The intratumoural subsite and relation of CD8+ and FOXP3+ T lymphocytes in colorectal cancer provide important prognostic clues

Background:

To find improved tools for prognostic evaluation in patients with colorectal cancer (CRC), we have analysed how infiltration of cytotoxic T lymphocytes (CD8⁺) and regulatory T lymphocytes (FoxP3⁺) correlates to prognosis, not only according to quantity and relation, but also to subsite within tumours of different molecular characteristics (microsatellite instability and CpG island methylator phenotype status).

Methods:

CD8 and FOXP3 expression was evaluated by immunohistochemistry in 426 archival tumour tissue samples from patients surgically resected for CRC. The average infiltration of CD8⁺ and FOXP3⁺ cells was assessed along the tumour invasive front, in the tumour centre and within the tumour epithelium (intraepithelial).

Results:

We found that infiltration of CD8⁺ T lymphocytes within the tumour epithelium provided the strongest prognostic information (P<0.001). At the tumour invasive front and tumour centre, FOXP3 expression withheld the strongest association to prognosis (P<0.001), suggesting FOXP3⁺ T-lymphocyte infiltration to be a better prognostic tool than CD8⁺ T lymphocytes at these intratumoural subsites. We further analysed the possible prognostic impact of the relation between these T-cell subsets, finding that a high intraepithelial CD8 expression was associated with a better patient outcome, independent of FOXP3 infiltration. In groups of low intraepithelial CD8 expression, however, a high infiltration rate of FOXP3⁺ cells at the tumour invasive front, significantly improved prognosis.

Conclusions:

Analyses of intraepithelial infiltration of CD8⁺ T lymphocytes, infiltration of FOXP3⁺ T lymphocytes at the tumour front or centre, and the relation between these subsets, may be a valuable tool for predicting prognosis in colon cancer.     

Fruit and vegetable consumption in relation to hepatocellular carcinoma in a multi-centre,European cohort study

Background:

Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case–control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations.

Methods:

In 486 799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d⁻¹ increments of vegetable/fruit intakes.

Results:

Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d⁻¹ increment): 0.83; 95% CI: 0.71–0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d⁻¹ increment): 1.01; 95% CI: 0.92–1.11.

Conclusions:

Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease.     

Alpha-1-fucosidase as a prognostic indicator for hepatocellular carcinoma following hepatectomy: a large-scale,long-term study

Background:

Preoperative alpha-L-fucosidase (AFU) has been used as a diagnostic biomarker for hepatocellular carcinoma (HCC), but its role as a prognostic predictor after partial hepatectomy has not been well defined. The study aimed to investigate the prognostic significance of preoperative serum AFU for HCC patients after hepatic resection.

Methods:

A retrospective training data set and a prospective validation data set were used to evaluate the prognosis of HCC after partial hepatectomy. A total of 669 patients with histopathologically confirmed HCC were enrolled. Univariate and multivariate analyses were used to identify the prognostic significance of preoperative serum AFU.

Results:

The retrospective training data set showed a preoperative AFU>35 u l⁻¹ should be used. The prospective validation data set showed preoperative AFU was an independent prognostic factor of overall survival (OS) (P=0.008; hazard ratio: 2.333; 95% confidence interval: 1.249–4.369). Patients with a preoperative AFU>35 u l⁻¹ had a lower recurrence-free survival rate and an OS rate than those with AFU⩽35 u l⁻¹, and they have a higher tendency to form macrovascular invasion. Furthermore, the prognostic significance of AFU>35 u l⁻¹ could also be applied to patients with alpha-fetoprotein levels of ⩽400 ng ml⁻¹.

Conclusions:

Preoperative serum AFU is a prognostic predictor of HCC.     

A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma

Background:

To date, no adjuvant treatment has been shown to have a clear benefit in patients with hepatocellular carcinoma (HCC). In this prospective phase I/IIa study, we evaluated the safety and efficacy of adjuvant dendritic cell (DC) therapy in HCC patients who received primary treatment for HCC.

Methods:

Twelve HCC patients who had no viable tumour after primary treatments were included. Dendritic cell vaccines pulsed with cytoplasmic transduction peptide-attached alpha-fetoprotein, glypican-3 and melanoma-associated antigen 1 recombinant fusion proteins were injected subcutaneously near to inguinal lymph nodes. Adverse effects, time to progression (TTP), and associated immune responses were evaluated after DC vaccination.

