tbuckley/cabot-search huggingface dataset:
A randomized controlled trial comparing modified gemcitabine plus oxaliplatin (mGEMOX) to gemcitabine plus cisplatin in the management of unresectable gall bladder cancer.
Authors: Atul Sharma, Surendra Pal Chaudhary, N. K. Shukla, B. K. Mohanti, S. V. S. Deo, Sujoy Pal, Vinod Raina, Sanjay Thulkar, Sreenivas Vishnubhatla, Rakesh Kumar, V. K. Iyer
Journal: Journal of Clinical Oncology (2013)

TPS4162 Background: In a recently conducted study we have shown that combination of gemcitabine and oxaliplatin is superior to 5 fluorouracil and leucoverine or best supportive care. (Sharma A, Dwary AD, Mohanti BK,et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer:A randomized controlled study. J Clin Oncol. 2010; 28: 4581-4586.) In another recent publication from UK, gemcitabine and cisplatin combination was found superior to gemcitabine alone in biliary tract cancers (J W Valle, HS Wasan, DD Palmer, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Eng J Med. 2010;362:1273-1281.).The current study is being planned to see whether the combination of gemcitabine and oxaliplatin is equivalent (equivalence study) to gemcitabine and cisplatin in these patients. Methods: Primary end point of the study is overall survival in subjects receiving mGEMOX or GemCis regimen. Secondary end points are: a) Comparison of progression free survival in 2 groups; b) Response rates in two groups; c) Identification of genes predictive of responses in a subset of patients; d) To evaluate role of PET CT in GBC patients predicting disease activity. Sample size was calculated taking median survival of 9.5 months in our previous study with mGEMOX and 11.7 months with GemCis. For this total of 216 patients are required (108 in each arm); to make for major protocol violation and lost to follow up additional 22 patients in each arm will be enrolled. Thus in total 260 patients (130) in each arm will be recruited. This will have alpha and beta values of 0.05 and 0.20 respectively. So far 103 patients have been enrolled and interim analysis is being planned. Treatment protocol: Cycles will be repeated every 3 weeks. Arm A- mGEMOX. Inj Oxaliplatin 80 mg/m 2 2 hours infusion in Dextrose 5% Day 1 and 8. Inj Gemcitabine 900 mg/m 2 IV 30 minutes infusion day 1 and 8 maximum of 6 cycles. Arm B- GEMCIS. Inj Cisplatin 25 mg/m 2 PO Days 1 and 8. Inj Gemcitabine 1000 mg/m 2 IV 30 minutes infusion day1and 8 maximum of 8 cycles. Clinical trial information: CTRI/2010/091/001406.
Venlafaxine to prevent oxaliplatin-induced neuropathy?: A pilot randomized placebo-controlled trial.
Authors: Collin Thomas Zimmerman, Pamela J. Atherton, Deirdre R. Pachman, Drew K. Seisler, Nina D. Wagner-Johnston, Shaker R. Dakhil, Jacqueline M. Lafky, Rui Qin, Axel Grothey, Charles L. Loprinzi
Journal: Journal of Clinical Oncology (2015)

e20734 Background: Previous pilot data suggested venlafaxine could prevent acute and chronic oxaliplatin-related neuropathy (Durand et al, Ann Oncol, 2012, p200). The purpose of this randomized, placebo-controlled, double-blinded pilot study was to try to obtain additional data to support conducting a phase III trial to test the use of venlafaxine to prevent oxaliplatin neurotoxicity. Methods: 50 patients scheduled to undergo oxaliplatin-based therapy (FOLFOX) for stage II-III (67%) or stage IV (33%) colon cancer, from 9 sites between 02/2012 and 03/2014, were randomized to receive venlafaxine XR (37.5 mg) or placebo, twice daily, through last dose of oxaliplatin, and then titrated off. Acute neuropathy was evaluated with a standard patient questionnaire (Loprinzi et al, JCO, 2014, p997). Prior to each oxaliplatin dose, neurotoxicity was evaluated via several mechanisms: the EORTC QLQ CIPN20, the NCI CTCAE v4.0, an oxaliplatin-specific scale, and a Rydel-Seiffer graduated tuning fork. Results: Baseline pt. characteristics were equivalent for the 2 arms, with a median age of 60. There was a trend toward benefit for the venlafaxine arm, when evaluated by the oxaliplatin-specific neuropathy scale and by acute neuropathy measures of 1) discomfort swallowing cold liquids and 2) throat discomfort, observed only for the first 2 oxaliplatin doses. These positive trends however, were outweighed by a lack of any such trends, or even trends favoring the placebo arm, in many other measurements including: 1) the CIPN20 sensory subscale (P = 0.55, primary endpoint), 2) CIPN20 motor, or autonomic neuropathy subscales, 3) any of the 20 individual items of the CIPN20 tool, 4) NCI CTCAE assessment, 5) the cumulative amount of administered oxaliplatin (median 716 mg vs 631 mg for placebo and venlafaxine, respectively , P = 0.34), 6) tuning fork data measuring vibration sensitivity, and 7) the majority of the acute neuropathy data. Conclusions: The present study does not support either the use of venlafaxine for preventing oxaliplatin-induced neuropathy in clinical practice or the initiation of a phase III trial to investigate venlafaxine in this setting. Clinical trial information: NCT01611155.
