Blood myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) are correlated with neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 436-436
Author(s):  
Iris Yeong- Fung Sheng ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Wei (Auston) Wei ◽  
Jaleh Fallah ◽  
...  

436 Background: MDSC have been linked to the chronic inflammatory microenvironment of tumor cells and pathologic outcomes in UC patients (pts) undergoing cystectomy. NLR is an established inflammatory biomarker with prognostic properties in mUC. We hypothesized that MDSCs correlate with NLR and OS in mUC. Methods: MDSCs were measured in blood samples from mUC patients by fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UC-MDSC: CD15-/CD14-). MDSC populations were presented as % of live nucleated blood cells from PB and absolute numbers from WB. Spearman’s correlation assessed correlations between MDSC & NLR. Kaplan Meier curves and log rank test estimated OS from the time of MDSC collection to last follow up or date of death. Results: Of 79 pts, 77% were men and 42% were never smokers with a median age of 69 (31-83). Overall, 71% had pure UC and 81% had lower tract UC. Prior therapies include intravesical therapy (22%), neoadjuvant chemotherapy (31%), and cystectomy/nephroureterectomy (61%). Median follow up was 12 months (range: 0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p≤0.001). Negative correlation was noted between NLR and WB UC-MDSC:PMN-MDSC ratios (rho = -0.27, p = 0.03), as well as NLR and PB UC-MDSC:PMN-MDSC (rho = -0.28, p = 0.02). Median survival was 17.7 months (95% CI: 11.0-NA months). Overall 1-yr and 3-yr survival were 0.60 (95% CI: 0.49-0.73) and 0.15 (95% CI: 0.03-0.67), respectively. Higher WB UC-MDSC levels were associated with shorter OS (HR 2.85, 95% CI: 1.43-5.65, p = 0.003). Conclusions: Specific MDSC subsets correlate with NLR. Higher WB UC-MDSC levels have negative prognostic roles for OS. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow up are needed.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 437-437
Author(s):  
Jaleh Fallah ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Wei (Auston) Wei ◽  
Iris Yeong- Fung Sheng ◽  
...  

437 Background: MDSCs play an important role in maintaining a tumor immunosuppressive microenvironment. The association of circulating levels of MDSCs with pCR (pT0N0) and outcomes was investigated in patients (pts) with non-metastatic UC undergoing cystectomy. Methods: Peripheral blood samples from pts with non-metastatic UC was collected. MDSCs were measured in freshly purified peripheral blood mononuclear cells, using flow cytometry. Total (T) MDSC was defined as CD33+/HLADR-. T-MDSC subtypes were polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+], and uncommitted (UC-MDSC: CD15-/CD14-]. MDSC populations were presented as % of live nucleated blood cells. Wilcoxon rank sum test was used to compare MDSCs between pCR groups. Kaplan-Meier and log-rank test were used to analyze RFS and OS. Results: MDSC data were available for 124 pts (106 male, 18 female), median age 68, 28 (23%) never smokers, 93 (75%) pure UC. Thirty four pts (27%) received intravesical BCG; 49 (39%) received neoadjuvant chemotherapy (NAC); 22 (19%) had pCR (pT0N0) following surgery. PMN-MDSC was the dominant subtype (42%) and frequency of UC-MDSC and M-MDSC was 40% and 17%, respectively. Circulating levels of T-MDSC and PMN-MDSC were significantly lower in pCR patients than those in non-pCR patients (Table). Sixteen deaths were observed and 21 pts recurred after surgery. The median follow-up time of patients alive was 18.7 months (range 0.3-42.4). The median OS or RFS of all patients was not reached. One-year and two-year OS rates were 94% and 83%, respectively. One-year and two-year RFS rates were 82% and 69%, respectively. There was no association between MDSC subtypes with OS or RFS. Conclusions: Total- and PMN-MDSC subtypes in blood were significantly correlated with pCR in pts with non-metastatic UC who undergo cystectomy. The relatively short follow-up may impact the association with RFS and OS; additional follow-up is needed. [Table: see text]


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4548-4548
Author(s):  
Moshe Chaim Ornstein ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Paul Elson ◽  
Samuel Haywood ◽  
...  

