Safety and preliminary efficacy of pembrolizumab following trans-arterial chemoembolization for hepatocellular carcinoma: the PETAL phase Ib study.

BACKGROUND: TACE may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy. METHODS: Patients with liver-confined HCC were planned to receive up to 2 rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30-days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, 21-days dose-limiting toxicities (DLT) from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumour and host determinants of response. RESULTS: Fifteen patients were included in the safety and efficacy population: 73% had non-viral cirrhosis, median age was 72 years. Child-Pugh (CP) class was A in 14 patients. Median tumour size was 4 cm. Ten patients (67%) received pembrolizumab after 1 TACE, 5 patients after 2 (33%). Pembrolizumab yielded no synergistic toxicity nor DLTs post-TACE. Treatment-related adverse events occurred in 93% of patients most commonly skin rash (40%), fatigue and diarrhoea (27%). After a median follow-up of 38.5 months, objective response rate (ORR) 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months (95%CI 7.30-NA). Median duration of response was 7.3 months (95%CI: 6.3-8.3). Median OS was 33.5 months (95%CI: 11.6-NA). Dynamic changes in peripheral T-cell subsets, circulating tumour DNA, serum metabolites and in stool bacterial profiles highlight potential mechanisms of action of multi-modal therapy. CONCLUSIONS: TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE.

A new prognostic model for predicting 30-day mortality in acute oncology patients.

INTRODUCTION: Acute oncology services (AOS) provide rapid review and expedited pathways for referral to specialist care for cancer patients. Blood tests may support AOS in providing estimates of prognosis. We aimed to develop and validate a prognostic model of 30-day mortality based on routine blood markers to inform an AOS decision to actively treat or palliate patients. METHODS AND MATERIALS: Using clinical data from 752 AOS referrals, multivariable logistic regression analysis was conducted to develop a 30-day mortality prognostic model. Internal validation and then internal-external cross-validation were used to examine overfitting and generalizability of the model's predictive performance. RESULTS: Urea, alkaline phosphatase, albumin and neutrophils were the strongest predictors of outcome. The model separated patients into distinct prognostic groups from the cross-validation (C Statistic: 0.70; 95% CI: 0.64-0.76). Admission year was included as a predictor in the model to improve the model calibration. CONCLUSION: The developed prediction model was able to classify patients into distinct prognostic risk groups, which is clinically useful for delivering an evidence-based AOS. Collation of data from other AOS centers would allow for the development of a more generalizable prognostic model.

The prognostic role of circulating tumor cells in heavily pretreated individuals with a low life expectancy.

AIMS: Studies of circulating tumor cells (CTCs) have generally recruited individuals with newly diagnosed metastatic cancer, with recent data also indicating their prognostic value in the adjuvant setting. Their role in dying patients has not been established. EXPERIMENTAL: CTCs were measured in 43 individuals with metastatic breast cancer estimated to have less than 6 months to live who had exhausted standard therapeutic options. RESULTS: Those with a CTC count of ≤ 100 had a median of 182 days to live, compared with those with a CTC count of >100 who had a median of 17 days until death (p = 0.009, log rank, HR: 3.1, 95% CI: 1.4-7.3). CONCLUSION: A CTC count of >100 is associated with imminent death. Provided external validity is demonstrated, such information would be useful for patients and their families who often request specific prognostic clarity and could improve the quality of end-of-life care.

Failure of translation of human adenovirus mRNA in murine cancer cells can be partially overcome by L4-100K expression in vitro and in vivo.

Adaptive immune responses may be vital in the overall efficacy of oncolytic viruses in human malignancies. However, immune responses to oncolytic adenoviruses are poorly understood because these viruses lack activity in murine cells, which precludes evaluation in immunocompetent murine cancer models. We have evaluated human adenovirus activity in murine cells. We show that a panel of murine carcinoma cells, including CMT64, MOVCAR7, and MOSEC/ID8, can readily be infected with human adenovirus. These cells also support viral gene transcription, messenger RNA (mRNA) processing, and genome replication. However, there is a profound failure of adenovirus protein synthesis, especially late structural proteins, both in vitro and in vivo, with reduced loading of late mRNA onto ribosomes. Our data also show that in trans expression of the nonstructural late protein L4-100K increases both the amount of viral mRNA on ribosomes and the synthesis of late proteins, accompanied by reduced phosphorylation of eIF2α and improved anticancer efficacy. These results suggest that murine models that support human adenovirus replication could be generated, thus allowing evaluation of human adenoviruses in immunocompetent mice.

Kisspeptin is released from human prostate cancer cell lines but plasma kisspeptin is not elevated in patients with prostate cancer.