Clinicodermoscopic features of Spitz naevi by age and anatomical site: a study of 378 Spitz naevi
Authors: Y. de Mestier, E. Moscarella, J. Marchetti Cautela, A. Lallas, C. Longo, I. Zalaudek, R. Hofmann-Wellenhof, G. Argenziano
Journal: British Journal of Dermatology (2017)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, Spitz naevi are benign melanocytic naevi characterized by spindled and epithelioid cells in histology and are seen in both children and adults.1,2 In the present study, we aimed to determine whether there is a difference in the dermoscopic features of Spitz naevi by age and anatomical site. Previous studies have demonstrated this association in congenital and common naevi.3 This study was conducted at the Skin Cancer Unit of the Arcispedale Santa Maria Nuova IRCSS in Reggio Emilia, Italy. We searched the image database from May 2002 to October 2014. Ethics committee approval was waived by the ethics committee of Reggio Emilia. We retrieved clinical and dermoscopic images of all lesions with a histopathological diagnosis of Spitz naevus (Fig. 1). Additionally, in patients aged ≤ 12 years, lesions undergoing dermoscopic follow‐up were also included. In these cases, the images from the first visit were included.
Phase Ib study of gemcitabine and oxaliplatin with erlotinib in patients with advanced biliary tract cancer.
Authors: Kristen Keon Ciombor, Dana Backlund Cardin, Emily Chan, Pamela McClanahan, Kang-Hsien Fan, Jayme Flynn, Ruth T. Young, April DeMers, Stephen James Smith, Jordan Berlin, Laura Williams Goff
Journal: Journal of Clinical Oncology (2012)

e14503 Background: Gemcitabine (GEM) with a platinum agent such as oxaliplatin (OX) is standard therapy for advanced biliary tract cancers (ABTC). The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has also shown modest benefit in ABTC. Erlotinib (E) induces G1/S cell cycle arrest and may exhibit sequence-specific synergy with GEM. Given continuously, it may antagonize the action of chemotherapy against cycling tumor cells but intermittent pulsatile dosing of EGFR TKIs in combination with chemotherapy may lead to maximum efficacy. The purpose of this study is to assess the tolerability of E when pulsed with GEM and OX (GEMOX). Methods: This investigator initiated, single institution phase Ib study (NCT00987766) used a standard 3+3 dose-escalation model in patients with ABTC, pancreas cancer or duodenal cancer. The primary endpoint was to evaluate the maximum tolerated dose (MTD) of pulsatile E in combination with GEMOX. Patients received escalating doses of E starting at 50 mg daily (given on D3-8) with GEM on D1 (dose rate 10 mg/m 2 /min) and OX on D2 every two weeks. Dose-limiting toxicity was defined as any treatment-related, first course (28 days) non-hematologic ≥Gr3 toxicity, except nausea/vomiting or Gr4 hematologic toxicity. Results: Nineteen patients have been enrolled and 4 dose levels have been explored. Two of two patients experienced DLT [Gr3 diarrhea (n=1), Gr4 anemia (n=1)] at a dose of 150 mg E + 1000 mg/m 2 GEM + 85 mg/m 2 OX, exceeding the MTD. Most frequent toxicities were nausea (68%), neuropathy (68%), fatigue (63%) diarrhea (52%) and rash (52%), most Gr1 or 2. Disease stabilization occurred in 12/17 (71%) evaluable patients (5/9 ABTC, 7/8 pancreas), and partial responses were seen in 4/17 evaluable patients (24%), all with ABTC (4/9). The rate of progression-free survival at 6 months was 75% in ABTC. Conclusions: The MTD and recommended phase 2 dose of E in combination with GEMOX was E 150 mg given on days 3-8 with GEM 800 mg/m 2 and OX 85 mg/m 2 in this population. Clinical activity of this combination was seen in the majority of patients. An expansion cohort of an additional ten patients with ABTC at the MTD is ongoing, and correlative studies on available tissue will be performed.
