitations included a small sample size, and larger prospective studies should be performed to confirm findings. CAE was associated with NCAE development. Early identification and treatment of NCAEs may reduce symptom burden and hospitalizations associated with NCAEs.

Clinical Correlation between Acute Exudative Polymorphous Paraneoplastic Vitelliform Maculopathy and Metastatic Melanoma Disease Activity: A 48-month Longitudinal Case Report.

PURPOSE: Longitudinal evaluation of acute exudative polymorphous paraneoplastic vitelliform maculopathy (AEPPVM) following diagnosis and treatment of metastatic melanoma. METHODS: Case report of a 47-year-old male with unknown primary metastatic melanoma and AEPPVM monitored before and during melanoma treatment using clinical exam, retinal imaging, and electroretinograms (ERG). Genetic testing and autoantibody panels were performed. RESULTS: He presented within a month of metastatic melanoma diagnosis with numerous bilateral vitelliform lesions in the posterior pole, consistent with AEPPVM. Metastatic disease was treated with immunotherapy, radiosurgery, and radiation over 48 months. Maculopathy and metastatic disease improved and worsened in parallel. Genetic testing was negative for bestrophin-1. An autoantibody panel was positive for anti-recoverin and transducin-α. CONCLUSION: AEPPVM is an uncommon paraneoplastic retinopathy found in patients with metastatic malignancy. To our knowledge, this is the first report demonstrating a temporal association between metastatic disease activity and quantifiable changes in retinal imaging over a 4-year period.

Surgical Considerations and Systemic Therapy of Melanoma.

Recent advances in effective medical therapies have markedly improved the prognosis for patients with advanced melanoma. This article aims to highlight the current era of integrated multidisciplinary care of patients with advanced melanoma by outlining current approved therapies, including immunotherapy, targeted therapy, radiation therapy, and other strategies used in both the adjuvant and the neoadjuvant setting as well as the evolving role of surgical intervention in the changing landscape of advanced melanoma.

Changing Therapeutic Landscape for Melanoma With Multiple Brain Metastases.

Over 90 000 people are expected to be diagnosed with melanoma in the United States this year. The development of brain metastases is particularly difficult to manage. Over the past few years, melanoma patients with multiple unresectable brain metastases for which stereotactic surgery might also not be a viable option have fortunately experienced a dramatic expansion in available management options given improvements made to targeted agents, immunotherapy, and radiotherapy. Whole-brain radiation therapy (WBRT) is a long-standing radiation technique that has become increasingly sophisticated. In this review, we summarize retrospective and prospective studies on individual advances in targeted agents, immunotherapy, and WBRT, highlighting important variables such as overall survival, intracranial progression-free survival, control and response rates, and toxicities. We also discuss the recent integration of these therapies into a multimodality approach, which has shown promise in the clinical setting although toxicities have not been insignificant. Finally, we describe ongoing prospective trials relevant to melanoma with brain metastases, and we conclude with our own thoughts on the optimal approach for these patients.

Predictors of Overall and Progression-Free Survival in Patients with Ocular Melanoma Metastatic to the Liver Undergoing Y90 Radioembolization.

