Caspase-cleaved cytokeratin-18 and tumour regression in gastro-oesophageal adenocarcinomas treated with neoadjuvant chemotherapy.

AIM: To examine cytokeratin-18 (CK-18) and caspase-cleaved CK-18 expression in tumours and correlate with clinicopathological outcomes including tumour regression grade (TRG) response. METHODS: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays. The first set consisted of 122 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 97 gastric/gastro-oesophageal cancer cases exposed to pre-operative platinum-based chemotherapy. Expression of CK-18 and caspase-cleaved CK-18 was investigated using immunohistochemistry. RESULTS: CK18 was commonly expressed in gastro-oesophageal tumours (92.6%). Fifty-six point seven percent of tumours previously exposed to neoadjuvant chemotherapy were positive for caspase-cleaved CK-18 expression compared to only 24.6% of tumours not previously exposed to neoadjuvant chemotherapy (P = 0.009). In patients who received neoadjuvant chemotherapy, caspase-cleaved cytokeratin-18 expression correlated with favourable TRG response (TRG 1, 2 or 3, P = 0.043). CONCLUSION: This is the largest study to date of CK-18 and caspase-cleaved CK-18 expression in gastro-oesophageal tumours. We provide the first evidence that caspase-cleaved CK-18 predicts tumour regression with neoadjuvant chemotherapy.

Expression of key hypoxia sensing prolyl-hydroxylases PHD1, -2 and -3 in pancreaticobiliary cancer.

AIMS: Tumour hypoxia is associated with an aggressive phenotype and resistance to chemotherapy and radiotherapy. The aim was to investigate whether key hypoxia sensing prolyl hydroxylases PHD1, PHD2 and PHD3 are dysregulated in pancreaticobiliary cancers, and to evaluate their potential clinical significance. METHODS AND RESULTS: Formalin-fixed human pancreatic tissue from 120 consecutive patients undergoing pancreatic resections between June 2001 and June 2006 was constructed into tissue microarrays. Expression of PHD1, PHD2 and PHD3 was analysed using immunohistochemistry and correlated with clinicopathological variables and disease-specific overall survival. PHD1, PHD2 and PHD3 were significantly overexpressed in pancreaticobiliary tumours compared with normal pancreatic ductal tissues (P = 0.03, P < 0.0001 and P < 0.0001, respectively). PHD3 expression in tumour tissue was associated with a trend towards worse overall disease-specific survival in ampullary adenocarcinomas (P = 0.035) and pancreatic adenocarcinomas (P = 0.084). Absence of PHD1 expression was significantly associated with perineural invasion in pancreatic adenocarcinomas (P = 0.02) and a trend towards significance was also seen for absence of PHD2 expression in pancreatic adenocarcinomas (P = 0.04). CONCLUSIONS: Our results provide the first clinical evidence that PHD1, PHD2 and PHD3 may be involved in pancreaticobiliary tumorigenesis.

Tumour regression grade (TRG) analyses in patients with resectable gastro-oesophageal adenocarcinomas treated with platinum-based neoadjuvant chemotherapy.

AIMS: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. The aims were to validate the utility of the tumour regression grade (TRG) in patients who have received chemotherapy and to investigate if (i) TRG correlates with tumour downstaging and (ii) TRG could provide a comparative platform for future predictive biomarker investigations. METHODS AND RESULTS: Three pathologists were blinded to the treatment approaches. Review included diagnosis, tumour grade, TNM staging, vascular invasion, perineural invasion, resection margin involvement and histopathological response to chemotherapy, as measured by TRG. In the neoadjuvant chemotherapy (CS) group (n = 84), 46.7% of gastric/gastro-oesophageal junction adenocarcinomas, and 45.5% of lower third oesophageal adenocarcinomas had TRG 1, 2 or 3 compared with 13.7% in the primary surgery group (n = 124) (P < 0.001 and P = 0.006, respectively). In the CS group, responders (TRG 1, 2 or 3) showed significant tumour downstaging [early ypT-stage disease (P = 0.002)]. In gastric cancers specifically, additional associations were seen with negative nodal disease (P = 0.044) and absence of vascular invasion (P = 0.027). CONCLUSIONS: TRG may reflect response to chemotherapy. In addition, positive correlations between TRG and ypTNM staging were demonstrated that would suggest tumour downstaging.

Is the initial feasibility of lobectomy for stage I non-small cell lung cancer in severe heterogeneous emphysema justified by long-term survival?

BACKGROUND: The feasibility of anatomical lobectomy in patients with bronchial carcinoma in an area of severe heterogeneous emphysema whose respiratory reserve is outside operability guidelines has previously been confirmed. A review was undertaken to determine whether this approach is justified by long-term survival. METHODS: A single surgeon's 8 year experience of 118 consecutive patients (74 men) of median age 70 years (range 45-84) who underwent upper lobectomy for pathological stage I non-small cell lung cancer (NSCLC) was reviewed. The preoperative characteristics, perioperative course and survival of the 27 cases with severe heterogeneous emphysema of apical distribution and a predicted postoperative forced expiratory volume in 1 s (ppoFEV(1)) of <40% (lobarLVRS group) were compared with the remaining 91 cases with a ppoFEV(1) of >40% (control group). RESULTS: Postoperative mortality was 1 of 27 in the lobarLVRS group and 2 of 91 in the control group (p = NS). Five-year survival in the lobarLVRS group was 35% compared with 65% in the control group without concomitant severe emphysema (p = 0.001), although rates of tumour recurrence were similar. CONCLUSIONS: Long-term survival after lobarLVRS for stage I lung cancer is limited by physiological rather than oncological factors. However, outcomes are still better than those reported for any other modality of treatment in this group of high-risk patients. This finding justifies the decision to offer lobectomy in these selected cases.