bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes with immune checkpoint inhibitor use in lung cancer patients with hepatic metastases.
Authors: Addepalli Srikala , Stroud Chipman Robert Geoffrey , Cherukuri Sulochana Devi , Cherry Cynthia R. , Sharma Nitika , Parent Teresa , Hardin Jessica , Walker Paul R. 
Published: November 2019

38 Background: Immune checkpoint inhibitors have shown promising responses in advanced lung cancer as well as a number of other malignancies. However, efficacy appears to be variable based on the site of disease. We reviewed the outcomes of patients with lung cancer and hepatic metastases from a single institution. Methods: We performed a retrospective analysis of the lung cancer patients treated at East Carolina University with the PD1 inhibitor Nivolumab. Patients were enrolled in an IRB approved study designed to evaluate predictive markers of response to immune checkpoint blockade. Clinical characteristics, laboratory data, and imaging studies were analyzed and recorded. Results: Data for 75 patients with lung cancer who received anti-PD1 therapy was analyzed. Of the 75 patients included, 13% (n = 9) had liver metastases. Average age of the patients was 61.8 years, 66% patients were male, 22% had squamous cell, 33% had adenocarcinoma and 44 % small cell neuroendocrine histology. Average number of prior therapies was 1.7 (range 1-4). Thirty three percent of patients had modified Glasgow prognostic score of 2 and a mean CRP of 63.61mg/L (range 0.1-172.7mg/ L) at the initiation of anti-PD1 therapy. They received an average of 4 cycles of anti-PD1 therapy. Forty four percent of patients received adjunctive therapy such as ablative radiation (33%) or immune modulating chemotherapy with the aim of augmenting the effect of the anti-PD1 therapy. None of the analyzed patients with liver metastases had an objective decrease in liver metastases and the average survival in these patients after starting anti-PD1 therapy was 132 days. Conclusions: To our knowledge, this study is the largest reported series examining patients with hepatic metastases from lung cancer treated with PD-1 inhibitors. Our observations are consistent with prior reports indicating poor outcomes with anti-PD1 therapy in patients with liver metastases. The mechanisms underlying such resistance must be elucidated so that more effective treatment combinations can be developed.
Correlation of PD-L1 expression with p16INK4A expression in nonoropharyngeal head and neck squamous cell carcinoma.
Authors: Chen San-Chi , Chang Peter , Wang Hsiao-Jung , Tai Shyh-Kuan , Chu Pen-Yuan , Yang Muh-Hwa 
Published: November 2019

39 Background: The expression of PD-L1 expression is important for tumor cells to evade the immune system. The level of its expression and its correlation to disease prognosis is unclear in non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC). Methods: A retrospective clinicopathologic analysis was performed for 106 non-OPHNSCC patients diagnosed during the period from 2007 to 2014. We made tissue arrays from the paraffin-embedded non-OPHNSCC samples obtained from the patients, and studied PD-L1 and p16INK4A expression by immunohistochemistry. Systemic inflammatory factors including C-reactive protein, serum white blood cell, neutrophil, monocyte, and lymphocyte count were also analyzed to study the correlation. Results: We found that PD-L1 was overexpressed in 32.1% (34/106) and p16INK4A in 20.8% (22/106) of the patients who were studied. The expression of PD-L1 was associated with p16INK4A expression ( p < 0.01), but was not associated with the level of systemic inflammatory factors. No significant prognostic values of PD-L1, p16INK4A, or other clinicopathologic factors were found except tumor stage (stage I/II vs. III/IV, p=0.03). Conclusions: This study demonstrates the correlation between PD-L1 and p16INK4A in non-OPHNSCC, which may provide important information for designing the clinical trials of anti-PD1/PDL1 treatment in head and neck cancer patients. [Table: see text]
Association of soluble PD-L1 (sPD-L1) with decreased survival in metastatic melanoma.
Authors: Dronca Roxana Stefania , Harrington Susan , Jegapragasan Mithulan , Kottschade Lisa A. , Nevala Wendy Kay , Enninga Elizabeth Ann , Markovic Svetomir , Dong Haidong 
Published: November 2019