PURPOSE: To investigate predictors of overall survival (OS) and progression-free survival (PFS) in patients with ocular melanoma metastatic to the liver undergoing yttrium-90 (Y90) radioembolization, including the effect of concurrent immunotherapy. METHODS: An IRB-approved retrospective review of 24 patients with ocular melanoma metastatic to the liver who underwent Y-90 treatment between June 2003 and January 2018 was performed. Data regarding patients' performance status at the time of Y90, intra-/extrahepatic tumor burden, and treatment response were evaluated. RECIST was used to determine objective tumor response. Kaplan-Meier analysis was used to calculate OS and PFS from the first Y90 therapy. Log-rank analysis was used to determine predictors of prolonged OS and PFS. RESULTS: Median OS from primary diagnosis and diagnosis of liver metastases was 66 months (mo) and 26.3 mo, respectively. Median OS for those who received immunotherapy within 3 months of undergoing Y90 was prolonged at 26.0 mo versus 9.5 mo for others (p = 0.014). Median OS for patients with an ECOG performance status of 0 was prolonged at 26 mo versus 5.5 mo for others (p = 0.003). Median hepatic PFS was prolonged in patients treated with Y-90 on concurrent immunotherapy at 10.3 mo versus 2.7 mo for TARE only (p = 0.002). Patients with an ECOG performance status of 0 had prolonged PFS (p = 0.002). CONCLUSIONS: Concurrent immunotherapy and an ECOG performance status of 0 at the time of Y90 therapy appear to be predictors of prolonged OS and PFS in patients with ocular melanoma metastatic to the liver.

Chemokine receptor 4 targeted protein MRI contrast agent for early detection of liver metastases.

Liver metastases often progress from primary cancers including uveal melanoma (UM), breast, and colon cancer. Molecular biomarker imaging is a new non-invasive approach for detecting early stage tumors. Here, we report the elevated expression of chemokine receptor 4 (CXCR4) in liver metastases in UM patients and metastatic UM mouse models, and development of a CXCR4-targeted MRI contrast agent, ProCA32.CXCR4, for sensitive MRI detection of UM liver metastases. ProCA32.CXCR4 exhibits high relaxivities (r 1 = 30.9 mM-1 s-1, r 2 = 43.2 mM-1 s-1, 1.5 T; r 1 = 23.5 mM-1 s-1, r 2 = 98.6 mM-1 s-1, 7.0 T), strong CXCR4 binding (K d = 1.10 ± 0.18 µM), CXCR4 molecular imaging capability in metastatic and intrahepatic xenotransplantation UM mouse models. ProCA32.CXCR4 enables detecting UM liver metastases as small as 0.1 mm3. Further development of the CXCR4-targeted imaging agent should have strong translation potential for early detection, surveillance, and treatment stratification of liver metastases patients.

False positive reactivity of recombinant, diagnostic, glycoproteins produced in High Five insect cells: effect of glycosylation.

Baculovirus-mediated expression of recombinant proteins for use in diagnostic assays is commonplace. We expressed a diagnostic antigen for cysticercosis, GP50, caused by the larval stage of Taenia solium, in both High Five and Sf9 insect cells. Upon evaluation of the specificity of recombinant GP50 (rGP50) in a western blot assay, we observed that 12.5% (21/168) of the serum samples from persons with a variety of parasitic infections other than cysticercosis reacted positive when rGP50 was produced in High Five cells. The same samples reacted negative when rGP50 was produced in Sf9 cells. The false positive reactivities of these other parasitic infection sera were abolished when rGP50, expressed in High Five cells, was deglycosylated. In addition, the same sera that reacted with rGP50 from High Five cells also reacted with recombinant human transferrin (rhTf) when expressed in High Five cells, but not Sf9 cells. High Five cells, but not Sf9 cells, modify many glycoproteins with a core alpha(1,3)-fucose. This same modification is found in the glycoproteins of several parasitic worms and is known to be immunogenic. Since the distribution of these worms is widespread and millions of people are infected, the use of recombinant proteins with N-linked glycosylation produced in High Five cells for diagnostic antigens is likely to result in a number of false positive reactions and a decrease in assay specificity.

The importance of surgery in scalp angiosarcomas.