Results:

Nine of 12 patients had no tumour recurrence up to 24 weeks after DC vaccination. Among a total of 144 adverse events, 129 events (89.6%) were regarded as adverse drug reactions, all of which were grade 1 or 2. The majority of patients showed enhanced anti-tumour immune responses after DC vaccination. Recurrence-free patients exhibited relatively stronger anti-tumour immune responses than patients who developed recurrence after DC vaccination, as evidenced by lymphocyte proliferation and IFN-γ ELISPOT assays. The median time of TTP was 36.6 months in the DC-vaccination group and 11.8 months in the control group (hazard ratio, 0.41; 95% confidence interval, 0.18–0.95; P=0.0031 by log-rank test).

Conclusions:

Adjuvant DC vaccine for HCC was safe and well tolerated in phase I/IIa study, and preliminary efficacy data are encouraging to warrant further clinical study in patients with HCC after primary treatments.     

Effect of hepatic arterial infusion chemotherapy of 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma in the Nationwide Survey of Primary Liver Cancer in Japan

Background:

The efficacy of hepatic arterial infusion chemotherapy for the treatment of advanced hepatocellular carcinoma (HCC) remains unclear.

Methods:

The outcome of 476 patients with HCC who underwent hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin (HAIC) were compared with 1466 patients who did not receive active therapy.

Results:

A survival benefit of the therapy after adjusting for known risk factors was observed (hazard ratio, 0.48; 95% CI, 0.41–0.56; P<0.0001). In propensity score-matched analysis (n=682), median survival time was longer for patients who underwent chemotherapy (14.0 months) than for patients who did not receive active treatment (5.2 months, P<0.0001).

Conclusion:

For advanced HCC, HAIC is considered to be an effective treatment.     

Sex and the clinical value of body mass index in patients with clear cell renal cell carcinoma

Background:

An increased body mass index (BMI) is significantly associated with favourable prognosis in renal cell carcinoma (RCC). This study investigated the associations among sex, BMI, and prognosis in clear cell RCC patients.

Methods:

We retrospectively analysed 435 patients with clear cell RCC who underwent a nephrectomy. The associations among sex, BMI, clinicopathologic factors, and cancer-specific survival (CSS) were analysed.

Results:

As a continuous variable, increased BMI was associated with higher CSS rate by univariate analysis in the whole population (hazard ratio, 0.888 per kg m^–2; 95% confidence interval, 0.803–0.982; P=0.021). A sub-population analysis by sex demonstrated that BMI was significantly associated with CSS in men (P=0.004) but not in women (P=0.725). Multivariate analysis revealed BMI to be an independent predictor of CSS in only men.

Conclusion:

Body mass index was significantly associated with clear cell RCC prognosis. However, the clinical value of BMI may be different between men and women.     

Impact of liver fibrosis on prognosis following liver resection for hepatitis B-associated hepatocellular carcinoma

Background:

This study aims to evaluate the impact of liver fibrosis severity on prognosis following liver resection among HBV–HCC patients.

Methods:

Data were extracted from a prospective database of 189 HBV–HCC patients treated at Mount Sinai between 1995 and 2008. Fibrosis staging of each surgical resection specimen using the modified Ishak method was performed by a single liver pathologist.

Results:

A wide range of Ishak fibrosis stage was observed among this patient population, with 29% having established cirrhosis (Ishak stage 6). Ishak stage 6 was independently associated with poor overall and recurrence-free survival. In patients with Ishak stage 1–5, Ishak stage did not affect survival; rather, tumour size was associated with poor overall survival, and tumour size, histologic activity index and serum AFP>20 ng ml⁻¹ were associated with poor recurrence-free survival. In patients with Ishak stage 6, poorly differentiated histology and tumour size were associated with poor overall survival, and tumour size was associated with poor recurrence-free survival.

Conclusion:

HBV–HCC develops with varying degrees of underlying liver fibrosis; however, progressive liver fibrosis does not affect the outcomes following resection until cirrhosis is reached. Established cirrhosis, as defined histologically by Ishak stage 6, is an independent predictor of poor overall and recurrence-free survival among these patients.     

