Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, ...death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.
Background
Although resection historically played a prominent role in the treatment of metastatic melanoma, recent advances have altered the therapeutic landscape, and potentially the role of ...surgery. We examined surgical selection and metastasectomy outcomes before and after the onset of the effective drug therapy era.
Methods
Patients with stage IV melanoma were identified and characterized by treatment era (either 1965–2007 or 2008–2015) and by systemic therapy agents. BRAF and/or MEK inhibitors, as well as checkpoint inhibitors, were included as modern agents. Selection factors for metastasectomy were examined by era. A matched-pair analysis of outcomes of surgical and non-surgical patients receiving modern systemic agents was performed.
Results
Among 2353 eligible patients, 1065 (45.2%) underwent surgical treatment. Factors associated with selection for metastasectomy in the early era included female sex, no prior stage III disease, single-organ involvement, and M1a (vs. M1c) disease (all
p
< 0.007). In the current era, the proportion of surgically treated patients increased modestly (54.5% vs. 44.7%,
p
= 0.02) and age was the only independent selection factor (
p
< 0.01). Surgery followed by modern therapy in 47 matched pairs was associated with higher 5-year melanoma-specific survival (MSS) versus modern therapy alone (58.8% vs. 38.9%,
p
= 0.049). Multivariable regression showed single-organ involvement (hazard ratio HR 0.43, 95% confidence interval CI 0.21–0.90,
p
= 0.02) and first-line surgery (HR 0.47, 95% CI 0.23–0.98,
p
= 0.04), as well as use of modern agents (HR 0.29, 95% CI 0.21–0.40,
p
< 0.001), were independently associated with improved MSS.
Conclusions and Relevance
While modern systemic agents have improved outcomes in stage IV melanoma, metastasectomy remains associated with favorable survival. Resection remains a viable therapeutic approach, possibly worthy of prospective evaluation.
Background
There are no definitive recommendations guiding amputation use in extremity soft tissue sarcomas (STSs). This study explores disparities in amputation rates and survival in patients with ...non-metastatic adult-type extremity STSs.
Methods
Patients with non-metastatic adult-type extremity STSs were identified from the 1998–2012 National Cancer Database. Factors affecting amputation were examined across all ages and separately in adults (> 40 years), adolescent/young adults (AYA: ages 15–39), and children (age < 15). Impact on 10-year overall survival (OS) was explored.
Results
Of 15,886 patients, 4.65% had an amputation. AYAs had the most amputations (6.4%) compared to children (5.9%) and adults (4.2%) (
p
< 0.001). Patients with public insurance (OR 1.3, CI 1.08–1.58) and from central states (OR 1.5, CI 1.2–1.86) were more likely to undergo amputation, whereas those from high income brackets (OR 0.8, CI 0.62–0.94) and treated at community cancer centers were less likely (OR 0.7, CI 0.62–0.90). Amputation was an independent risk factor for death at 10 years, with the greatest impact in AYAs compared to older adults (HR 1.7,
p
< 0.001). Treatment in eastern or central states, lower income, lack of private insurance, and comorbidities were all associated with decreased OS (all
p
< 0.05). Female gender (HR 0.8, CI 0.78–0.89) and high-volume centers (HR 0.8, CI 0.74–0.94) were associated with improved OS.
Conclusions
Although amputations for extremity STSs are rare, disparities exist across age groups, insurance and geography when it comes to the use of amputation in patients with extremity STSs. Moreover, having an amputation is an independent risk factor for death, with the greatest impact in AYAs.
