Postoperative survival following perioperative MAGIC versus neoadjuvant OE02-type chemotherapy in oesophageal adenocarcinoma.

The optimal management of resectable oesophageal adenocarcinoma is controversial, with many centres using neoadjuvant chemotherapy following the Medical Research Council (MRC) oesophageal working group (OE02) trial and the MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. The more intensive MAGIC regimen is used primarily in gastric cancer but some also use it for oesophageal cancer. A database of cancer resections (2001-2013) provided information on survival of patients following either OE02 or MAGIC-type treatment. The data were compared using Kaplan-Meier analysis. Straight-to-surgery patients were also reviewed and divided into an 'early' cohort (2001-2006, OE02 era) and a 'late' cohort (2006-2013, MAGIC era) to estimate changes in survival over time. Subgroup analysis was performed for responders (tumour regression grade [TRG] 1-3) versus non-responders (TRG 4 and 5) and for anatomical site (gastro-oesophageal junction [GOJ] vs oesophagus). An OE02 regimen was used for 97 patients and 275 received a MAGIC regimen. Those in the MAGIC group were of a similar age to those undergoing OE02 chemotherapy but the proportion of oesophageal cancers was higher among MAGIC patients than among those receiving OE02 treatment. MAGIC patients had a significantly lower stage following chemotherapy than OE02 patients and a higher median overall survival although TRG was similar. On subgroup analysis, this survival benefit was maintained for GOJ and oesophageal cancer patients as well as non-responders. Analysis of responders showed no difference between regimens. 'Late' group straight-to-surgery patients were significantly older than those in the 'early' group. Survival, however, was not significantly different for these two cohorts. Although the original MAGIC trial comprised few oesophageal cancer cases, our patients had better survival with MAGIC than with OE02 chemotherapy in all anatomical subgroups, even though there was no significant change in operative survival over the time period in which these patients were treated. The use of the MAGIC regimen should therefore be encouraged in cases of operable oesophagogastric adenocarcinoma.

Assessment of a rapid liquid-based cytology method for measuring sputum cell counts.

Differential sputum cell counting is not widely available despite proven clinical utility in the management of asthma. We compared eosinophil counts obtained using liquid-based cytology (LBC), a routine histopathological processing method, and the current standard method. Eosinophil counts obtained using LBC were a strong predictor of sputum eosinophilia (≥3%) determined by the standard method suggesting LBC could be used in the management of asthma.

Analysis of lymphatic and blood vessel invasion biomarkers in T1 esophagogastric adenocarcinomas for improved patient prognostication.

Lymphovascular invasion (LVI) in T1 esophagogastric adenocarcinoma may predict risk of recurrence despite definitive treatment with surgery or endoscopic resection. Podoplanin and CD34 are emerging biomarkers of lymphatic and blood vessel invasion, respectively, and could be adopted to refine LVI assessment. A consecutive series of 65 patients with T1 adenocarcinomas diagnosed at Nottingham University Hospitals were investigated. T1 tumors from 43/65 patients who received primary surgery only were suitable for LVI evaluation by hematoxylin and eosin (H&E) staining as well as by CD34 and Podoplanin immunohistochemistry. LVI was correlated to clinicopathological features and recurrence free survival. H&E staining detected LVI in 11.6% (5/43) of T1 tumors. CD34 and Podoplanin immunohistochemistry significantly improved LVI detection to 25.6% (11/43). Compared with LVI by H&E, immunohistochemical evaluation of blood vessel invasion (CD34) or lymphatic vessel invasion (Podoplanin) was significantly associated with higher grade (P = 0.005), submucosal invasion (T1b) (P = 0.018), lymph node positivity (N1) (P = 0.029) and poor recurrence free survival (P = 0.0003). Our study provides evidence that CD34 and Podoplanin immunohistochemistry could improve LVI detection and allow better prognostication of patients and optimum selection of definitive treatment. Larger multicenter studies are required for further validation that could have significant clinical implications.

Evaluation of touch preparation cytology during frozen-section diagnoses of pulmonary lesions.

BACKGROUND: Intraoperative frozen section (FS) examination in thoracic surgery is a reliable method for diagnosis and staging of pulmonary lesions and provides a valuable guide in directing the extent of the ongoing surgical procedure. However, the contribution of touch preparation cytology (TPC) to FS diagnosis remains unclear. Aim To assess the utility of routinely performed TPC during FS diagnoses of pulmonary lesions. METHODS: In this study FS and TPC for all patients who had undergone FS diagnoses of pulmonary lesions in a 6-year period were reviewed by two pathologists. RESULTS: A total of 155 consecutive patients underwent intraoperative FS procedure, and 110 of those cases had TPC available for review. TPC was diagnostic or contributory to FS diagnosis in 97 (88%) cases, and non-contributory in 13 cases, mainly due to low or inadequate cellularity. TPC provided useful information regarding tumour subtyping, but it was less sensitive in the diagnosis of mucinous neoplasms and was less specific in the assessment of bronchial resection margins. In granulomatous lesions with or without necrosis, TPC was diagnostic in 10 (91%) cases. In five cases (including four cases of tuberculosis), TPC was the only diagnostic tool since FS was not completed. In conclusion, TPC showed high sensitivity and specificity rates and was contributory to FS diagnosis of pulmonary lesions. TPC provides a fast, less-expensive method of diagnosis, utilises a minimal amount of tissue, and can save processing of fresh frozen tissues in certain situations such as tuberculous lesions.

Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy.

AIMS: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response. METHODS AND RESULTS: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry. In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P=0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P=0.006) and was associated with poor disease-specific (P=0.020) and overall survival (P=0.040). CONCLUSIONS: We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy.

Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers.

BACKGROUND: Altered DNA repair may be associated with aggressive tumour biology and impact upon response to chemotherapy and radiotherapy. We investigated whether expression of human AP endonuclease (APE1), a key multifunctional protein involved in DNA BER, would impact on clinicopathological outcomes in ovarian, gastro-oesophageal, and pancreatico-biliary cancer. METHODS: Formalin-fixed human ovarian, gastro-oesophageal, and pancreatico-biliary cancers were constructed into TMAs. Expression of APE1 was analysed by IHC and correlated to clinicopathological variables. RESULTS: In ovarian cancer, nuclear APE1 expression was seen in 71.9% (97 out of 135) of tumours and correlated with tumour type (P=0.006), optimal debulking (P=0.009), and overall survival (P=0.05). In gastro-oesophageal cancers previously exposed to neoadjuvant chemotherapy, 34.8% (16 out of 46) of tumours were positive in the nucleus and this correlated with shorter overall survival (P=0.005), whereas cytoplasmic localisation correlated with tumour dedifferentiation (P=0.034). In pancreatico-biliary cancer, nuclear staining was seen in 44% (32 out of 72) of tumours. Absence of cytoplasmic staining was associated with perineural invasion (P=0.007), vascular invasion (P=0.05), and poorly differentiated tumours (P=0.068). A trend was noticed with advanced stage (P=0.077). CONCLUSIONS: Positive clinicopathological correlations of APE1 expression suggest that APE1 is a potential drug target in ovarian, gastro-oesophageal, and pancreatico-biliary cancers.

The sensitivity of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma.

Pleural malignant mesothelioma (MM), which is an aggressive neoplasm with a high mortality, frequently manifests initially as pleural effusions. The sensitivity of cytologic examination for its diagnosis varies widely in literature and most of the figures are from earlier studies with conventional cytologic preparations. The objective of this study was to provide the current evidence on the role and sensitivity of cytologic examination of pleural fluid in the diagnosis of MM. We reviewed the cytologic findings in pleural effusions of a large series of histologically proven MM (234 cases) diagnosed in our institution between 2001 and 2008. Of all cases, 154 (66%) had cytologic material examined. A specific diagnosis of MM was rendered or suspected in 53% (79 patients). The lowest sensitivity (20%) was noticed in sarcomatoid MM cases. MM was favored over adenocarcinoma in 97% of patients with positive cytologic findings that have been confirmed with immunohistochemistry. In this series, five cases were inadequate and five cases were initially reported as atypical, whereas 65 cases (44%) were reported as negative for malignancy. On review of the cytology slides, only four cases were upgraded from benign to suspicious compared to four cases downgraded from suspicious to atypical but no significant improvement to the diagnosis could be made on revision. These data suggested that a cytologic diagnosis contributed useful information in patients with epithelioid and biphasic pleural MM. Limitations of the cytologic examination of MM should also be acknowledged.

Cytological assessment of conventional transbronchial fine needle aspiration of lymph nodes.

OBJECTIVES: Transbronchial fine needle aspiration (TBNA) is a minimally invasive bronchoscopic technique that allows pathological examination of mediastinal and hilar lymph nodes. The aim of this study was to assess the cytopathological outcome of TBNA. METHODS: One hundred and eighty-seven patients who underwent TBNA of mediastinal and hilar lesions from May 2000 to June 2007 were reviewed. RESULTS: TBNA results were considered to be adequate if the cytological material revealed a malignant lesion or sufficient number of benign lymphoid cells. In the current study, 40 cases (21.9%) were reported as inadequate. When inadequate tests were excluded, the overall sensitivity and accuracy of TBNA in the diagnosis of malignant lesions were 83.5% and 88.0% respectively. The lowest sensitivity was noted in lymph node involvement by lymphoma. Regarding the workload associated with TBNA cytology, we found that the average number of conventionally prepared cytological slides per case was high (17 slides per case). CONCLUSION: Our results confirm that conventional TBNA is a sensitive and useful technique but it is relatively expensive and the protocols should be adapted to allow appropriate material to be collected for ancillary diagnostic tests.