64Cu-MM-302 Positron Emission Tomography Quantifies Variability of Enhanced Permeability and Retention of Nanoparticles in Relation to Treatment Response in Patients with Metastatic Breast Cancer
Authors: Helen Lee, Anthony F. Shields, Barry A. Siegel, Kathy D. Miller, Ian Krop, Cynthia X. Ma, Patricia M. LoRusso, Pamela N. Munster, Karen Campbell, Daniel F. Gaddy, Shannon C. Leonard, Elena Geretti, Stephanie J. Blocker, Dmitri B. Kirpotin, Victor Moyo, Thomas J. Wickham, Bart S. Hendriks
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. Experimental Design: We assessed the EPR effect in patients using a 64Cu-labeled nanoparticle, 64Cu-MM-302 (64Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by PET/CT. Nineteen patients with HER2-positive metastatic breast cancer underwent 2 to 3 PET/CT scans postadministration of 64Cu-MM-302 as part of a clinical trial of MM-302 plus trastuzumab with and without cyclophosphamide (NCT01304797). Results: Significant background uptake of 64Cu-MM-302 was observed in liver and spleen. Tumor accumulation of 64Cu-MM-302 at 24 to 48 hours varied 35-fold (0.52–18.5 %ID/kg), including deposition in bone and brain lesions, and was independent of systemic plasma exposure. Computational analysis quantified rates of deposition and washout, indicating peak liposome deposition at 24 to 48 hours. Patients were classified on the basis of 64Cu-MM-302 lesion deposition using a cut-off point that is comparable with a response threshold in preclinical studies. In a retrospective exploratory analysis of patient outcomes relating to drug levels in tumor lesions, high 64Cu-MM-302 deposition was associated with more favorable treatment outcomes (HR = 0.42). Conclusions: These findings provide important evidence and quantification of the EPR effect in human metastatic tumors and support imaging nanoparticle deposition in tumors as a potential means to identify patients well suited for treatment with therapeutic nanoparticles. Clin Cancer Res; 23(15); 4190–202. ©2017 AACR.
Post-gastrectomy nutrition risk index can be a good predictive factor for survival.