4 Background: Membrane expression of PD-L1 on tumor cells is associated with poor survival in patients with advanced malignancies including metastatic melanoma (MM). In addition, tumor-associated PD-L1 has been proposed as a predictor of response to anti-PD-1 therapy, although responses are observed in some cases of PD-L1 negative MM. We hypothesize that tumor-derived PD-L1 has additional systemic effects through the release of biologically active soluble forms of PD-L1 (sPD-L1) into the circulation, which further impedes the anti-tumor immune response and contributes to poor clinical outcomes in MM. Methods: We developed a sPD-L1 ELISA and biochemically confirmed the identity of the detected protein. We measured the levels of sPD-L1 in 276 patients with MM enrolled on 3 clinical trials who had stored pre-treatment plasma samples and 37 healthy volunteers (HV) undergoing blood donation at Mayo Clinic. We also measured sPD-L1 in baseline samples from 38 MM patients treated with anti-PD1 (pembrolizumab) 2 mg/kg every 3 weeks. ROC analysis was used to compute sPD-L1 concentration cut-off value and Wald test was used to asses the difference of overall survival (OS) in patients with low versus high sPD-L1 concentration. Results: We found that sPD-L1 levels were significantly elevated in MM patients compared with HV (p=0.0011). Mean sPD-L1 level in MM was 1.73 ng/mL (range: 0.13-18.29) compared with 0.77 ng/mL (range: 0.11–6.02) for HV. Patients with higher levels (>0.293 ng/mL) had a median OS of 11.3 months compared to 14.8 months for patients with sPD-L1 level ≤ 0.293 ng/mL (p=0.040). Similarly to tumor-related PD-L1 findings, patients who had clinical benefit (OR/PR/SD) after 4 cycles of anti-PD1 had higher sPD-L1 levels at baseline (2.1 vs. 1.1 ng/mL). Conclusions: To our knowledge, our study is the first to report a correlation of sPD-L1 with MM patient outcome, although a larger study is needed to establish the utility of sPD-L1 as an independent prognostic and possibly predictive biomarker.
The difference in prognostic value of tumour-infiltrating T cells according to adjuvant chemotherapy in radiochemonaïve gastroesophageal cancer.
Authors: Svensson Maria Christina , Berntsson Jonna , Hedner Charlotta , Borg David , Nodin Bjorn , Leandersson Karin , Krzyzanowska Agnieszka , Bjartell Anders , Eberhard Jakob , Jirstrom Karin 
Published: November 2019

41 Background: Several studies have demonstrated a beneficial prognostic impact of tumour-infiltrating lymphocytes (TILs) in oesophageal and gastric adenocarcinoma, but whether this association differs according to adjuvant chemotherapy has not been reported. Herein, we examined the prognostic impact of different TIL subsets according to adjuvant chemotherapy in these cancer types. Methods: Immunohistochemistry was applied to assess the density of T cells (CD3+, CD8+, FoxP3+) and natural killer (NK)/T cells (CD56+) in radiochemonaïve tumors from a consecutive cohort of 174 patients with resected oesophageal or gastric adenocarcinoma. Cox proportional hazard’s modelling was applied to examine the impact of the investigated markers on time to recurrence (TTR) and overall survival (OS). Results: Dense infiltration of CD3+, CD8+, and FoxP3+ cells were all associated with a significantly prolonged TTR in univariable Cox regression analysis (hazard ratio[HR] = 0.57; 95% confidence interval [CI] 0.37-0.89; HR = 0.31, 95% CI 0.13-0.77, and HR = 0.44, 95% CI 0.28-0.68). This association remained significant for CD8+ and FoxP3+ cells in multivariable analysis, adjusted for age, tumour location, TNM stage, differentiation grade, resection margin and adjuvant chemotherapy ( HR = 0.30, 95% CI 0.11-0.77, and HR = 0.52, 95% CI 0.32-0.84), and borderline significant for CD3+ cells (HR = 0.63, 95% CI 0.39-1.02). Similar associations were observed for all markers in relation to OS. Notably, analysis in strata according to adjuvant chemotherapy revealed that none of the investigated lymphocyte subsets carried prognostic information in patients having received treatment (n = 13; 7.5%), with a significant treatment interaction between CD3+ and CD8+ cells and adjuvant chemotherapy (pinteraction0.035 and 0.021). Conclusions: These results confirm the prognostic value of a high density of TILs in gastroesophageal adenocarcinoma, but also indicate that adjuvant chemotherapy is only beneficial in patients with tumors displaying a low density of TILs. These results are of potential clinical relevance and need to be confirmed in additional, preferentially randomized, studies.
Immunosenescence and cancer immunotherapy.
Authors: Pawelec Graham P. 
Published: November 2019