Pin1 facilitates NF-κB activation and promotes tumour progression in human hepatocellular carcinoma

Background:

NF-κB promotes HCC progression; however, therapies targeting NF-κB are not used due to severe adverse reactions. Pin1 is reported to induce tumour progression in vitro. However, the role of Pin1 in HCC is unclear. Moreover, little is known about the mechanism of Pin1-mediated NF-κB activation.

Methods:

Fresh surgical specimens were collected from 144 HCC patients. Pin1 and NF-κB-p65 expression was evaluated by immunohistochemistry and western blotting. NF-κB activation was assessed by EMSA.

Results:

Pin1 was increased in HCC compared to adjacent liver tissue. The multivariate analysis revealed that high Pin1 expression was an independent factor for poor prognosis. In HCC with high Pin1 expression, tumour size was larger and portal vein invasion was increased. Pin1 expression was correlated with phosphorylated (p−) NF-κB-p65(Thr254) and p-NF-κB-p65(Ser276), and thereby NF-κB activation. Pin1-induced NF-κB activation accelerated cell cycle progression, induced angiogenesis, and inhibited apoptosis. Pin1 knockdown in HCC cells inhibited the phosphorylation of NF-κB-p65(Ser276), and reduced NF-κB activation, which resulted in inhibiting tumour cell progression. When HCC cells were treated with the Pin1 inhibitors, p-NF-κB-p65(Ser276) expression and NF-κB activation was reduced, and cell proliferation was inhibited.

Conclusions:

Pin1 is associated with aggressive tumour progression and poor prognosis in HCC by mediating NF-κB activation.     

A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients

Background:

Human hepatocellular carcinoma (HCC) cells are largely deficient of argininosuccinate synthetase and thus auxotrophic for arginine. This study aims to investigate the efficacy and pharmacodynamics of pegylated arginine deiminase (ADI-PEG 20), a systemic arginine deprivation agent, in Asian HCC patients.

Methods:

Patients with advanced HCC who were not candidates for local therapy were eligible and randomly assigned to receive weekly intramuscular injections of ADI-PEG 20 at doses of 160 or 320 IU m⁻². The primary end point was disease-control rate (DCR).

Results:

Of the 71 accruals, 43.6% had failed previous systemic treatment. There were no objective responders. The DCR and the median overall survival (OS) of the intent-to-treat population were 31.0% (95% confidence interval (CI): 20.5–43.1) and 7.3 (95% CI: 4.7–9.9) months respectively. Both efficacy parameters were comparable between the two study arms. The median OS of patients with undetectable circulating arginine for more than or equal to and <4 weeks was 10.0 (95% CI: 2.1–17.9) and 5.8 (95% CI: 1.4–10.1) months respectively (P=0.251, log-rank test). The major treatment-related adverse events were grades 1–2 local and/or allergic reactions.

Conclusions:

ADI-PEG 20 is safe and efficacious in stabilising the progression of heavily pretreated advanced HCC in an Asian population, and deserves further exploration.     

A nomogram predicting pulmonary metastasis of hepatocellular carcinoma following partial hepatectomy

Background:

Pulmonary metastasis (PM) following curative hepatectomy for hepatocellular carcinoma (HCC) is indicative of a poor prognosis. This study aimed to develop a nomogram to identify patients at high risks of PM.

Methods:

A primary cohort of patients who underwent curative hepatectomy for HCC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2010 was prospectively studied. A nomogram predicting PM was constructed based on independent risk factors of PM. The predictive performance was evaluated by the concordance index (c-index), calibration curve and decision curve analysis (DCA). During the study period, a validation cohort was included at the First Affiliated Hospital of Fujian Medical University.

Results:

Postoperative PMs were detected in 106 out of 620 and 45 out of 218 patients, respectively, in two cohorts. Factors included in the nomogram were microvascular invasion, serum alpha-fetoprotein, tumour size, tumour number, encapsulation and intratumoral CD34 staining. The nomogram had a c-index of 0.75 and 0.82 for the two cohorts for predicting PM, respectively. The calibration curves fitted well. In the two cohorts, the DCA demonstrated positive net benefits by the nomogram, within the threshold probabilities of PM >10%.

