Gemcitabine, carboplatin, and Epstein-Barr virus-specific autologous cytotoxic T lymphocytes for recurrent or metastatic nasopharyngeal carcinoma: VANCE, an international randomized phase III trial.

BACKGROUND: Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T-cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous phase II trial of locally recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective antitumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared with conventional chemotherapy treatment. PATIENTS AND METHODS: This multicenter, randomized, phase III trial evaluated the efficacy and safety of GC followed by EBV-CTL versus GC alone as first-line treatment of R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the USA were included. Subjects were randomized to first-line GC (four cycles) and EBV-CTL (six cycles) or GC (six cycles) in a 1 : 1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety. CLINICALTRIALS: gov identifier: NCT02578641. RESULTS: A total of 330 subjects with NPC were enrolled. Most subjects in both treatment arms received four or more cycles of chemotherapy and most subjects in the GC + EBV-CTL group received two or more infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC + EBV-CTL subjects. The median OS was 25.0 months in the GC + EBV-CTL group and 24.9 months in the GC group (hazard ratio = 1.19; 95% confidence interval 0.91-1.56; P = 0.194). Only one subject experienced a grade 2 serious adverse event related to EBV-CTL. CONCLUSIONS: GC + EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS versus chemotherapy. This is the largest adoptive T-cell therapy trial reported in solid tumors to date.

The potential role of artificial intelligence-assisted chest X-ray imaging in detecting early-stage lung cancer in the community-a proposed algorithm for lung cancer screening in Malaysia.

INTRODUCTION: The poor prognosis of lung cancer has been largely attributed to the fact that most patients present with advanced stage disease. Although low dose computed tomography (LDCT) is presently considered the optimal imaging modality for lung cancer screening, its use has been hampered by cost and accessibility. One possible approach to facilitate lung cancer screening is to implement a risk-stratification step with chest radiography, given its ease of access and affordability. Furthermore, implementation of artificial-intelligence (AI) in chest radiography is expected to improve the detection of indeterminate pulmonary nodules, which may represent early lung cancer. MATERIALS AND METHODS: This consensus statement was formulated by a panel of five experts of primary care and specialist doctors. A lung cancer screening algorithm was proposed for implementation locally. RESULTS: In an earlier pilot project collaboration, AI-assisted chest radiography had been incorporated into lung cancer screening in the community. Preliminary experience in the pilot project suggests that the system is easy to use, affordable and scalable. Drawing from experience with the pilot project, a standardised lung cancer screening algorithm using AI in Malaysia was proposed. Requirements for such a screening programme, expected outcomes and limitations of AI-assisted chest radiography were also discussed. CONCLUSION: The combined strategy of AI-assisted chest radiography and complementary LDCT imaging has great potential in detecting early-stage lung cancer in a timely manner, and irrespective of risk status. The proposed screening algorithm provides a guide for clinicians in Malaysia to participate in screening efforts.

Systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer.

AIM: Current management of locally advanced rectal cancer includes neoadjuvant chemoradiation in selected patients to increase the chance of a tumour-free circumferential resection margin. There is uncertainty over the role of and selection criteria for additional systemic therapy in this group of patients. In this retrospective study we investigate the association between markers of systemic inflammatory response (SIR) and outcome from treatment. METHOD: One hundred and fifteen patients with locally advanced rectal cancer undergoing preoperative chemoradiation had recording of full blood count parameters including neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratios (PLR). Postoperative surgical margins (R status) and pathological stage were documented. Outcome measures were overall survival (OS), time to local recurrence (TTLR) and disease-free survival (DFS). Cox regression analysis was performed to identify predictors of outcome. RESULTS: Only NLR and R status were significant predictors for all outcome measures on univariate and multivariate analysis. Elevated NLR (≥5) was associated with decreased OS, [hazard ratio (HR) and 95% CI, 7.0 (2.6-19.2)], decreased TTLR [HR 3.8 (1.3-11.2)] and shorter DFS [HR 4.1 (1.7-9.8)]. Median survival for patients with an elevated NLR was 18.8 months compared with 54.4 months without an elevated NLR (P<0.001). CONCLUSION: In addition to postoperative R-status, an elevated NLR is also a valuable prognostic marker in patients undergoing chemoradiation for locally advanced rectal carcinoma. It is associated with worse OS, TTLR and DFS. An elevated NLR may be a useful additional tool in guiding the decision-making process for adjuvant or neoadjuvant therapies.

The role of imaging in the pre-operative staging and post-operative follow-up of rectal cancer.

