Clinical benefit of baseline imaging in Merkel cell carcinoma: Analysis of 584 patients.

BACKGROUND: Merkel cell carcinoma (MCC) guidelines derive from melanoma and do not recommend baseline cross-sectional imaging for most patients. However, MCC is more likely to have metastasized at diagnosis than melanoma. OBJECTIVE: To determine how often baseline imaging identifies clinically occult MCC in patients with newly diagnosed disease with and without palpable nodal involvement. METHODS: Analysis of 584 patients with MCC with a cutaneous primary tumor, baseline imaging, no evident distant metastases, and sufficient staging data. RESULTS: Among 492 patients with clinically uninvolved regional nodes, 13.2% had disease upstaged by imaging (8.9% in regional nodes, 4.3% in distant sites). Among 92 patients with clinically involved regional nodes, 10.8% had disease upstaged to distant metastatic disease. Large (>4 cm) and small (<1 cm) primary tumors were both frequently upstaged (29.4% and 7.8%, respectively). Patients who underwent positron emission tomography-computed tomography more often had disease upstaged (16.8% of 352), than those with computed tomography alone (6.9% of 231; P = .0006). LIMITATIONS: This was a retrospective study. CONCLUSIONS: In patients with clinically node-negative disease, baseline imaging showed occult metastatic MCC at a higher rate than reported for melanoma (13.2% vs <1%). Although imaging is already recommended for patients with clinically node-positive MCC, these data suggest that baseline imaging is also indicated for patients with clinically node-negative MCC because upstaging is frequent and markedly alters management and prognosis.

Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: Analysis of 188 cases of localized disease and proposed management algorithm.

BACKGROUND: Merkel cell carcinoma (MCC) management typically includes surgery with or without adjuvant radiation therapy (aRT). Major challenges include determining surgical margin size and whether aRT is indicated. OBJECTIVE: To assess the association of aRT, surgical margin size, and MCC local recurrence. METHODS: Analysis of 188 MCC cases presenting without clinical nodal involvement. RESULTS: aRT-treated patients tended to have higher-risk tumors (larger diameter, positive microscopic margins, immunosuppression) yet had fewer local recurrences (LRs) than patients treated with surgery only (1% vs 15%; P = .001). For patients who underwent surgery alone, 7 of 35 (20%) treated with narrow margins (defined as ≤1.0 cm) developed LR, whereas 0 of 13 patients treated with surgical margins greater than 1.0 cm developed LR (P = .049). For aRT-treated patients, local control was excellent regardless of surgical margin size; only 1% experienced recurrence in each group (1 of 70 with narrow margins ≤1 cm and 1 of 70 with margins >1 cm; P = .56). LIMITATIONS: This was a retrospective study. CONCLUSIONS: Among patients treated with aRT, local control was superb even if significant risk factors were present and margins were narrow. We propose an algorithm for managing primary MCC that integrates risk factors and optimizes local control while minimizing morbidity.

Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases per year in the United States, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV oncoprotein (T-antigens) have been correlated with MCC tumor burden. The present study assesses the clinical utility of MCPyV-oncoprotein antibody titers for MCC prognostication and surveillance. METHODS: MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly diagnosed MCC were followed prospectively (median follow-up, 1.9 years). Among the seropositive patients, antibody titer and disease status were serially tracked. RESULTS: Antibodies to MCPyV oncoproteins were rare among healthy individuals (1%) but were present in most patients with MCC (114 of 219 patients [52%]; P < .01). Seropositivity at diagnosis independently predicted decreased recurrence risk (hazard ratio, 0.58; P = .04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. After initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 time points), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence, whereas a decreasing titer had a negative predictive value of 97%. CONCLUSIONS: Determination of oncoprotein antibody titer assists in the clinical management of patients with newly diagnosed MCC by stratifying them into a higher risk seronegative cohort, in which radiologic imaging may play a more prominent role, and into a lower risk seropositive cohort, in which disease status can be tracked in part by oncoprotein antibody titer. Cancer 2017;123:1464-1474. © 2016 American Cancer Society.

The Relationship Between Patient-Specific Factors and Discharge Destination After COVID-19 Hospitalization.