42 Background: Geriatric oncology, important for the ever-increasing numbers of elderly cancer patients, has thus far focused primarily on tolerance to chemotherapy. With the advent of breakthrough immunomodulatory antibody treatments relying on the patient´s own immune system to control the tumor, the issue of immunosenescence becomes extremely important. There is increasingly a valid concern that anti-cancer immunity may be compromised in the elderly due to i) their low amounts of naïve T-cells (leading to holes in the repertoire for neoantigens) and ii) “exhaustion” of potentially tumor-specific memory T-cells. Encouragingly, but only anecdotally, accumulated clinical experience (thus far, limited to melanoma treated with anti-CTLA-4 antibodies) suggests that advanced aged does not result in decreased responses or increased side effects. However, the fraction of patients experiencing clinical benefit was low, and broader and more detailed studies focusing on the age question are required. Methods: In our own work, we have established prognostic phenotypic and functional “immune signatures” using peripheral blood from younger melanoma and breast cancer patients, which comprise phenotypic T-cell and myeloid-derived suppressor cell quantification and measurement of pro- and anti-inflammatory CD4+ and CD8+ T-cell responses to shared tumor antigens such as NY-ESO-1 and Her2 in vitro using intracytoplasmic flow cytometry to detect 6 cytokines simultaneously. Results: We found that these peripheral immune signatures were equally prognostic in older patients ( > 80 years of age). Conclusions: We therefore conclude that immunosenescence should not be a barrier to anti-tumor immunity in elderly people treated with immunomodulatory antibodies, at least for responses targeting shared tumor antigens. It remains to be established whether responses to tumor neoantigens are compromised by immunosenescence. Given the current emphasis on neoantigen responsiveness, this remains a concern.
The prognostic impact of tumor-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite.
Authors: Berntsson Jonna , Svensson Maria Christina , Leandersson Karin , Nodin Bjorn , Krzyzanowska Agnieszka , Bjartell Anders , Eberhard Jakob , Jirstrom Karin 
Published: November 2019

47 Background: Several studies report dense infiltration of tumour-infiltrating T cells and natural killer cells to be associated with an improved prognosis in colorectal cancer (CRC); but whether these associations differ by tumour location remain unknown. This study investigated the prognostic impact of immune cell infiltration in CRC, with particular reference to the anatomical subsite of the primary tumour. Methods: Immunohistochemical expression of CD3, CD8, FoxP3, and CD56 was analysed in tissue microarrays with tumours from 557 incident CRC cases from a prospective population-based cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. Results: In the entire cohort, dense infiltration of all the investigated immune cells correlated significantly with an improved 5-year OS in both univariable and multivariable analysis, adjusted for age, TNM stage, differentiation grade, and vascular invasion. Dense infiltration of CD3+ and CD8+ cells were independent favourable prognostic factors for tumours in the right colon (hazard ratio [HR] = 0.53, 95 % confidence interval [CI] 0.29-0.95 and HR = 0.35, 95% CI 0.19-0.65, respectively), but not in the left colon or rectum. When microsatellite instability status was included in the adjusted model, only CD8+ cells remained an independent favourable prognostic factor in right-sided tumours. Dense infiltration of FoxP3+ cells was an independent favourable prognostic factor for tumours in the rectum (HR = 0.54, 95% CI 0.30-0.99), but not in the right or left colon. Infiltration of CD56+ cells did not carry any independent prognostic impact after stratifying for primary tumour site. Conclusions: The results from this study demonstrate that the prognostic impact of certain T cell subsets in CRC differs by primary tumour site, being most evident in right-sided tumours. These findings indicate that tumour location may be an important factor to take into consideration in therapeutic decisions, including eligibility for immunotherapy.
Potential role of hypovitaminosis D in renal cell carcinoma patients treated with immune-checkpoint inhibitors.
Authors: Bersanelli Melissa , Vaglio Augusto , Sverzellati Nicola , Galetti Maricla , Incerti Monia , Parziale Raffaele , Corrado Michele , Cosenza Agnese , Ferri Leonarda , Leonardi Francesco , Buti Sebastiano 
Published: November 2019