Developments in rectal cancer imaging have revolutionised the management of this condition. It has become increasingly important for oncologists and surgeons to have a working insight into radiological assessment in order to make informed clinical decisions. In this context, we discuss the role that imaging plays in the pre-operative staging, post-operative follow-up and therapy of this disease including some novel advances in the field. Rectal cancer outcomes have improved due to modern surgical techniques, namely total mesorectal excision. Meticulous pre-operative assessment remains key. Conventional TNM staging now appears less crucial compared to assessing tumour distance from the potential plane of surgical resection (particularly the circumferential margin bounded by the mesorectal fascia), and this is reliant on high-quality imaging. Those with margin threatening disease can be offered downstaging chemoradiotherapy to facilitate successful resection. Endorectal ultrasound is useful for T staging and CT for detecting metastases. Malignant lymph node identification remains a problem and the use of size and morphological criteria may lead to misdiagnosis. In the post-operative setting, intensive follow-up is associated with improved outcomes but there are many variations in protocols. Most modalities struggle to differentiate tumour from reactive or fibrotic tissue and functional imaging is being investigated as the solution. PET scanning, particularly PET/CT, has been a major recent development. It has superior utility in detecting recurrent disease, including when conventional imaging is negative, detects occult metastases and may significantly enhance our ability to deliver accurate radiotherapy. Imaging has also opened up avenues for guided therapies aimed at ablating liver metastases. Radiofrequency ablation, in particular, is being used successfully and can improve survival of stage four patients.

Acute supraclavicular skin toxicity in patients undergoing radiotherapy for breast cancer: an evaluation of the 'T'-grip method of patient positioning.

AIMS: Supraclavicular fossa (SCF) radiotherapy plays an important part in the adjuvant management of breast cancer but data on acute radiotherapy toxicity are lacking, particularly when differing patient treatment positions are used to allow computed tomography planning or to reduce cardiac doses. MATERIALS AND METHODS: We evaluated SCF and breast/chest wall acute skin toxicity in a cohort of 92 women with breast cancer, who were planned in a 'T'-grip (n = 72) or 90 degrees-grip (n = 20) position, while 'on treatment' and at 6 weeks. The modified Radiation Therapy Oncology Group (RTOG) criteria were used to score toxicity. Data on age, body mass index, smoking history, type of breast operation, prior chemotherapy, radiation dose, number of fields and field size were recorded and correlated with outcome. RESULTS: Maximum SCF reaction score was RTOG 2a, with no moist desquamation observed. SCF reactions were less severe compared with chest wall reactions and no worse than breast reactions. There was significant resolution of toxicity at 6 weeks. SCF radiotherapy in 'T'-grip patients was well tolerated and no worse than the 90 degees-grip group. Pain scores and sore throat occurrences were minimal. Univariate and multivariate analyses showed that smoking was associated with worsening SCF toxicity (odds ratio [OR] 2.92; P = 0.045) and delayed healing. Incremental SCF dose worsened toxicity (OR 3.65; P = 0.023). Smoking worsened breast but not chest wall toxicity. CONCLUSIONS: SCF radiotherapy was at least as well tolerated as breast radiotherapy and better tolerated than chest wall radiotherapy. The 'T'-grip position did not affect toxicity negatively. Smoking and radiation dose affected SCF toxicity.

Is the paraneoplastic syndrome of inappropriate antidiuretic hormone secretion in lung cancer always attributable to the small cell variety?

The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a well recognised paraneoplastic phenomenon and the vast majority are associated with small cell lung carcinoma. Rarely however, the non-small cell variety can sometimes be responsible and this report describes such an occurrence. Uniquely in this case, after chemotherapy the paraneoplastic SIADH improved in parallel with a tumour response and this has not been reported previously.

Chk1 is essential for chemical carcinogen-induced mouse skin tumorigenesis.

Chk1 is a key regulator of DNA damage checkpoint responses and genome stability in eukaryotes. To better understand how checkpoint proficiency relates to cancer development, we investigated the effects of genetic ablation of Chk1 in the mouse skin on tumors induced by chemical carcinogens. We found that homozygous deletion of Chk1 immediately before carcinogen exposure strongly suppressed benign tumor (papilloma) formation, and that the few, small lesions that formed in the ablated skin always retained Chk1 expression. Remarkably, Chk1 deletion rapidly triggered spontaneous cell proliferation, γ-H2AX staining and apoptosis within the hair follicle, a principal site of origin for carcinogen-induced tumors. At later times, the ablated skin was progressively repopulated by non-recombined Chk1-expressing cells and ultimately normal sensitivity to tumor induction was restored when carcinogen treatment was delayed. In marked contrast, papillomas formed normally in Chk1 hemizygous skin but showed an increased propensity to progress to carcinoma. Thus, complete loss of Chk1 is incompatible with epithelial tumorigenesis, whereas partial loss of function (haploinsufficiency) fosters benign malignant tumor progression.

Guillain-Barre syndrome occurring after adjuvant chemo-radiotherapy for endometrial cancer.

BACKGROUND: The association between Guillain-Barre syndrome (GBS) and malignancy is uncommon and has not been previously reported in gynecological cancers. CASE: Our case documents this syndrome occurring in a patient shortly after completion of adjuvant chemo-radiotherapy for endometrial carcinoma. We review the current literature and discuss potential pathogenic mechanisms of this likely paraneoplastic association. CONCLUSION: GBS in cancer patients is a potentially life-threatening condition and should be differentiated from simple chemotherapy toxicity, particularly as effective treatment is available.