Conclusion:

The nomogram was accurate in predicting PM following curative hepatectomy for HCC.     

Prediction of vascular invasion in hepatocellular carcinoma by next-generation des-r-carboxy prothrombin

Background:

In hepatocellular carcinoma (HCC), des-r-carboxy prothrombin (DCP) more accurately reflects the malignant potential than alpha-fetoprotein (AFP). Next-generation DCP (NX-DCP) was created to overcome some of the limitations of conventional DCP. This study assessed the predictive value of NX-DCP for vascular invasion in HCC.

Methods:

We prospectively studied 82 consecutive patients who were scheduled to undergo resection for HCC. Patients were divided into two groups according to the presence or absence of pathological vascular invasion. The predictive powers of AFP, conventional DCP, and NX-DCP for vascular invasion were compared by receiver operating characteristic curve analysis, and correlations with tumour markers and the presence of vascular invasion were assessed.

Results:

Vascular invasion was pathologically confirmed in 21 patients (positive group) and absent in 61 patients (negative group). The NX-DCP level was significantly higher in the positive group than in the negative group (510.0 mAU ml⁻¹ (10–98 450) vs 34.0 mAU ml⁻¹ (12–541), P<0.0001), while the AFP level did not differ significantly between the groups (9.7 ng ml⁻¹ (1.6–43 960.0) vs 11.0 ng ml⁻¹ (1.6–1650.0), P=0.49). The area under the curve (AUC) of NX-DCP (AUC=0.813, sensitivity=71.4%, 1−specificity=13.1%) had good sensitivity for the prediction of vascular invasion, while the AUC of AFP was 0.550 (sensitivity=28.6%, 1−specificity=1.60%). The suitable cutoff value for identifying pathological vascular invasion in HCC was 33 mm (AUC: 0.783, sensitivity=71.43%, 1−specificity=11.48%).

Conclusions:

The NX-DCP level can be used to predict the presence of vascular invasion in HCC.     

mTOR inhibition improves fibroblast growth factor receptor targeting in hepatocellular carcinoma

Background:

Systemic therapy has proven only marginal effects in hepatocellular carcinoma (HCC) so far. The aim of this study was to evaluate the effect of targeting fibroblast growth factor receptor (FGFR) on tumour and stromal cells in HCC models.

Methods:

Human and murine HCC cells, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), hepatic stellate cells (HSCs), human HCC samples, FGFR inhibitor BGJ398 and mammalian target of rapamycin (mTOR) inhibitor rapamycin were used. Effects on growth, motility, signalling and angiogenic markers were determined. In vivo subcutaneous and syngeneic orthotopic tumour models were used.

Results:

In tumour cells and ECs, targeting FGFR showed significant inhibitory effects on signalling and motility. Minor effects of FGFR inhibition were observed on VSMCs and HSCs, which were significantly enhanced by combining FGFR and mTOR blockade. In vivo daily (5 mg kg⁻¹) treatment with BGJ398 led to a significant growth inhibition in subcutaneous tumour models, but only a combination of FGFR and mTOR blockade impaired tumour growth in the orthotopic model. This was paralleled by reduced tumour cell proliferation, vascularisation, pericytes and increased apoptosis.

Conclusions:

Targeting FGFR with BGJ398 affects tumour cells and ECs, whereas only a combination with mTOR inhibition impairs recruitment of VSMCs and HSCs. Therefore, this study provides evidence for combined FGFR/mTOR inhibition in HCC.     

HCC-ART score,a simple,highly sensitive and specific test for early diagnosis of hepatocellular carcinoma: a large-scale,multicentre study

Background:

A simple scoring system is needed to discriminate HCC from patients with chronic liver diseases (CLD). The simplest score would be one that requires only variables that can be documented simply from routine laboratory tests without the need for sophisticated tests.

Methods:

Data from the estimation group (1351 patients) and the validation group (2208 patients) were retrospectively analysed. Liver fibrosis-negative control and liver cirrhosis were compared with HCC. Area under ROC curve (AUC) were used to develop HCC-α-fetoprotein-routine test (HCC-ART).