4548 Background: MDSC are potent immunosuppressive cells with prognostic implications in many solid tumors. We previously reported significant correlations between MDSC and clinicopathologic features in localized UC. We hypothesized that different MDSC populations may correlate with inflammatory biomarkers and clinicopathologic features in mUC. Methods: Peripheral blood samples were collected from 46 mUC pts. MDSCs were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations & clinicopathologic factors. Results: Of 46 pts:78% men, median age at diagnosis 69 (31-83), 33% never smokers, 76% pure UC, 76% bladder primary, 28% prior intravesical therapy, 35% prior neoadjuvant chemotherapy, 56% prior cystectomy, 83% overweight/obese. G-MDSC was the predominant subset in WB (43%) and PBMC (39%), although M-MDSC were almost equally predominant in PBMC (35%). There was a correlation between the WB and PBMC values of T-, I-, and M- MDSC (p≤0.05). Higher % WB I-MDSC correlated with lower blood neutrophil/lymphocyte ratio (NLR) (p = 0.009), while higher WB G-MDSC and %PBMC G-MDSC were associated with higher NLR (p = 0.03 and p = 0.02, respectively). Higher I-MDSC / G-MDSC ratio was associated with lower NLR (r = -0.35, p = .02) and with various clinicopathologic parameters. Conclusions: HigherI-MDSC / G-MDSC ratio correlates inversely with NLR, which is considered an inflammatory biomarker and had prognostic value in other studies. The mechanism of MDSC interaction with inflammatory response in mUC pts merits evaluation and is being investigated in a larger cohort of UC pts on chemotherapy or immunotherapy (with longer follow up).


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14204-e14204
Author(s):  
Masahiko Shibata ◽  
Daisuke Ujiie ◽  
Mai Ashizawa ◽  
Tomohiro Kikuchi ◽  
Hirokazu Okayama ◽  
...  

e14204 Background: Although a causal relationship for inflammation and immunity of cancer is more widely accepted today, the precise cell mechanisms mediating this relationship have not been elucidated. Accumulating evidence suggests that myeloid-derived suppressor cells (MDSC), may contribute to the negative regulation of immune responses during cancer and inflammation. IL-17 is a pro-inflammatory cytokine that is primarily secreted by T helper (Th)17 cells and we have reported that IL-17 correlates with immunosuppressive conditions in patients with cancer. Methods: PBMC (peripheral blood mononuclear cells) were harvested from 106 patients including 43 with gastric and 63 with colorectal cancer. PBMC were stimulated with PHA (phytohemagglutinin) and the production of IL-17 was measured by ELISA. MDSC were detected by flow cytometry (CD11b+,CD14-,CD33+). The levels of CRP (C-reacting protein) and NLR (neutrophil to lymphocyte ratio) were used as inflammatory markers. Results: Both of MDSC and IL-17 production were increased in patients with advanced stages, and correlated with each other, inflammatory markers and immune suppression. The patients were divided with average levels of MDSC and IL-17 production and the prognosis were analyzed with Kaplan-Meier method. The overall survival of patients with high MDSC or high IL-17 production were significantly worse than those with low MDSC or low IL-17 production, respectively, in patients with stages III and IV, although the differences were not significant in patients with stages I and II. Conclusions: Thus these inflammatory markers are closely related with systemic inflammation involving IL-17 and with immunosuppression driven by MDSC, and are effective prognostic indicators in patients with stages III and IV gastric and colorectal cancer.


Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Matthew M Grabowski ◽  
Balint Otvos ◽  
Tyler J Alban ◽  
Marcella Diaz ◽  
Justin D Lathia ◽  
...  

Abstract INTRODUCTION A potential barrier to successful immunotherapy response in glioblastoma (GBM) is myeloid-derived suppressor cells (MDSCs): an immature immunosuppressive cell elevated in the circulation and tumor of GBM patients. Given a limited set of biomarkers predictive of response to immunotherapy in GBM, we explored the change in MDSC levels with immunotherapy to predict treatment response. METHODS A retrospective analysis was performed on patients in a randomized, phase 2 study of nivolumab and bevacizumab at GBM first recurrence. Clinical and radiographic data were analyzed for disease progression or treatment response via Response Assessment in Neuro-Oncology (RANO) criteria. Blood was collected prior to treatment and at first imaging follow-up. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and analyzed. Characterization of circulating immune cells was performed using flow cytometry. RESULTS A total of 9 patients were identified as responders or nonresponders at a median time of 8.7 wk (range 6.9-10.0) after therapy initiation. MDSCs, as a percentage of total PBMCs, were elevated at baseline in responders compared to nonresponders (4.9% ± 0.7 vs 2.6% ± 0.2, P = .019), which reversed at follow up (1.8% ± 0.4 vs 5.8% ± 1.1, P = .032). There was a 6.4 fold decrease in MDSCs as a percentage of total PBMCs between baseline and first imaging follow-up in responders as compared to nonresponders (P = .001). When looking at subtypes of MDSCs, a 4.9 fold decrease in granulocytic MDSCs (G-MDSCs) was noted in responders over nonresponders (P = .010). Further investigation of this cohort by simultaneous single-cell analysis of transcriptome and surface epitopes is ongoing. CONCLUSION Differences in circulating MDSC levels that were specific to responders and nonresponders were seen both before and after therapy initialization, with decreases in MDSCs (specifically G-MDSCs) being correlated with treatment response. Characterization of MDSCs in the peripheral blood may be helpful in identifying GBM patients likely to benefit from immunotherapy.