OBJECTIVE: The aim of this study was to determine the discharge destinations and associated patient-specific factors among patients hospitalized with COVID-19. DESIGN: A retrospective cohort study was carried out at a single-site tertiary acute care hospital. RESULTS: Among 2872 patients, discharge destination included home without services ( n = 2044, 71.2%), home with services ( n = 379, 13.2%), skilled nursing facility (117, 4.1%), long-term acute care hospital ( n = 39, 1.3%), inpatient rehabilitation facility ( n = 97, 3.4%), acute care facility ( n = 23, 0.8%), hospice services ( n = 20, 0.7%), or deceased during hospitalization ( n = 153, 5.3%). Adjusting by covariates, patients had higher odds of discharge to a rehabilitation facility (skilled nursing facility, long-term acute care hospital, or inpatient rehabilitation facility) than home (with or without services) when they were older (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.80-3.11; P < 0.001), had a higher Charlson Comorbidity Index score (3-6: OR, 2.36; 95% CI, 1.34-4.15; P = 0.003; ≥7: OR, 2.76; 95% CI, 1.56-4.86; P < 0.001), were intubated or required critical care (OR, 2.15; 95% CI, 1.48-3.13; P < 0.001), or had a longer hospitalization (3-7 days: OR, 12.48; 95% CI, 3.77-41.32; P < 0.001; 7-14 days: OR, 28.14; 95% CI, 8.57-92.43; P < 0.001). Patients were less likely to be discharged to a rehabilitation facility if they received remdesivir (OR, 0.44; 95% CI, 0.31-0.64; P < 0.001). CONCLUSIONS: Patient-specific factors associated with COVID-19 hospitalization should be considered by physicians when prognosticating patient rehabilitation.

Mercury biomagnification in benthic, pelagic, and benthopelagic food webs in an Arctic marine ecosystem.

Mercury (Hg) is a ubiquitous toxic metal that biomagnifies in food webs, and can reach high concentrations in top predators. Evaluating Hg biomagnification in Arctic marine food webs is critical for understanding Hg dynamics and estimating exposure to understudied fish and wildlife consumed by humans. The majority of studies conducted on Hg biomagnification in the Arctic have focused on pelagic food webs. Benthic and benthopelagic food webs in Arctic marine ecosystems also support many species of subsistence and commercial importance, and data are lacking for these systems. In this study, we investigated food web structure and Hg biomagnification for the benthic, pelagic, and benthopelagic marine food webs of inner Frobisher Bay in Nunavut. Stable isotope ratios of carbon (δ13C) and nitrogen (δ15N), as well as total (THg) and methyl (MeHg) mercury concentrations were measured in fish, invertebrates, and zooplankton. Biomagnification in each food web was quantified with Trophic Magnification Slopes (TMS) and Trophic Magnification Factors (TMF). The highest TMS and TMF values were exhibited by the benthopelagic food web (TMS = 0.201; TMF = 1.59), followed by the pelagic food web (TMS = 0.183; TMF = 1.52), and lastly the benthic food web (TMS = 0.079; TMF = 1.20), with δ15N explaining 88%, 79%, and 9% of variation in Hg concentrations, respectively. TMS and TMF values were generally low compared to other Arctic marine food webs. Results from food web structure analyses indicated that the benthic food web had the greatest trophic diversity, trophic redundancy, and largest isotopic niche area of all food webs studied. Greater food web complexity may thus result in reduced MeHg biomagnification, but further study is required. Acquiring Hg and food web structure data is critical for predicting the effects of climate-induced environmental change on Hg dynamics, especially in the context of Arctic marine ecosystems.

Recurrence and Mortality Risk of Merkel Cell Carcinoma by Cancer Stage and Time From Diagnosis.