Results:

Hepatocellular carcinoma-AFP-routine test showed diagnostic accuracy for liver cirrhosis vs HCC with ROC curves of 0.99%, sensitivity of 97%, and specificity of 96% in the estimation, and 0.95%, 90%, and 83%, respectively, in the validation. Sensitivity (97%) and specificity (100%) were obtained to discriminate HCC from liver fibrosis. Area under curve for AFP at 400 U l⁻¹ was 0.70, sensitivity was 41%, and specificity was 99% in the estimation, and 0.77%, 54%, and 99%, respectively, in the validation. The AUC for HCC-ART in HCC with single tumour, absent vascular invasion, size <2 cm and CLIP score (0–1) were 0.95, 0.93, 0.86, 0.87, respectively, compared with 0.72, 0.71, 0.71, 0.50, respectively, for AFP.

Conclusion:

Hepatocellular carcinoma-AFP-routine test could increase the accuracy of HCC screening and surveillances and could be used worldwide without extra efforts.     

Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer

Background:

Foxp3⁺ regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown.

Methods:

Foxp3⁺, CD3⁺, CD4⁺, CD8⁺ and IL-17⁺ cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated.

Results:

Stromal Foxp3⁺ cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3⁺ cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3⁺ cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade.

Conclusions:

Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer.     

Stromal infiltration of CD8 T cells is associated with improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma

Background:

Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a better prognosis than those with HPV-negative tumours. There is interest in de-escalating their treatment but strategies are needed for risk stratification to identify subsets with a poor prognosis. This study investigated tumour-infiltrating lymphocytes (TILs) in relation to HPV tumour status and patient survival.

Methods:

Biopsies from 218 patients diagnosed with OPSCC between 2002 and 2011, who underwent chemo/radiotherapy were analysed for HPV by PCR, in-situ hybridisation and p16 immunohistochemistry (IHC). One hundred and thirty-nine samples with concordant HPV detection were analysed for CD3, CD4, CD8 and FoxP3 expression in tumour and stromal regions using multiplexIHC and multispectral image analysis. Labelling of smooth muscle actin (SMA) identified activated stroma.

Results:

Human papillomavirus-positive compared with HPV-negative OPSCC had higher infiltration in both tumour and stromal areas of CD4 and CD8 T cells but not FoxP3 T regulatory cells. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). There was significantly higher SMA expression in HPV-positive compared with -negative tumours, which did not correlate with survival.

Conclusions:

Studies of TILs for risk stratification in OPSCC should assess stromal infiltration.     

Familial diagnostic experiences in paediatric oncology

Background:

Diagnostic delays may not have significant prognostic implications in paediatric oncology, but psychological impacts remain understudied.

Methods:

Interviews exploring diagnostic experiences were conducted with childhood cancer survivors (n=19), parents (n=78) and siblings (n=15).

Results:

Median diagnostic time was 3 weeks. Participants described a mixture of rapid diagnoses (28.9%), plus delayed appraisal intervals (that is, parent- or patient-associated diagnostic delays; 40.0%) and diagnostic intervals (that is, healthcare-associated delays; 46.7%). Families experiencing delays described guilt and anger and deleterious impacts on the family–clinician relationship. Some believed delays impacted on treatment and prognosis.

Conclusions:

The effect of the diagnostic experience can be considerable.     

Major histocompatibility complex class I expression impacts on patient survival and type and density of immune cells in biliary tract cancer

Background:

Biliary tract cancers (BTC) are rare malignant tumours with a poor prognosis. Previously, we have presented a detailed characterisation of the inflammatory infiltrate in BTC. Here, we analysed the impact of the expression of major histocompatibility complex class I (MHC I) on patient survival and the quantity, as well as the quality of tumour-infiltrating immune cell types in BTC.

Methods:

MHC I expression was assessed semi-quantitatively in 334 BTC, including extrahepatic (n=129) and intrahepatic cholangiocarcinomas (n=146), as well as adenocarcinomas of the gallbladder (n=59). In addition, 71 high-grade biliary intraepithelial lesions (BilIN 3) were included. Results were correlated with data on antitumour inflammation and investigated with respect to their association with clinicopathological variables and patient survival.