2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 362-362 ◽  
Author(s):  
Moshe Chaim Ornstein ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Paul Elson ◽  
Samuel Haywood ◽  
...  

362 Background: MDSC are heterogeneous immunosuppressive cells with potential predictive/prognostic role in cancer. The association between MDSC, clinicopathologic factors and pathologic response in pts with UC merits evaluation. Methods: Peripheral blood and/or tissue was collected from 120 pts. MDSC were measured in fresh unfractionated whole blood (WB), in peripheral blood mononuclear cells (PBMC) and fresh tumor tissue. MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- ((T)otal MDSC). MDSC subsets were defined as LinloCD33+/HLADR- and (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-, CD11b+ ). MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors and pT0N0%. Results: Of 120 pts, 82 were non-metastatic: 58 had only blood, 23 had blood & tissue, 1 had only tissue available for analysis. Of these 82 non-metastatic pts, 70 were men, median age 68; 81 pts had primary UC histology, 1 small cell cancer, 24 had mixed UC histology; 24 had prior intravesical therapy, 34 had neoadjuvant therapy (79% cisplatin-based, 21% unknown), 4 pts had post-op recurrence. At cystectomy: 15/82 pT0, 22/82 pT3/4; 37/82 CIS; 8/78 pN+. Significant associations were seen between MDSC blood levels and mixed histology, CIS, pN+, and lower pT0N0% (Table). Tumor M-MDSCs were associated with pN+ (p=0.05). There was significant correlation between tumor and WB % M-MDSC (r=0.55, p=0.007), and tumor and WB % G-MDSC (r=0.46, p=0.03). Conclusions: Blood MDSC levels correlate with several clinicopathologic factors and may predict pathological complete response (pT0N0). Assessment of association between MDSC levels, outcome and immunotherapy response is ongoing including in metastatic pts. [Table: see text]


Swiss Surgery ◽  
2000 ◽  
Vol 6 (1) ◽  
pp. 6-10
Author(s):  
Knoefel ◽  
Brunken ◽  
Neumann ◽  
Gundlach ◽  
Rogiers ◽  
...  

Die komplette chirurgische Entfernung von Lebermetastasen bietet Patienten nach kolorektalem Karzinom die einzige kurative Chance. Es gibt jedoch eine, anscheinend unbegrenzte, Anzahl an Parametern, die die Prognose dieser Patienten bestimmen und damit den Sinn dieser Therapie vorhersagen können. Zu den am häufigsten diskutierten und am einfachsten zu bestimmenden Parametern gehört die Anzahl der Metastasen. Ziel dieser Studie war es daher die Wertigkeit dieses Parameters in der Literatur zu reflektieren und unsere eigenen Patientendaten zu evaluieren. Insgesamt konnte von 302 Patienten ein komplettes Follow-up erhoben werden. Die gebildeten Patientengruppen wurden mit Hilfe einer Kaplan Meier Analyse und konsekutivem log rank Test untersucht. Die Literatur wurde bis Dezember 1998 revidiert. Die Anzahl der Metastasen bestätigte sich als ein prognostisches Kriterium. Lagen drei oder mehr Metastasen vor, so war nicht nur die Wahrscheinlichkeit einer R0 Resektion deutlich geringer (17.8% versus 67.2%) sondern auch das Überleben der Patienten nach einer R0 Resektion tendenziell unwahrscheinlicher. Das 5-Jahres Überleben betrug bei > 2 Metastasen 9% bei > 2 Metastasen 36%. Das 10-Jahres Überleben beträgt bislang bei > 2 Metastasen 0% bei > 2 Metastasen 18% (p < 0.07). Die Anzahl der Metastasen spielt in der Prognose der Patienten mit kolorektalen Lebermetastasen eine Rolle. Selbst bei mehr als vier Metastasen ist jedoch gelegentlich eine R0 Resektion möglich. In diesen Fällen kann der Patient auch langfristig von einer Operation profitieren. Das wichtigere Kriterium einer onkologisch sinnvollen Resektabilität ist die Frage ob technisch und funktionell eine R0 Resektion durchführbar ist. Ist das der Fall, so sollte auch einem Patienten mit mehreren Metastasen die einzige kurative Chance einer Resektion nicht vorenthalten bleiben.