IMPORTANCE: Merkel cell carcinoma (MCC) often behaves aggressively; however, disease-recurrence data are not captured in national databases, and it is unclear what proportion of patients with MCC experience a recurrence (estimates vary from 27%-77%). Stage-specific recurrence data that includes time from diagnosis would provide more precise prognostic information and contribute to risk-appropriate clinical surveillance. OBJECTIVE: To estimate risk of stage-specific MCC recurrence and mortality over time since diagnosis. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 618 patients with MCC who were prospectively enrolled in a Seattle-based data repository between 2003 and 2019. Of these patients, 223 experienced a recurrence of MCC. Data analysis was performed July 2019 to November 2021. MAIN OUTCOMES AND MEASURES: Stage-specific recurrence and survival, as well as cumulative incidence and Kaplan-Meier analyses. RESULTS: Among the 618 patients included in the analysis (median [range] age, 69 [11-98] years; 227 [37%] female), the 5-year recurrence rate for MCC was 40%. Risk of recurrence in the first year was high (11% for patients with pathologic stage I, 33% for pathologic stage IIA/IIB, 30% for pathologic stage IIIA, 45% for pathologic stage IIIB, and 58% for pathologic stage IV), with 95% of recurrences occurring within the first 3 years. Median follow-up among living patients was 4.3 years. Beyond stage, 4 factors were associated with increased recurrence risk in univariable analyses: immunosuppression (hazard ratio [HR], 2.4; 95% CI, 1.7-3.3; P < .001), male sex (HR, 1.9; 95% CI, 1.4-2.5; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; 95% CI, 1.4-4.0; P = .001), and older age (HR, 1.1; 95% CI, 1.0-1.3; P = .06 for each 10-year increase). Among 187 deaths in the cohort, 121 (65%) were due to MCC. The MCC-specific survival rate was strongly stage dependent (95% at 5 years for patients with pathologic stage I vs 41% for pathologic stage IV). Among patients presenting with stage I to II MCC, a local recurrence (17 arising within/adjacent to the primary tumor scar) did not appreciably diminish survival compared with patients who had no recurrence (85% vs 88% MCC-specific survival at 5 years). CONCLUSIONS AND RELEVANCE: In this cohort study, the MCC recurrence rate (approximately 40%) was notably different than that reported for invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) following definitive therapy. Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest.

Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance.

Approximately one-third of Merkel cell carcinoma (MCC) patients eventually develop distant metastatic disease. Little is known about whether the location of the primary lesion is predictive of initial distant metastatic site, or if survival likelihood differs depending on the metastatic site. Such data could inform imaging/surveillance practices and improve prognostic accuracy. Multivariate and competing-risk analyses were performed on a cohort of 215 MCC patients with distant metastases, 31% of whom had two or more initial sites of distant metastasis. At time of initial distant metastasis in the 215 patients, metastatic sites (n = 305) included non-regional lymph nodes (present in 41% of patients), skin/body wall (25%), liver (23%), bone (21%), pancreas (8%), lung (7%), and brain (5%). Among the 194 patients who presented with MCC limited to local or regional sites (stage I-III) but who ultimately developed distant metastases, distant progression occurred in 49% by 1 year and in 80% by 2 years following initial diagnosis. Primary MCC locations differed in how likely they were to metastasize to specific organs/sites (P < .001). For example, liver metastases were far more likely from a head/neck primary (43% of 58 patients) versus a lower limb primary (5% of 39 patients; P < .0001). Skin-only distant metastasis was associated with lower MCC-specific mortality as compared to metastases in multiple organs/sites (HR 2.7; P = .003), in the liver (HR 2.1; P = .05), or in distant lymph nodes (HR 2.0; P = .045). These data reflect outcomes before PD1-pathway inhibitor availability, which may positively impact survival. In conclusion, primary MCC location is associated with a pattern of distant spread, which may assist in optimizing surveillance. Because it is linked to survival, the site of initial distant metastasis should be considered when assessing prognosis.

Merkel Cell Carcinoma Patients Presenting Without a Primary Lesion Have Elevated Markers of Immunity, Higher Tumor Mutation Burden, and Improved Survival.

Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear.Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors.Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; P < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; P = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (P < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; P < 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, P = 0.016).Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival. Clin Cancer Res; 24(4); 963-71. ©2017 AACR.

Assessment of endogenous and therapeutic arteriogenesis by contrast ultrasound molecular imaging of integrin expression.