50 Background: hypovitaminosis D is frequent in renal diseases but it was never reported in metastatic renal cell carcinoma (mRCC). The interaction between vitamin D and its receptor (VDR) has a key role for T-cell activation. Naïve T-cells do not express VDR and had very low expression of phospholipase C-γ1 (PLC-γ1), with low responsiveness to T-cell receptor (TCR). Initial TCR signaling induces VDR expression and upregulates PLC-γ1 via the kinase p38 pathway. VDR interaction with high concentrations of vitamin D and PLC-γ1 increase are required to trigger classical TCR signaling, increasing T-cell responsiveness. On these basis, we hypothesized that hypovitaminosis D could contribute to lower responsiveness to immune-checkpoint inhibitors (CKI). Methods: we assessed vitamin D levels of mRCC patients undergoing therapy with CKI, with the aim to reveal hypovitaminosis D, evaluate its prevalence and hypothesize its potential role in the outcome of treatment with CKI. Results: of 10 mRCC patients pretreated with tyrosine-kinase inhibitors, vitamin D levels assessed before the first treatment with nivolumab (anti-PD1 CKI) revealed deficiency in 80% of cases (8 patients). Hypovitaminosis D was severe ( < 20 ng/ml) in 7 cases and moderate ( < 30 ng/ml) in one. The 2 patients without deficiency (20%), had vitamin D values near to the lower limit of normality. Oral supplementation with cholecalciferol was given when necessary, likely confounding the possible influence of vitamin D deficiency on the outcome of CKI treatment. Vitamin D normal values after two months of therapy were recovered in the great majority of cases. Interestingly, the only patient who achieved a good objective response to treatment had normal values of vitamin D before therapy. Conclusions: hypovitaminosis D could have a relevant prevalence in mRCC patients. Considering the role of vitamin D in T-cell activation, assessment of its levels and initiation of a supplementation before immunotherapy should be considered to enhance responsiveness. On the basis of these observations, we are planning a perspective multicenter study to investigate the role of hypovitaminosis D in mRCC patients treated with CKI (PRoviDenCe study).
Skin test results with common and melanoma antigens compared to clinical outcomes of melanoma patients treated with intralesional (IL) dinitrochorobenzene (DNCB) or IL bacillus Calmette-Guerin (BCG).
Authors: Cohen Max H. , Herberman: Deceased Ronald B. 
Published: November 2019

59 Background: In a previous study involving in vitro serial testing in patients receiving IL BCG or IL DNCB we determined that measurements of serial in vitro phytohemagglutinin stimulation levels correlated with the patients’ clinical courses. The current evaluation attempted to determine which in vivo skin test studies were useful in this setting. Methods: All patients had locally progressive melanoma satellosis, or in-transit metastases, but no evidence of distant metastasis past regional lymph nodes. Patients had been randomized to repeatedly receive either IL BCG (9 patients), or IL DNCB (9 patients) into cutaneous or subcutaneous metastases. A "BCG worse outcome group" consisted of 6 patients in whom distant metastasis was detected within 2 to 20 months, and who died within 9 to 24 months. A "BCG better outcome group" consisted of 3 patients who were alive and in whom no distant metastases were detected after 12 to 39 months. Similarly, the 9 patients randomized to be treated with intralesional DNCB were also subsequently divided into two groups: A "DNCB worse outcome group" consisted of 6 patients in whom distant metastasis was detected within 5 to 11 months, and who died within 6 to 12 months. A "DNCB better outcome group" consisted of 3 patients who were alive and in whom no distant metastases were detected after 8 to 20 months. Following informed consent, patients were serially skin tested, as possible, with Purified Protein Derivative antigen (PPD), Mumps antigen, Streptokinase/Streptodornase (SKSD), and inactivated melanoma extracts, using coded syringes. Results: In comparing the two "better outcome" groups with the two "worse outcome" groups, patients who prior to treatment had a positive reaction to melanoma extracts appeared to fare better than those who did not. All patient groups tended to react positively to SKSD, a general sign of immune capability. Conclusions: Among the skin tests compared, testing with melanoma extract appeared to correlate best with clinical courses in patients undergoing BCG or DNCB intralesional treatments for progressive melanoma satellosis or in-transit metastases.
Concordance of tumor and immune cell staining with Ventana SP142, Ventana SP263, Dako 28-8 and Dako 22C3 PD-L1 tests in NSCLC patient samples.
Authors: Scott Marietta , Ratcliffe Marianne J , Sharpe Alan , Barker Craig , Scorer Paul , Rebelatto Marlon , Al-Masri Hytham , Walker Jill 
Published: November 2019