Results:

BTC showed a wide spectrum of different MHC I expression patterns ranging from complete negativity in some tumours to strong homogenous expression in others. In BilIN 3, significantly higher MHC I expression levels were seen compared to invasive tumours (P=0.004). Patients with strong tumoural MHC I expression had a significantly higher overall survival probability (median survival benefit: 8 months; P=0.006). MHC I expression strongly correlated with the number of tumour-infiltrating T-lymphocytes (CD4⁺ and CD8⁺) and macrophages.

Conclusions:

Differences of MHC I expression predict patient outcome and show correlations with specific components of the inflammatory infiltrate in BTC. These findings contribute to a better understanding of immune response and immune escape phenomena in cholangiocarcinogenesis.     

Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer

Background:

Identification of tumour-associated antigens (TAAs) that induce cytotoxic T lymphocytes (CTLs) specific to cancer cells is critical for the development of anticancer immunotherapy. In this study, we aimed at identifying a novel TAA of pancreatic cancer for immunotherapy.

Methods:

On the basis of the genome-wide cDNA microarray analysis, we focused on KIF20A (also known as RAB6KIFL/MKlp2) as a candidate TAA in pancreatic cancer cells. The HLA-A2 (A*02:01)-restricted CTL epitopes of KIF20A were identified using HLA-A2 transgenic mice (Tgm) and the peptides were examined to check whether they could generate human CTLs exhibiting cytotoxic responses against KIF20A⁺, HLA-A2⁺ tumour cells in vitro.

Results:

KIF20A was overexpressed in pancreatic cancer and in some other malignancies, but not in their non-cancerous counterparts and many normal adult tissues. We found that KIF20A-2 (p12–20, LLSDDDVVV), KIF20A-8 (p809–817, CIAEQYHTV), and KIF20A-28 (p284–293, AQPDTAPLPV) peptides could induce HLA-A2-restricted CTLs in HLA-A2 Tgm without causing autoimmunity. Peptide-reactive human CTLs were generated from peripheral blood mononuclear cells of HLA-A2⁺ healthy donors by in vitro stimulation with the three peptides, and those CTLs successfully exhibited cytotoxic responses to cancer cells expressing both KIF20A and HLA-A2.

Conclusion:

KIF20A is a novel promising candidate for anticancer immunotherapeutic target for pancreatic cancers.     

Sorafenib for advanced hepatocellular carcinoma (HCC): impact of rationing in the United Kingdom

Background:

The prognosis for hepatocellular carcinoma (HCC) is dependent upon tumour stage, performance status (PS), severity of underlying liver disease, and the availability of appropriate therapies. The unavailability of sorafenib may have a significantly adverse effect on the prognosis of UK patients with advanced HCC. During the study period, access to sorafenib was at the discretion of local health funding bodies, a process that may delay or deny access to the drug and that remains in place for Wales, Scotland, and Northern Ireland. Here, we attempt to address the impact of this system on patients with advanced HCC in the United Kingdom.

Methods:

This is a retrospective study performed in the two largest specialist hepatobiliary oncology units in the United Kingdom. Funding applications were made to local funding bodies for patients with advanced HCC for whom sorafenib was considered appropriate (advanced HCC not suitable for loco-regional therapies, compensated chronic liver disease, PS 0–2).

Results:

A total of 133 applications were made, of which 57 (43%) were approved and 76 (57%) declined. Demographics and prognostic factors were balanced between the two groups. This cohort had a number of adverse prognostic features: patients were predominantly PS 1–2; the majority had multifocal disease with the largest lesion being >5 cm; and macroscopic vascular invasion, metastases, and AFP >1000 ng ml⁻¹, were each present in one-third of cases. The median time from application to funding decision was 17 days (range 3–260 days). For the primary ‘intention-to-treat'' analysis, median overall survival was 4.1 months when funding was declined, and 9.5 months when funding was approved (hazard ratio (HR) 0.48; 95% CI 0.3186–0.7267; P=0.0005).

Conclusion:

These data support the use of sorafenib for patients with advanced HCC as an effective intervention. In the United Kingdom, this applies to a relatively small group of patients, estimated to total ∼800 per year who, unfortunately, do not survive long enough to themselves lobby for the availability of this drug. These data provide a comparison of sorafenib with supportive care and demonstrate the potential detrimental impact on patient outcomes of rationing health-care resources on the basis of cost.