Authors: Keiichi Fujiya, Taiichi Kawamura, Katsuhiro Omae, Noriyuki Nishiwaki, Sanae Kaji, Makoto Hikage, Rie Makuuchi, Masanori Tokunaga, Yutaka Tanizawa, Etsuro Bando, Masanori Terashima
Journal: Journal of Clinical Oncology (2017)

101 Background: Preoperative malnutrition worsens morbidity and survival, however the role of post-gastrectomy nutritional status in survival remains unclear. The nutrition risk index (NRI) described by Buzby is a scoring system for identifying patients with preoperative poor nutrition status. However, the significance of NRI in evaluating post-gastrectomy nutritional status has not yet been established. Therefore, we aimed to clarify whether malnutrition condition evaluated by NRI after surgery can be a predictive factor for long-term survival in patients with gastric cancer. Methods: Pathological stage I, II, and III gastric cancer patients who underwent curative gastrectomy between 2002 and 2013 were included in this study. NRI was calculated using the following formula; (1.489 × serum albumin, g/L) + (41.7 × current weight/usual weight), and we defined an NRI of above 97.5 as normal nutrition (N group) and 97.5 or below as malnutrition (M group). NRI was evaluated before gastrectomy and 1, 3 and 12 months after gastrectomy. The correlations of clinicopathological characteristics, surgical treatment and overall survival, with nutritional status were retrospectively evaluated. Results: A total of 2552 patients were enrolled. There were significant differences in age, sex, body mass index, performance status, co-morbidity, histology and malignant stage between the groups before gastrectomy. Overall survival in the M group was significantly poorer, both before gastrectomy (adjusted HR 1.31; p &lt; 0.001) and at 1 month (adjusted HR 1.52; p &lt; 0.001), 3 months (adjusted HR 1.35; p = 0.004) and 12 months (adjusted HR 1.37; p = 0.006) after gastrectomy. In multivariate analysis, low NRI at 12 months after gastrectomy, age, co-morbidity and malignant stage were independently associated with overall survival. Overall survival in patients who fulfilled preoperative normal nutrition status criteria was also significantly poorer at 12 months after gastrectomy in the M group. Conclusions: Malnutrition after surgery, as well as before surgery, had a significant impact on overall survival. Postoperative nutritional statue evaluated by NRI may be a good predictive marker for long-term survival.
Preclinical activity of BC2059, a novel compound that degrades beta-catenin, in colon cancer models.
Authors: Sunil Sharma, Raffaella Soldi, Glynn Weldon Gilcrease, Stephen Horrigan
Journal: Journal of Clinical Oncology (2012)

e14090 Background: BC2059 (BetaCat Pharmaceuticals) is a novel small molecule that degrades ß-catenin in a proteosomally dependent manner in cancer cells. Methods: We tested the activity of BC2059 in vitro, in patient derived colon cancers in 3-dimensional cultures and in vivo using HT-29 xenografts. We also used a novel doxycycline driven siRNA model that downregulates ß-catenin to test activity of BC2059. Results: BC2059 was highly active with IC90s in MTS assays (μM): SW480 (0.44), Colo205 (0.66), Colo201 (0.03), HT29 (0.92) and relatively inactive in SW48 (9.83) or L cells (normal) (4). In a 3-Dimensional culture system where we grew patient-derived colon cancer cells in a matrigel system and measured cell death by ethidium bromide exclusion, surprisingly, the average EC50 was 200 picomolar indicating that the compound was much more effective in patient derived samples. In matrigel tumor invasion assays, BC2059 demonstrated potent inhibition of tumor invasion. In HT-29 mouse xenografts, BC2059 series demonstrated tumor growth inhibition with no weight loss with depletion of ß-catenin. We also used chromatin immunoprecipitation (CHIP) assays to demonstrate depletion of ß-catenin on myc and axin promoters. In combination experiments, BC2059 displayed synergy in vitro with 5-fluorouracil in vitro. We used a doxycycline driven siRNA system in colon cancer cell lines and show that the compound activity is synergistic with depletion of ß-catenin. We also conducted combination of BC2059 series of compounds using a proteasome inhibitor MG132 and demonstrate reversal of activity with proteasome inhibition. Conclusions: In conclusion, BC2059 demonstrates potent activity in vitro and in vivo against colon cancer models singly or in combination. Further, it is surprisingly potent in patient derived colon cancer models. It appears to degrade ß-catenin in a proteosomally dependent manner on important effectors like myc and axin. It merits further evaluation in this tumor type.
Pharmacokinetic (PK) and pharmacodynamic (PD) analysis from a phase I study of PF-03446962, a fully human mab against ALK1, a TGF-beta receptor involved in tumor angiogenesis.