Pancreatic tumors are being discovered more frequently secondary to the widespread use of cross-sectional imaging for diagnostic purposes. Because this is the most prevalent subtype of pancreatic ...malignancies, the recommended management of this disease has been well standardized. The patient subsequently underwent distal pancreatectomy with final pathology demonstrating UC-OGC. 4 We describe the diagnosis and management of a patient with UC-OGC which was discovered on a PET scan performed for staging of a newly diagnosed marginal B-cell lymphoma. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Background Disconnected pancreatic duct syndrome (DPDS) typically complicates acute necrotizing pancreatitis (ANP) and presents as a pseudocyst months after the initial episode of pancreatitis. ...However, our experience suggests that the presentation of DPDS may be quite varied and might require significant evaluation and judgment before surgical intervention. We sought to determine the presentations of DPDS and assess the management of the various forms of presentation. Study Design A retrospective review of all patients with DPDS between July 2005 and June 2011 was performed. Patients were included when CT scan demonstrated a clear disconnected pancreas that was confirmed at operation. Medical records were reviewed in detail to determine clinical presentation, management, and outcomes. Results Of the 50 patients identified, 66% were male, with a mean age of 53 ± 16 years. Mortality was 2% and 3 patients (6%) required late reoperation. The DPDS presented in 3 forms: diagnosed concurrently with ANP (concurrent DPDS; n = 28); delayed presentation with a pseudocyst (delayed DPDS; n = 15); and as a consequence of chronic pancreatitis (CP) (CP DPDS; n = 7). Concurrent DPDS was treated with necrosectomy including body/tail resection within 60 days of onset and complicated by a grade B/C fistula in 36%. Delayed DPDS required distal pancreatectomy 440 days after diagnosis, with a 7% fistula rate. Chronic pancreatitis DPDS was treated with lateral pancreatojejunostomy at 417 days with no fistulas. Conclusions Disconnected pancreatic duct syndrome presents concurrently with ANP, in a delayed fashion, or infrequently in the setting of CP. Prompt recognition and classification with appropriate operative therapy results in low mortality and nonoperatively managed pancreatic fistulas.
Background
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy for which surgery is the mainstay of treatment and for which adjuvant radiation is infrequently employed; however, small, ...single-institution series suggest adjuvant radiation may improve outcomes.
Methods
All patients with non-metastatic ACC treated with either surgery alone or surgery followed by adjuvant radiation were identified in the 2004–2013 National Cancer Database. Factors associated with receipt of radiation and the impact of adjuvant radiation on survival were determined by multivariable analysis.
Results
Of 1184 patients, 171 (14.4%) received adjuvant radiation. Patient demographics were similar between the two groups, but those receiving radiation were more likely to have had positive margins following surgery (37.4 vs. 14.6%;
p
<
0.001), evidence of vascular invasion (14.0 vs. 5.1%;
p
=
0.05), and receive concurrent chemotherapy (57.3 vs. 28.8%;
p
<
0.001). After adjustment for tumor and other treatment factors, only positive margins following surgery was associated with an increased likelihood of receiving adjuvant radiation (odds ratio 3.84, 95% confidence interval CI 1.95–7.56). Radiation therapy did not confer a difference in median overall survival in the general cohort. However, for patients with positive margins, adjuvant radiation was associated with a 40% decreased yearly risk of death after adjustment for concurrent chemotherapy (hazard ratio 0.60, 95% CI 0.40–0.92;
p
=
0.02). This survival advantage was not evident for other traditional high-risk features.
Conclusion
Adjuvant radiation appears to decrease the risk of death in ACC patients with positive margins following surgical resection, but only a small percentage are currently receiving radiation. Multidisciplinary treatment with surgery and radiation should be considered for these patients.
Background
Neoadjuvant chemotherapy (NAC) is increasingly utilized to optimize survival in proximal pancreatic adenocarcinoma. However, few studies have explored the impact of NAC in distal pancreas ...cancer.
Methods
Patients with resectable pancreatic adenocarcinoma of the body or tail treated with either upfront pancreatectomy or NAC followed by surgery were identified in the 2006–2014 National Cancer Database. Trends in utilization, predictors of use, and impact of NAC on overall survival were determined.
Results
Of 1485 patients, 176 (11.9%) received NAC. Use of NAC increased from 9.3% in 2006 to 16.9% in 2013 odds ratio 1.14; 95% confidence interval (CI) 1.05–1.24;
p
= 0.001. NAC patients were younger, had higher clinical stage, and preoperative CA 19-9 levels (all
p
< 0.05). After adjustment for patient-, tumor-, and treatment-related factors, increased clinical stage was the greatest independent predictor of neoadjuvant approach (
p
< 0.001). On multivariable analysis, survival benefit from NAC did not reach threshold of significance (95% CI 0.66–1.04;
p
= 0.10) for the entire cohort. However, NAC was associated with a significant survival advantage in clinical stage III with a 51% decreased yearly risk of death (adjusted hazard ratio 0.49; 95% CI 0.25–0.98;
p
= 0.04). A trend towards improved survival with NAC was observed among stage IIA (
p
= 0.09) and IIB (
p
= 0.07) patients.
