Citations

Context.— Distinguishing pulmonary sarcomatoid carcinoma from pleural sarcomatoid mesothelioma is challenging because of overlapping histology, immunophenotype, and clinical features. Reliable immunohistochemical markers to aid in this distinction would be very valuable. Recent studies have proposed that MUC4 expression is common in sarcomatoid carcinoma but not in sarcomatoid mesothelioma, with the converse pattern reported for GATA3. Objective.— To further explore the utility of MUC4 and GATA3 in distinguishing pulmonary sarcomatoid carcinoma from sarcomatoid mesothelioma. Design.— Well-characterized cases of sarcomatoid carcinoma (n = 32) and sarcomatoid mesothelioma (n = 64) were included. Diagnoses were confirmed by thoracic pathologists with incorporation of immunophenotype, clinical, and radiographic features. Whole-tissue sections were stained for GATA3 and MUC4. Results.— Patients with sarcomatoid carcinoma and sarcomatoid mesothelioma had similar mean age and male predominance. GATA3 was positive in 63 of 64 sarcomatoid mesotheliomas (98%; 42 diffuse, 16 patchy, 5 focal), and 15 of 32 sarcomatoid carcinomas (47%; 3 diffuse, 8 patchy, 4 focal). MUC4 was positive in 2 of 64 sarcomatoid mesotheliomas (3%; 1 patchy, 1 focal), and in 12 of 32 sarcomatoid carcinomas (38%; 5 diffuse, 6 patchy, 1 focal). Conclusions.— Diffuse GATA3 expression favors sarcomatoid mesothelioma over sarcomatoid carcinoma, which rarely shows diffuse expression (sensitivity and specificity of diffuse staining 66% and 94%, respectively). Focal and patchy GATA3 expression is observed in both tumor types, and therefore is not helpful in this distinction. Sensitivity of MUC4 for sarcomatoid carcinoma was low in our cohort, positive in only 38% with frequent patchy staining, but it was quite specific.

AbstractSevere cases of COVID-19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID-19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo-capillary barriers. The authors performed a systematic literature review and random-effects meta-analysis to determine the potential value of MSC therapy for treating COVID-19-infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO2/FiO2 ratio, alveolo-capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources.Significance statement The potential benefits of mesenchymal stromal cell (MSC) therapy for patients with COVID-19 acute respiratory distress syndrome support the rapid commencement of clinical trials, as well as the compassionate use of MSCs that already have documented safety profiles from FDA-approved studies.

Objective To examine whether receiving a fecal occult blood test after a negative sigmoidoscopy reduced mortality from colorectal cancer. Methods We used a nested case–control design with incidence-density matching in historical cohorts of 1,877,740 50–90-year-old persons during 2006–2012, in an integrated health-system setting. We selected 1758 average risk patients who died from colorectal cancer and 3503 matched colorectal cancer-free persons. Colorectal cancer-specific death was ascertained from cancer and mortality registries. Screening histories were determined from electronic and chart–audit clinical data in the 5- to 10-year period prior to the reference date. We evaluated receipt of subsequent fecal occult blood test within five years of the reference date among patients with negative sigmoidoscopy two to six years before the reference date. Results Of the 5261 patients, 831 patients (204 colorectal cancer deaths/627 controls) had either negative sigmoidoscopy only ( n = 592) or negative sigmoidoscopy with subsequent screening fecal occult blood test ( n = 239). Fifty-six (27.5%) of the 204 patients dying of colorectal cancer and 183 (29.2%) of the 627 colorectal cancer-free patients received fecal occult blood test following a negative sigmoidoscopy. Conditional regressions found no significant association between fecal occult blood test receipt and colorectal cancer death risk, overall (adjusted odds ratio = 0.93, confidence interval: 0.65–1.33), or for right (odds ratio = 1.02, confidence interval: 0.65–1.60) or left-colon/rectum (odds ratio = 0.77, confidence interval: 0.39–1.52) cancers. Similar results were obtained in sensitivity analyses with alternative exposure ascertainment windows or timing of fecal occult blood test. Conclusions Our results suggest that receipt of at least one fecal occult blood test during the several years after a negative sigmoidoscopy did not substantially reduce mortality from colorectal cancer.

Purpose. Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. Results. Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm. Conclusions. Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.

Abstract Subtle differences in immune response may play a role in non-Hodgkin lymphoma (NHL) etiology. Because adult immune response may be influenced by early childhood exposures, we examined the role of childhood crowding, history of atopic disease, and other childhood immune-related exposures on the risk of non-Hodgkin lymphoma in a multi-center case-control study. Interviews were completed with 1,321 cases ascertained from population-based cancer registries in Seattle, Detroit, Los Angeles and Iowa, and with 1,057 frequency-matched controls, selected by random-digit dialing and from the Health Care Financing Administration (HCFA) database. The association between NHL risk in relation to atopy and other exposures was assessed using multivariable logistic regression methods. Most types of allergy were associated with protection from NHL, with hay fever especially protective against all NHL combined (Odds Ratio [OR] = 0.71, 95% confidence interval [CI]= 0.54–0.94), diffuse large B-cell lymphoma [DLBCL] (OR=0.61, 95% CI=0.41–0.91), and follicular lymphoma (OR=0.70, 95% CI=0.45–1.09). A history of eczema increased risk of follicular lymphoma (OR=1.92, 95% CI= 1.08–3.41) but not DLBCL (OR=1.06, 95% CI= 0.55.2.04). Asthma in childhood was not associated with risk of NHL. Risk of DLBCL (OR =1.72, 95% CI=1.17–2.52), but not follicular lymphoma (OR=1.15, 95% CI=0.75–1.76) was elevated for the youngest compared to the oldest of siblings. Neither number of siblings nor years between births of siblings were significantly associated with risk. These results suggest that some immune-related exposures may affect NHL risk.