Authors: Laura Williams Goff, Hossein Borghaei, Roger B. Cohen, Jordan Berlin, Cristina Noberasco, Corrado Gallo Stampino, Erjian Wang, James Andrew Williams, Patricia A English, Filippo De Braud
Journal: Journal of Clinical Oncology (2012)

e13606 Background: The proangiogenic activity of Transforming Growth Factor β (TGF-β) on vasculature is exerted by selectively binding to its receptor, activin receptor like kinase 1 (ALK1). PF-03446962 is a fully human mAb against ALK1. Updated results on anti-tumor activity of PF-03446962 from a Phase 1 study in patients (pts) with solid tumors are reported along with PK and PD data. Methods: Effects of PF-03446962 on soluble proteins related to angiogenesis and the TGFβ pathway were investigated with respect to PK, PD, and antitumor activity. Results: 44 pts have been enrolled on 8 dose levels (0.5 - 15 mg/kg). PF-03446962 is administered i.v. on Day 1, 29 and then q 2 weeks. The dose of 10 mg/kg was defined as the maximum tolerated dose. 3 PRs were observed: one HCC resistant to anti-VEGF therapy, one NSCLC and one RCC who received VEGFR2 tyrosine kinase inhibitors (TKIs) as part of the whole previous systemic therapy. SD ≥16 weeks was observed in 7/44 pts. 2/5 HCC pts pre-treated with VEGFR2 TKIs showed a time-to-progression (TTP) of 5 months. Based on PK data, plasma concentrations at 4.5 -10mg/kg doses exceeded predicted efficacious concentrations over the entire dosing period. Cmax, Tmax AUC and terminal elimination half-life values following a dose of 10 mg/kg in 7 patients were 290μg/mL, 1.5hrs, 40236 μg/mL*hr and 302hrs. Mean values of the following soluble (s) plasma proteins increased at the end of cycle 1 compared to baseline (mean value, % increase, paired t-test p value): TGFβ (+77%, p=0.28), sVEGF-A (+60%, p= 0.15), and sVEGFR1 (+113%, p=0.10), whereas mean values of 10 other angiogenesis/TGFβ pathway proteins changed &lt;20% from baseline. Conclusions: PF-03446962 is a first-in-class anti ALK1 mAb. Increases in Cmax and AUC were proportional to increases in dose in the therapeutic dose range. Preliminary assessments of PD data supports previous laboratory observations of interaction between ALK1 and VEGF signalling pathways for pericyte protection of blood vessels. Based on preliminary results, PF-0344692 appears to be a promising novel antiangiogenic agent and further investigations in pts who failed anti-VEGF/VEGFR2 TKIs are warranted.
COL4A1 is a Novel Causative Gene Responsible for Congenital Hemolytic Anemia, Representing Characteristic Clinical Course in Infants
Authors: Hiromi Ogura, Shouichi Ohga, Takako Aoki, Taiju Utsugisawa, Hidehiro Takahashi, Asayuki Iwai, Kenichiro Watanabe, Yusuke Okuno, Kenichi Yoshida, Satoru Miyano, Seishi Ogawa, Seiji Kojima, Hitoshi Kanno
Journal: Blood (2015)
Cost-effective analysis of the use of EGFR inhibitors (E) for wild-type (WT) KRAS unresectable metastatic colorectal cancer (mCRC).
Authors: Maria C. Riesco Martinez, Scott R. Berry, Yoo-Joung Ko, Nicole Mittmann, Kelly Lien, Shazia Hassan, Angie Giotis, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2013)

6552 Background: Patients (pts) with unresectable WT KRAS mCRC benefit from fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (Bev) and E. The most cost-effective strategy to combine them remains unclear. Methods: A Markov model was constructed for a hypothetical cohort of pts with mCRC to examine the costs and outcomes of 3 treatment strategies: (A): 1st line (1L) Bev+FP+O/I, 2nd line (2L) FP+I/O, 3rd line (3L) E, (B): 1L Bev+FP+O/I, 2L FP+I/O, 3L E+I, and (C): 1L E+FP+O/I, 2L Bev+FP+I/O, 3L best supportive care (BSC). Efficacy and probability data of the treatments were obtained from clinical trials identified through a systematic review of the literature. Resource utilization data were derived from a chart review of 65 consecutive pts treated at Odette Cancer Centre (OCC) since 2009 and from the literature. Utilities were obtained by surveying oncologists (n= 24) across