Conclusions
Neoadjuvant chemotherapy is associated with improved overall survival in Stage III distal pancreatic adenocarcinoma and shows promise in earlier stage disease. However, only a small percentage of patients receive NAC. Prospective evaluation of NAC in distal pancreatic adenocarcinoma is warranted based on these findings.
Current guidelines recommend excisional/complete biopsy for melanoma diagnosis, owing to high rates of residual disease found at wide local excision (WLE) after partial biopsy techniques. We sought ...to determine any survival disadvantage associated with the presence of residual invasive melanoma in the WLE after diagnosis with a partial biopsy technique.
Data were examined from Multicenter Selective Lymphadenectomy Trials I and II (MSLT-I and -II), 2 large melanoma trials. Patients diagnosed with excisional/complete biopsy were excluded. Clinicopathologic characteristics, melanoma-specific survival (MSS), distant disease-free survival (DDFS), and disease-free survival (DFS) of those with residual invasive melanoma in the definitive WLE and those with no residual melanoma were compared. Matched pairing was used to reduce variability between groups.
From 1994 through 2014, 3,939 patients were enrolled in these trials and 874 (22%) were diagnosed using partial biopsy techniques. Of these, 399 (46%) had residual tumor in the WLE. Only 6 patients had residual tumor in their WLE resulting in T-upstaging of their tumor. Match-pairing formed two cohorts (1:1) of patients with and without residual invasive tumor after WLE. A total of 514 patients were paired; 288 (56%) males, 148 (28.8%) aged 60 or older, 192 (37.4%) with truncal melanomas, 214 (41.6%) had Breslow thickness 2 mm or greater, and 376 (73.2%) had positive sentinel nodes. Kaplan-Meier analysis showed no statistical difference in 10-year MSS (73.6% ± 3.3% vs 73.9% ± 3.7%, p = 0.891), DDFS (68.7% ± 3.4% vs 65.3% ± 4.0%, p = 0.548), or DFS (59.6% ± 3.7% vs 59.4% ± 3.9%, p = 0.783).
Survival in patients with primary melanoma does not appear to be worse in patients who undergo a partial biopsy technique and are later found to have residual invasive tumor in the WLE specimen.
Background and Objectives
Melanoma mutational burden is high and approximately 50% have oncogenic mutations in BRAF. We sought to evaluate age‐related mutational differences in melanoma.
Methods
We ...analyzed melanoma samples in the Genomics Evidence Neoplasia Information Exchange database. Targetable mutations were identified using the Precision Oncology Knowledge Base (OncoKB).
Results
We found 1194 patients with a common set of 30 genes. The top mutated genes in patients <40 years old (y/o) (n = 98) were BRAF (59%), TP53 (31%), NRAS (17%), and PTEN (14%); in 40–59 y/o (n = 354) were BRAF (51%), NRAS (30%), TP53 (26%), and APC (13%); and in ≥60 y/o (n = 742) were BRAF (38%), NRAS (33%), TP53 (26%), and KDR (19%). BRAF mutations were almost mutually exclusive from NRAS mutations in <40 y/o (58/59). Mutational burden increased with age, with means of 2.39, 2.92, and 3.67 mutations per sample in patients <40, 40–59, and ≥60 y/o, respectively (p < 0.0001). There were 10 targetable mutations meeting OncoKB criteria for melanoma: BRAF (level 1), RET (level 1), KIT (level 2), NRAS (level 3A), TP53 (level 3A), and FGFR2, MET, PTEN, PIK3CA, and KRAS (level 4).
Conclusions
Mutations in melanoma have age‐related differences and demonstrates potential targetable mutations for personalized therapies.
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