Abstract Smoldering Waldenström’s Macroglobulinemia (SWM) is defined as a serum IgM monoclonal protein ≥3 g/dL and/or ≥10% bone marrow lymphoplasmacytic infiltration but no evidence of constitutional symptoms, symptomatic anemia, or hyperviscosity. Forty-eight patients with SWM were identified at Mayo Clinic from 1974 to 1995. Patients with a diagnosis of chronic lymphocytic leukemia or lymphoma or history of any antineoplastic therapy before diagnosis of SWM were excluded. The median age at diagnosis was 63 years (range 39–87 years). Only one patient (2%) was < 40 years of age, but 14 percent were < 50 years old. Thirty-two (67%) were men, and 16 (33%) were women. At diagnosis, hepatomegaly was noted in 10%, splenomegaly in 4%, and lymphadenopathy in 8%. The initial hemoglobin level ranged from 8.7 to 15.3 g/dL (median 11.8). The anemia in all 4 patients with an initial hemoglobin < 10 g/dL was due to other causes such as myelodysplastic syndrome, bronchopleural fistula, Barrett’s esophagus, and Coumadin administration. The initial leukocyte level ranged from 3.2 to 13.2 × 109/L (median 5.7), and platelets ranged from 101 to 578 × 109/L (median 285.5). Only one patient had a serum creatinine > 2.0 mg/dL and it was unrelated to SWM. The serum monoclonal protein level at the time of diagnosis ranged from 1.5 to 5.2 g/dL (median 3.3); 12 (25%) were < 3 g/dL, while 10 (21%) were ≥4 g/dL. IgM kappa accounted for 75%, IgM lambda 21%, and 2 (4%) were biclonal. Immunofixation of the urine was positive in 97% (kappa 80%, lambda 17%, indeterminate 3%) of those tested. The size of the urine M protein ranged from unmeasurable to 1.4 g/24h (median 0.04 g/24h). Serum albumin ranged from 2.5 to 4.3 g/dL (median 3.6). Five patients (10%) had an albumin value < 3 g/dL. Ten (26%) had a reduction of 1 uninvolved immunoglobulin, while 8 (21%) had a reduction of both IgG and IgA immunoglobulins. Lymphoplasmacytic infiltration of the bone marrow ranged from 3% to 80%, (median 30%). Three (6%) had less than 10% infiltration, while 13 (27%) had 50% or greater infiltration. The 48 patients were followed for a total of 292 (range 0.5 to 22.6 years; median 3.7) person-years, during which time 33 progressed to symptomatic WM and one to AL amyloidosis. The expected number of WM based on the SEER data was 0.004 cases. Thus, relative risk of progression to WM was increased 7,586-fold (95% CI, 5,083 to 10,373). The median time to progression was 4.6 years. The absolute risk of progression to WM was 6% at 1 year, 39% at 3 years, and 55% at 5 years. The median survival after progression to symptomatic WM was 5.1 years. Seventy-three percent of patients died, indicating a robust follow-up. We evaluated sex, hemoglobin level, size of serum M protein, reduction of uninvolved immunoglobulins, presence of urinary monoclonal light chains, serum albumin level, and the proportion of lymphoplasmacytic infiltration of the bone marrow as risk factors for progression. Significant risk factors for progression with univariate analysis included size of the serum M protein, hemoglobin level, reduction in uninvolved immunoglobulins, and degree of bone marrow lymphoplasmacytic cell infiltration. Multivariate modeling revealed that the size of the M protein and the degree of bone marrow infiltration were the most important risk factors. We conclude that smoldering WM is a distinct clinical entity that needs to be differentiated from IgM MGUS and symptomatic Waldenstrom’s Macroglobulinemia.

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is defined by a monoclonal protein concentration in serum of 3 g/dL or less and a proportion of plasma cells in the bone marrow of 10% or less, absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the proliferation of the monoclonal plasma cells. Two major questions remain unanswered: What proportion of patients with MGUS in the population is unrecognized clinically? What is the likely duration of MGUS at the time of its discovery? Methods: We examined the serum of 21,463 (77%) of the 28,038 enumerated residents of Olmsted County, Minnesota, in a population-based screening study and found that MGUS was present in 1.3% of persons 50 years of age and 3.8% of those 70 years of age. The risk of progression of MGUS to multiple myeloma (MM), primary amyloidosis (AL), Waldenstrom’s macroglobulinemia (WM), or related plasma cell disorders was 1% per year. Results: By age 70, only 21% of Olmsted County residents with MGUS, as determined by the prevalence study, had been recognized by routine clinical practice (Fig. 1). This is probably higher in Olmsted County than elsewhere because serum protein electrophoresis is frequently ordered on Mayo Clinic patients. The incidence of MGUS, estimated from the prevalence data, indicates onset of the condition long before clinical recognition. The duration of MGUS prior to detection at age 70 is shown in Fig. 2. Thus, 30% of patients recognized to have MGUS at age 70 probably had MGUS onset before age 50 and 55% had a prior (unrecognized) MGUS already by age 60. The median duration of MGUS prior to its recognition on the basis of clinical practice is 11 years (median). Linear extrapolation of the incidence curve implies a first appearance of MGUS around 30 years of age. Figure 1 Figure 1 Figure 2 Figure 2