Canada using EQ-5D. Costs were obtained from the Ontario Ministry of Health and Long/Term Care, Ontario Case Costing Initiative, OCC and the literature. The analysis was conducted from the Canadian public healthcare system perspective over a 5 year time horizon with a 5% discount in 2012 Canadian dollars (CAD$) for cost and outcome. Incremental cost-effectiveness analyses were conducted comparing costs and outcomes of the 3 strategies. One way and probabilistic sensitivity analyses (SA) were conducted (n=10,000). Results: All 3 strategies appeared to be of relatively similar efficacy clinically, but C is more expensive than A or B by &gt;45% (see Table). The model is primarily driven by the acquisition cost of drugs. B is most cost-effective when the willingness-to-pay (WTP) threshold &gt;$120,000/QALY. SA showed that C would be cost-effective only when the progression-free survival of E is better than Bev in 1L with hazard ratio &lt;0.24 at WTP of $150,000/QALY. Conclusions: 1L use of E followed by 2L Bev in mCRC is not cost-effective at the current pricing of E relative to Bev. [Table: see text]
Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease
Authors: Rachel L. Taylor, Neil R.A. Parry, Stephanie J. Barton, Christopher Campbell, Claire M. Delaney, Jamie M. Ellingford, Georgina Hall, Claire Hardcastle, Jiten Morarji, Elisabeth J. Nichol, Lindsi C. Williams, Sofia Douzgou, Jill Clayton-Smith, Simon C. Ramsden, Vinod Sharma, Susmito Biswas, I. Chris Lloyd, Jane L. Ashworth, Graeme C. Black, Panagiotis I. Sergouniotis
Journal: Ophthalmology (2017)
Immune analysis of fibrolamellar hepatocellular carcinoma.
Authors: Mehmet Akce, Luis M Vence, Jorge M Blando, Padmanee Sharma, Manal Hassan, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2017)

324 Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma (HCC) with about 200 annual cases reported globally. Surgical resection is the main treatment. Although FLHCC develops in the absence of cirrhosis surrounding hepatic parenchyma may have mononuclear cell and lymphocyte infiltrates. Immunotherapy by targeting programmed death 1 (PD-1) has emerged as a potential therapy for HCC and multiple clinical trials are being conducted, however little is known about immunological features of FLHCC. We aimed to analyze tumor microenvironment by immunohistochemistry and flow cytometry. Methods: Surgical samples of two FLHCC cases, 23 year old woman (case 1) and 25 year old man (case 2) who underwent neoadjuvant chemotherapy with 5 Fluorouracil + Interferon followed by surgical resection were analyzed. Expression of CD4, CD8, PD-1, programmed death ligand 1(PD-L1), CD45RO, CD 57, CD68, OX 40, inducible costimulator (ICOS), FoxP3, Gr-B was evaluated by immunohistochemistry. Flow cytometry analysis of CD8, CD4 effector (Teff) and regulatory (Treg) T cells were performed. Immune monitoring studies were conducted by the Immunotherapy Platform at MD Anderson Cancer Center. Results: By immunohistochemistry,expression of PD-1 and PDL-1 in the tumor sampleswas asfollows:PD-1 (5.9%) and PDL-1 (4.1%) of total cells in case 1 versus PD-1 (6.3%) and PDL-1 (3.5%) in case 2. FoxP3 expression was 0.3% and 1%, whereas ICOS expression was 0.2% and 1% in case 1 and 2, respectively. By flow cytometry analysis, case 1 presented the following frequencies: CD8+CTLA4+ (40%), CD8+PD1+ (40%) of total CD8 T cells, CD4+TeffCTLA4+ (55%), CD4+TeffPD1+ (30%), CD4+TeffICOS+ (15%) of total CD4 Teff cells and CD4+TregCTLA+ (90%), CD4+TregPD1+ (30%), CD4+TregICOS+ (70%) of total CD4 Tregs. Similarly, in case 2 the percentages were CD8+CTLA-4+ (20%), CD8+PD1+ (40%), CD4+TeffCTLA4+ (25%), CD4+TeffPD1+ (65%), CD4+TeffICOS+ (30%), CD4+TregCTLA+ (90%), CD4+TregPD1+ (70%), CD4+TregICOS+ (80%). Conclusions: PD-1, PDL-1, CTLA-4 and ICOS expression in FLHCC might render support to consideration of potential utilization of antibodies against PD-1, PDL-1 and CTLA-4 for treatment for a devastating cancer with unmet need for treatment.