BACKGROUND: Scalp angiosarcomas (SA) are rare, representing <1% of soft tissue sarcomas. The optimal management of these tumors is unknown, with management based on small case series. We sought to assess the impact of different therapies on overall survival (OS), the practice patterns nationally, and identify factors associated with OS for non-metastatic scalp angiosarcomas. METHODS: A prospectively maintained database was used to identify non-metastatic scalp angiosarcomas who received some form of definitive therapy. Logistics regression, Kaplan-Meier, and Cox proportional-hazard models were utilized. RESULTS: A total of 589 patients met study entry criteria with a median follow-up of 4.2 years. The majority (482 patients, 81.8%) had upfront definitive resection and an additional 317 patients (65.8%) received postoperative radiation. Of the 107 patients who didn't have surgery, the majority (65 patients, 60.7%) received definitive radiation and 42 patients (39.3%) received radiation and chemotherapy. One-year and five-year survival estimates for patients not receiving definitive surgery were 68.0% (95%CI: 57.5-76.4) and 18.0% (95%CI: 10.2-27.5) respectively compared to 78.2% (95%CI: 74.0-81.9) and 34.1% (95%CI: 28.9-39.3) for patients receiving definitive surgery (p < 0.01). On multivariable analysis, age ≥65 years, tumor size ≥5 cm, and not receiving definitive surgery was associated with worse OS. CONCLUSIONS: The majority of patients with non-metastatic scalp angiosarcomas had upfront definitive surgery, with a subsequent improvement in OS, including when accounting for other patient and tumor factors. Postoperative radiation was frequently given. Our large series confirmed age and tumor size as prognostic factors for this rare disease.

Characterization and cloning of T24, a Taenia solium antigen diagnostic for cysticercosis.

The third and final diagnostic antigen of the lentil lectin purified glycoproteins (LLGP) extracted from the larval stage of Taenia solium has been characterized, cloned, and expressed. T24 is an integral membrane protein that belongs to the tetraspanin superfamily. It migrates at a position corresponding to 24-kDa and as a homodimer at 42-kDa. Antibodies from cysticercosis patients recognize secondary structure epitopes that are dependent upon correctly formed disulfide bonds. A portion of T24, the large, extracellular loop domain, was expressed in an immunologically reactive form in insect cells. When tested in a Western blot assay with a large battery of serum samples, this protein, T24H, has a sensitivity of 94% (101/107), for detecting cases of cysticercosis with two or more viable cysts, and a specificity of 98% (284/290). The identification and expression of T24H sets the stage for the development of an ELISA suitable for testing single samples and for large-scale serosurveys that is not dependent upon the isolation and purification of antigens from parasite materials.

Characterization and cloning of GP50, a Taenia solium antigen diagnostic for cysticercosis.

GP50, a Taenia solium protein diagnostic for cysticercosis has been cloned, sequenced, and characterized. GP50 is one diagnostic component of the lentil lectin purified glycoprotein (LLGP) antigens that have been used for antibody-based diagnosis of cysticercosis in a Western blot assay for nearly 15 years. GP50 is a glycosylated and GPI-anchored membrane protein. The native protein migrates at 50kDa, but the predicted molecular weight of the mature protein is 28.9. Antigenically active recombinant GP50 has been expressed in a baculovirus expression system. The antigenic activity of both the native and recombinant proteins is dependent upon the correct formation of disulfide bonds. GP50, purified from cysticerci, has two homologs expressed in the adult worm, TSES33 and TSES38. Both are diagnostic for taeniasis. In spite of the amino acid similarities between GP50 and the TSES proteins, each appears to be a stage-specific antigen. A preliminary evaluation of recombinant GP50 in a Western blot assay showed 100% specificity for cysticercosis and 90% sensitivity for cysticercosis positive serum samples reactive with the GP50 component of LLGP.

Application of physiologically-based pharmacokinetic modeling to investigate the toxicological interaction between chlorpyrifos and parathion in the rat.