BACKGROUND: We hypothesized that molecular imaging with contrast-enhanced ultrasound (CEU) and microbubbles targeted to endothelial integrins could be used to noninvasively assess early angiogenic responses to ischemia and growth factor therapy. METHODS AND RESULTS: Hindlimb ischemia was produced in 48 rats by ligation of an iliac artery. Half of the animals received intramuscular sustained-release fibroblast growth factor-2 (FGF-2). Immediately after ligation and at subsequent intervals from 4 to 28 days, blood flow and oxygen tension in the proximal adductor muscles were measured by CEU perfusion imaging and phosphor quenching, respectively. Targeted CEU imaging of alpha(v)- and alpha5beta1-integrin expression was performed with microbubbles bearing the disintegrin echistatin. Iliac artery ligation produced a 65% to 70% reduction in blood flow and oxygen tension. In untreated ischemic muscle, muscle flow and oxygen tension partially recovered by days 14 to 28. In these animals, signal from integrin-targeted microbubbles was intense and peaked before flow increase (days 4 to 7). In comparison to untreated animals, FGF-2-treated muscle had a greater rate and extent of blood flow recovery and greater signal intensity from integrin-targeted microbubbles, which peaked before maximal recovery of flow. On immunohistology, arteriolar but not capillary density increased in the ischemic limb after ligation, the rate and degree of which were greater in FGF-2-treated rats. Immunofluorescence demonstrated intense staining for alpha(v) in arterioles, the temporal course of which correlated with targeted imaging. CONCLUSIONS: Targeted CEU can be used to assess endogenous and therapeutic arteriogenesis before recovery of tissue perfusion. These results suggest that molecular imaging of integrin expression may be useful for evaluating proangiogenic therapies.

Single-fraction radiation therapy in patients with metastatic Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated cancer with limited therapeutic options for metastatic disease. Cytotoxic chemotherapy is associated with high response rates, but responses are seldom durable and toxicity is considerable. Here, we report our experience with palliative single-fraction radiotherapy (SFRT) in patients with metastatic MCC. We conducted retrospective analyses of safety and efficacy outcomes in patients that received SFRT (8 Gy) to MCC metastases between 2010 and 2013. Twenty-six patients were treated with SFRT to 93 MCC tumors located in diverse sites that included skin, lymph nodes, and visceral organs. Objective responses were observed in 94% of the measurable irradiated tumors (86/92). Complete responses were observed in 45% of tumors (including bulky tumors up to 16 cm). "In field" lesion control was durable with no progression in 77% (69/89) of treated tumors during median follow-up of 277 days among 16 living patients. Clinically significant toxicity was seen in only two patients who had transient side effects. An exploratory analysis suggested a higher rate of in-field progression in patients with an immunosuppressive comorbidity or prior recent chemotherapy versus those without (30% and 9%, respectively; P = 0.03). Use of SFRT in palliating MCC patients was associated with an excellent in field control rate and durable responses at treated sites, and with minimal toxicity. SFRT may represent a convenient and appealing alternative to systemic chemotherapy for palliation, for which most patients with oligometastatic MCC are eligible. SFRT may also synergize with emerging systemic immune stimulants by lowering tumor burden and enhancing presentation of viral/tumor antigens.

Valvular flow abnormalities are often identified by a resting focused Doppler examination performed at the time of stress echocardiography.

BACKGROUND: Patients are usually referred for stress echocardiography to assess whether there is inducible myocardial ischemia. At some centers, a focused Doppler examination is also performed. We sought to determine the clinical value of this additional study by examining how often valvular flow abnormalities were identified that might affect clinical care. METHODS: We reviewed 1272 consecutive stress echocardiogram reports from a 1-year period, including 1223 tests that contained focused Doppler data. Important Doppler findings were defined as at least moderate mitral regurgitation, at least mild aortic regurgitation, any aortic or mitral valve stenosis, or any resting left ventricular outflow tract gradient. RESULTS: Overall, focused Doppler identified an important Doppler abnormality in 214 patients (17%). At least moderate mitral regurgitation was identified in 67 patients (5%) and at least mild aortic regurgitation was identified in 163 patients (13%). In addition, aortic stenosis (n = 14; 1%), mitral stenosis (n = 5; 0.4%), and resting outflow tract gradient (n = 2; 0.2%) were noted. A prior echocardiogram had been performed at our institution in 317 patients (26%). For this subset, a new important Doppler finding, a two-step change in regurgitant grade, or a one-step change in stenosis severity was noted in 28 patients (9%). Among patients who had a previous study, the prevalence of new findings was the same (9%) in those who had been studied within the previous year as in those whose previous study had been performed more than 2 years before. CONCLUSION: Focused Doppler documents valvular flow abnormalities in 17% of patients referred for stress echocardiography, thereby enhancing the potential overall value of the test. The frequency of new findings was independent of the time interval from the previous Doppler study. These data should be considered when clinicians choose a stress imaging modality.