2021 ◽  
Vol 10 (10) ◽  
pp. 2213
Author(s):  
Alessia Scatena ◽  
Pasquale Petruzzi ◽  
Filippo Maioli ◽  
Francesca Lucaroni ◽  
Cristina Ambrosone ◽  
...  

Peripheral blood mononuclear cells (PBMNCs) are reported to prevent major amputation and healing in no-option critical limb ischemia (NO-CLI). The aim of this study is to evaluate PBMNC treatment in comparison to standard treatment in NO-CLI patients with diabetic foot ulcers (DFUs). The study included 76 NO-CLI patients admitted to our centers because of CLI with DFUs. All patients were treated with the same standard care (control group), but 38 patients were also treated with autologous PBMNC implants. Major amputations, overall mortality, and number of healed patients were evaluated as the primary endpoint. Only 4 out 38 amputations (10.5%) were observed in the PBMNC group, while 15 out of 38 amputations (39.5%) were recorded in the control group (p = 0.0037). The Kaplan–Meier curves and the log-rank test results showed a significantly lower amputation rate in the PBMNCs group vs. the control group (p = 0.000). At two years follow-up, nearly 80% of the PBMNCs group was still alive vs. only 20% of the control group (p = 0.000). In the PBMNC group, 33 patients healed (86.6%) while only one patient healed in the control group (p = 0.000). PBMNCs showed a positive clinical outcome at two years follow-up in patients with DFUs and NO-CLI, significantly reducing the amputation rate and improving survival and wound healing. According to our study results, intramuscular and peri-lesional injection of autologous PBMNCs could prevent amputations in NO-CLI diabetic patients.


2021 ◽  
pp. 1-9
Author(s):  
Leonard Naymagon ◽  
Douglas Tremblay ◽  
John Mascarenhas

Data supporting the use of etoposide-based therapy in hemophagocytic lymphohistiocytosis (HLH) arise largely from pediatric studies. There is a lack of comparable data among adult patients with secondary HLH. We conducted a retrospective study to assess the impact of etoposide-based therapy on outcomes in adult secondary HLH. The primary outcome was overall survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox proportional hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Ninety adults with secondary HLH seen between January 1, 2009, and January 6, 2020, were included. Forty-two patients (47%) received etoposide-based therapy, while 48 (53%) received treatment only for their inciting proinflammatory condition. Thirty-three patients in the etoposide group (72%) and 32 in the no-etoposide group (67%) died during follow-up. Median survival in the etoposide and no-etoposide groups was 1.04 and 1.39 months, respectively. There was no significant difference in survival between the etoposide and no-etoposide groups (log-rank <i>p</i> = 0.4146). On multivariable analysis, there was no association between treatment with etoposide and survival (HR for death with etoposide = 1.067, 95% CI: 0.633–1.799, <i>p</i> = 0.8084). Use of etoposide-based therapy was not associated with improvement in outcomes in this large cohort of adult secondary HLH patients.


2021 ◽  
Author(s):  
Rosa Agra Bermejo ◽  
Carla Cacho-Antonio ◽  
Eva Gonzalez-Babarro ◽  
Adriana Rozados-Luis ◽  
Marinela Couselo-Seijas ◽  
...  

Abstract Background: Inflammation is one of the mechanisms involved on heart failure (HF) pathophysiology. Thus, the acute phase reactant protein, orosomucoid, was associated with a worse post-discharge prognosis in de novo acute HF (AHF). However, the presence of anti-inflammatory adipokine, omentin, might protect and reduce the severity of the disease. We wanted to evaluate the value of omentin and orosomucoid combination for stratifying risk of these patients.Methods and Results: Two independent cohorts of patients admitted for de novo AHF in two centers were included in the study (n=218). Orosomucoid and omentin circulating levels were determined by ELISA at discharge. Patients were follow-up for 317 (3-575) days. A predictive model was determined for primary endpoint, death and/or HF readmission. Differences in survival were evaluated using a Log-rank test. According cut-off values of orosomucoid and omentin, patients were classified on UpDown (high orosomucoid and low omentin levels), equal (both proteins high or low) and DownUp (low orosomucoid and high omentin levels). The Kaplan Meier determined worse prognosis for the UpDown group (Long-rank test p=0.02). The predictive model that includes the combination of orosomucoid and omentin groups (OROME) + NT-proBNP values achieved a higher C-index=0.84 than the predictive model with NT-proBNP (C-index=0.80) or OROME (C-index=0.79) or orosomucoid alone (C-index=0.80). Conclusions: The orosomucoid and omentin determination stratifies de novo AHF patients in high, mild and low risk of rehospitalization and/or death for HF. Its combination with NT-proBNP improves its predictive value in this group of patients.


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