Environmental exposure is usually due to the presence of multiple chemicals. In most cases, these chemicals interact with each other at both pharmacokinetic and pharmacodynamic toxicity mechanisms. In the absence of data, joint toxicity assessment of a mixture is based on default dose or response additivity. Although, the concept of additivity is mostly accepted at low dose levels, these levels need to be determined quantitatively to validate the use of additivity as an absence of any possible synergistic or antagonistic interactions at low environmental exposure levels. The doses at which interaction becomes significant define the interaction threshold. In most cases, estimation of these low-dose interaction thresholds experimentally is economically costly and challenging because of the need to use a large number of laboratory animals. Computational toxicology methods provide a feasible alternative to establish interaction thresholds. For example, a physiologically based pharmacokinetic (PBPK) model was developed to estimate an interaction threshold for the joint toxicity between chlorpyrifos and parathion in the rat. Initially, PBPK models were developed for each chemical to estimate the blood concentrations of their respective metabolite. The metabolite concentrations in blood out-put was then linked to acetylcholinesterase kinetics submodel. The resulting overall PBPK model described interactions between these pesticides at two levels in the organism: (a) the P450 enzymatic bioactivation site, and (b) acetylcholinesterase binding sites. Using the overall model, a response surface was constructed at various dose levels of each chemical to investigate the mechanism of interaction and to calculate interaction threshold doses. The overall model simulations indicated that additivity is obtained at oral dose levels below 0.08mg/kg of each chemical. At higher doses, antagonism by enzymatic competitive inhibition is the mode of interaction.

Understanding patients' attitudes toward communication about the cost of cancer care.

PURPOSE: Recent publications have promoted physician-patient communication on cost as a means of decreasing overall spending and minimizing patients' financial burden in oncology. No study has assessed patients' perspectives on cost communication in oncology. We sought to describe oncology patients' attitudes toward cost communication, explore potential predictors for patients' communication preferences, and assess how patients with cancer consider cost when making management decisions. METHODS: A 31-item questionnaire was developed to measure oncology patients' communication preferences regarding the cost of cancer care, focusing on out-of-pocket costs. Items were adapted from other instruments when possible. After piloting, patients were recruited from an academic ambulatory oncology practice. Basic descriptive statistics were applied. RESULTS: Of the 771 patients approached, 256 responded (response rate, 33%). Most (68%) preferred to know about out-of-pocket costs before treatment. A majority (59%) wanted their physician to discuss these costs with them. Although 76% reported feeling comfortable discussing cost with their physician, 74% were amenable to discussing cost with someone other than their physician. Most patients did not consider out-of-pocket costs (57%) or the health care costs of the country (61%) in their decision making, nor did they believe their physician should (55%). Patients receiving active chemotherapy were less likely to want to discuss out-of-pocket costs with their physician (P = .035). CONCLUSION: Patients' comfort with and desire to discuss cancer costs exceed that of oncologists, suggesting a need to educate oncologists on this important topic. A patient's desire to understand treatment-associated cost does not equate with a desire for cost to influence medical decision making.

Characterization of the 8-kilodalton antigens of Taenia solium metacestodes and evaluation of their use in an enzyme-linked immunosorbent assay for serodiagnosis.

The Western blot for cysticercosis, which uses lentil lectin purified glycoprotein (LLGP) antigens extracted from the metacestode of Taenia solium, has been the "gold standard" serodiagnostic assay since it was first described in 1989. We report that the diagnostic antigens at 14, 18, and 21 kDa, as well as some larger disulfide-bonded antigens, are actually all members of a very closely related family of proteins, the 8-kDa antigens. The genes for 18 unique, mature proteins have been identified. Nine of these were chemically synthesized and tested in an enzyme-linked immunosorbent assay with a battery of defined serum samples, including 32 cysticercosis-positive serum samples reactive with the 8-kDa antigens of LLGP on Western blotting, 34 serum samples from patients with other parasitic infections, and 15 normal human serum samples. One of the 8-kDa antigens, TsRS1, is 100% sensitive and 100% specific. TsRS1 will be one component of a cocktail of three to four synthetic or recombinant antigens, based on the diagnostic bands of the Western blot, which will be used for the serodiagnosis of cysticercosis.