7 Background: PD-1/PD-L1 directed antibodies are emerging as effective therapeutics in multiple oncology settings. Multiple diagnostic PD-L1 tests are being used to understand how PD-L1 expression predicts response to these therapies. It is vital to compare these assays to understand the risk if assays are used interchangeably. Tumor cell (TC) PD-L1 expression by the Ventana SP263 and the Dako 28-8 and 22C3 assays has proven concordant at multiple clinically relevant cut offs.(Ratcliffe et al AACR 2016 [LB-094]); (Ratcliffe et al ESMO 2016 [955PD]). The current study builds on the previous study by inclusion of immune cell (IC) scoring and the Ventana SP142 assay. Methods: 493 tumor biopsy samples from NSCLC patients stained with the Ventana SP263 and Dako 22C3 and 28-8 were scored for IC PD-L1 expression, calculated as % of infiltrating IC expressing PD-L1 at any intensity. A subset of 200 tumor blocks from this cohort were sectioned and stained with SP142 and serial sections restained with SP263 to ensure an appropriate comparison. Concordance between IC and TC between these 2 assays is reported. Results: There was strong agreement in IC scoring with the Ventana SP263 and Dako 22C3 and 28-8 assays. The SP142 assay showed lower concordance for IC and reduced TC PD-L1 staining/concordance vs SP263 (Table). Conclusions: This study shows analytical similarity between the Ventana SP263, Dako 28-8 or 22C3 assays when measuring TC or IC PD-L1 expression, and high concordance between patient classification at matching TC or IC cut offs. This strengthens the evidence that these 3 assays could be used interchangeably. The Ventana SP142 assay shows clear analytical differences for both IC and TC staining, suggesting it is not appropriate to interchange with the other assays. [Table: see text]
Analysis of hybridoma and CHO-derived pritumumab for therapeutic applications.
Authors: Babic Ivan , Mukthavaram Rajesh , Jiang Pengfei , Nomura Natsuko , Glassy Eric , Glassy Mark Charles , Kesari Santosh 
Published: November 2019

71 Background: Pritumumab, a natural huma IgG1 kappa antibody was obtained from a regional draining lymph node of a patient with cervical carcinoma through traditional hybridoma technology. Methods: Both cell lines and tissues were processed and analyzed for FACS analysis, Western blots, and immunohistochemistry. Results: Specificity analysis of the target antigen, an altered form of vimentin (ecto-domain vimentin (EDV)) shows it to be limited to cell surface expression on cancer cells. Clinically, 249 Japanese brain cancer patients were treated with a low dose pritumumab regimen, either at 1mg once a week or 1mg twice a week, and overall response rates of between 25-30% were seen with several complete and partial responses. A recombinant version of the mAb was made using the GPEx system in CHO cells. In a series of comparable studies the CHO mAb was compared with the original hybridoma. Binding specificity with both flow cytometry and immunohistochemical (IHC) analysis, Western blot analysis, and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) activity confirms the comparability of the two versions. IHC analysis suggests restricted binding to tumor cells and not normal cells and tissues. Further studies include establishing a xenograft model with both SCID and athymic nude mice in which pritumumab was effective in preventing tumor growth in nude mice but not in SCID mice. Analysis of a blood brain barrier model suggests pritumumab shows minimal distribution in normal brain tissues and significant binding in tumor areas of brain tissues indicating the mAb crosses the tumor brain barrier. Conclusions: Overall, these data together suggest pritumumab is suitable for development as an anti-tumor therapeutic.
Avelumab in chemotherapy-refractory metastatic Merkel cell carcinoma: Subgroup analysis of efficacy.
Authors: Kaufman Howard L. , Russell Jeffrey , Hamid Omid , Bhatia Shailender , Terheyden Patrick , D'Angelo Sandra P. , Shih Kent C. , Lebbe Celeste , Linette Gerald P , Milella Michele , Brownell Isaac , Lewis Karl D. , Lorch Jochen H. , von Heydebreck Anja , Mahnke Lisa , Nghiem Paul 
Published: November 2019

80 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. In a phase 2 trial in previously treated metastatic MCC (mMCC; JAVELIN Merkel 200, NCT02155647), avelumab, a fully human IgG1 anti–PD-L1 antibody, showed durable responses and a manageable safety profile, including confirmed objective response rate (ORR) of 31.8% (95.9% CI 21.9-43.1), 6-mo duration of response (DOR) rate estimate of 92%, and 6-mo progression-free survival (PFS) rate of 40% (95% CI 29-50). We report post-hoc subgroup analyses from this trial. Methods: Pts with mMCC and prior disease progression on chemotherapy received avelumab 10 mg/kg (1h IV) Q2W. Tumors were assessed every 6 wks (RECIST v1.1) by independent review. Kaplan-Meier method was used to estimate 6-mo DOR and PFS rate. Results: 88 pts were treated with avelumab and followed for ≥ 6 mos (data cutoff Mar 3, 2016). Responses occurred in all subgroups analyzed (Table). Trends of higher ORR and 6-mo PFS rates were seen in pts with fewer prior lines, lower disease burden (sum of target lesion diameters), or PD-L1+ tumors. 6-mo response durability was similar across evaluable subgroups. Conclusions: In post-hoc analyses, avelumab showed durable efficacy across subgroups. This trial is enrolling treatment-naive pts with mMCC to receive 1L avelumab. Clinical trial information: NCT02155647. [Table: see text]