Kisspeptin, the product of the KiSS-1 gene, inhibits metastasis and stimulates the hypothalamo-pituitary-gonadal axis. Kisspeptin is therefore a putative target in the treatment of hormone-sensitive malignancies. Prostatic carcinoma remains a significant cause of mortality despite improvements in therapy. The role of kisspeptin in prostatic carcinoma remains undefined. We therefore aimed to investigate release of kisspeptin by prostatic cancer cell lines; investigate expression of KiSS-1 in human prostate tissue; investigate whether patients with prostate carcinoma have elevated plasma kisspeptin. 1) Culture medium from prostatic carcinoma cell lines LNCaP, DU145 and PC3 was assayed for kisspeptin immunoreactivity (-IR). Kisspeptin-IR release was detectable from all three cell lines. The effect of hydroxyflutamide, gefitinib and resveratrol on kisspeptin-IR release from these cell lines was also investigated. No effect of the drugs tested on release of kisspeptin-IR was observed. 2) Expression of KiSS-1 in human prostate tissue (n=4) was investigated using in situ hybridisation. Expression of KiSS-1 was detected in human prostate tissue. 3) Plasma kisspeptin-IR was compared in 92 patients with prostatic carcinoma and 73 male controls. Kisspeptin-IR was not detected in the plasma of either patients with prostate cancer or control patients. We have therefore shown for the first time the release of kisspeptin-IR by prostatic carcinoma cell lines. We have also shown that KiSS-1 is expressed in human prostate tissue, and that circulating levels of kisspeptin-IR are not elevated in patients with prostatic carcinoma. Further work is required to determine the role of kisspeptin in the prostate.

Successful treatment with etoposide phosphate in patients with previous etoposide hypersensitivity.

OBJECTIVE: To review the experience of treatment with etoposide phosphate in patients with acute etoposide hypersensitivity treated in a large tertiary referral center hospital specializing in curable malignancies. CASE SUMMARIES: The cases of 6 patients with advanced malignancies who experienced acute etoposide hypersensitivity are documented. There were 3 male and 3 female patients and their ages ranged from 16 to 68. Four patients had curable malignancies with trophoblast tumors or germ cell tumors and two were receiving palliative chemotherapy for other malignancies. All of the 6 patients who experienced etoposide hypersensitivity developed their symptoms in the first few minutes of the initial infusion. The most common symptoms were chest pain, facial flushing, and bronchospasm. All of the patients had emergency treatment with discontinuation of the infusion and usually the administration of hydrocortisone and chlorpheniramine, which lead to the rapid resolution of their symptoms. For the next cycle of chemotherapy each patient was rechallenged with etoposide phosphate, with steroid cover given in only two of the cases. None of the 6 patients experienced any hypersensitivity symptoms on treatment with etoposide phosphate and in one the steroids were withdrawn for all the subsequent cycles. The 4 patients with curable malignancies all remain disease free, while the 2 palliative patients obtained significant control of their disease. DISCUSSION: Etoposide is one of the most important chemotherapy drugs in the treatment of many curable malignancies but an acute hypersensitivity reaction occurs in around 1% of patients. Retreatment with etoposide in these patients is difficult and generally alternative drugs/regimens have to be used. A small number of case reports have suggested that etoposide phosphate can be safely used in these patients and 6 cases have been found in the pharmacy records where this has been done. In all of the patients, treatment with etoposide phosphate proceeded without any symptoms or the use of repeated steroid cover in 5 of the 6 patients. CONCLUSION: Etoposide hypersensitivity is a rare clinical problem and responds promptly to drug discontinuation, steroids, and chlorpheniramine. Patients with previous etoposide hypersensitivity can safely be treated with etoposide phosphate and do not need any additional hypersensitivity prophylaxis.

Management and outcome of healthy women with a persistently elevated beta-hCG.

PURPOSE: Raised serum beta human chorionic gonadotrophin (beta-hCG) not due to pregnancy can occur as a consequence of (1) gestational trophoblastic neoplasia (GTN), (2) non-gestational trophoblastic tumours, (3) a false-positive beta-hCG, (4) the menopause or (5) a high normal level. Accurate differentiation between these causes is vital to avoid potentially inappropriate investigations and therapies, which may induce infertility or other serious adverse events. Here we report the United Kingdom experience of patients with an elevated beta-hCG of initial uncertain cause and provide a clinical algorithm for the management of such cases. METHOD: The Charing Cross and Weston Park Hospital GTN databases were screened to identify patients referred with an elevated beta-hCG who were not pregnant and had no previous diagnosis of GTN. RESULTS: Between 1981 and 2004 fourteen women presented with persistently raised serum beta-hCG resulting in diagnostic problems. False-positive beta-hCG was excluded in all. Three patients developed gestational choriocarcinoma after 9-29 months. However, in 11 women no cause for the persistently elevated beta-hCG was found. One of these achieved chemotherapy-induced normalisation of serum beta-hCG, but the remaining 10 underwent surgery and/or chemotherapy without benefit. Thus, 71% (10/14) of patients remain well with unexplained elevated beta-hCG levels. CONCLUSION: Elevated serum and urinary beta-hCG levels in healthy women should be investigated systematically to exclude an underlying malignant process and to avoid inappropriate surgical and medical intervention. Long-term follow-up is required as tumours may not become apparent for many months or years.