Antibiotic susceptibility of thermo-tolerant Escherichia coli 2 isolated from drinking water of Khairpur City, Sindh, Pakistan.

A total 72 drinking water sample were collected and analyzed by membrane filtration method during 1 year study from various points in Khairpur City. Out of these 58 (80.55%) samples were found to be contaminated with thermo-tolerant Escherichia coli 2. The susceptibility of these isolates to 35 antibiotics was studied by disc diffusion method and the organism was highly sensitive to levoflaxin, cefipime, enoxobid, noroxin, tarivid, ciproxin, avelox, amikacin, kanamycin, rocifin, pipenedic acid and slightly sensitive to cravit, naladixic acid, neomycin, cefizox, fortum cefotaxime, cefizox, fortum, tobramycin and cefoperoxone. The resistance against 16 antibiotics such as meropenem, linkomycin, fusidic acid, orbenin, penicillin, streptomycin, bacitracin, minocin, zinacef, amoxil, ceclor, claracid, cephalexin, augmentin, cephradin and dalacin was shown by these isolates. We report the presence of multi-drug resistance in thermo-tolerant Escherichia coli isolated in municipal water with different levels of prevalence in Khairpur City. In this study a higher number of positive results were obtained in all sampling points indicating the more fecally polluted municipal water.

Biomarkers of response to therapy in oesophago-gastric cancer.

Cancer of the oesophagus, gastro-oesophageal junction (GOJ) and stomach remains a major health problem worldwide. The evidence base for the optimal management of patients with operable oesophago-gastric cancer is evolving. Accepted approaches include preoperative chemotherapy followed by surgery (oesophageal cancer), chemo-radiotherapy alone (oesophageal cancer) and perioperative chemotherapy (gastric and gastro-oesophageal adenocarcinomas). The underlying principles behind neoadjuvant therapy are to improve resectability of the tumour by tumour shrinkage/downstaging and to treat occult metastatic disease as early as possible. The response rate to cytotoxic therapy is about 40% in oesophago-gastric cancer. Available evidence suggests that a favourable histopathological response to cytotoxic therapy may be a useful positive predictive marker in oesophago-gastric cancer. However, the ability to predict tumour response in routine clinical practice is difficult and is an area of intense investigation. There is evolving evidence for the role of predictive biomarkers in cancer in general and oesophago-gastric cancer in particular. We provide an overview on the current status of radiological and biological predictive biomarkers. We have focussed on clinical translational investigations and, where appropriate, provided pre-clinical insights. Whether predictive markers will be routinely incorporated in clinical practice remains to be seen as biomarker research is expensive and the data generated from these investigations are complex. It is clear that a concerted international effort between academia and industry is critical if personalised medicine as a practical reality for our cancer patients is to be realised.

A rare case of follicular thyroid carcinoma in ovarian struma.

Struma ovarii is a form of specialised mature teratoma, with predominantly mature thyroid tissue in an ovarian teratoma as seen in 2% of cases. Its malignant transformation is even rarer and is seen in only 5% of those cases. This 40-year-old female patient had an incidental finding of a pelvic mass during investigation of secondary amenorrhoea. She underwent a staging laparotomy and pelvic clearance. The histopathology revealed a bilateral mature teratoma of the ovary with follicular thyroid carcinoma in the right ovarian struma (malignant struma). A total thyroidectomy was performed followed by a whole body 31I scintigraphy which did not reveal any abnormal uptake of isotope. The patient remains well after four years and is being followed-up with serial serum thyroglobulin surveillance.

Expression of mesothelial markers in malignant mesotheliomas: an immunohistochemical evaluation of 173 cases.

OBJECTIVE: To see the distribution of Calretinin, thrombomodulin, CK5/6 and HBME-1 markers in various subtypes of mesotheliomas and extend the published data on this topic. The positivity of adenocarcinoma specific markers (CEA and BerEP4) in malignant mesotheliomas have also been evaluated. METHODS: Various markers in 173 cases of malignant mesotheliomas received over a period of 8 years were evaluated by immunohistochemistry. RESULTS: In majority of malignant mesotheliomas i.e., epithelioid and biphasic types, the positive staining patterns complement the gold standard histologic diagnosis. However, in a small minority mainly sarcomatoid variant, heavy reliance cannot be placed on these markers. CEA and BerEP4 are useful negative markers of mesotheliomas, although occasionally these are positive in clear cut mesotheliomas. CONCLUSIONS: Specificity of various markers in malignant mesotheliomas should be assessed according to histologic subtypes. The existing generation of markers is not reliable in diagnosis of sarcomatoid mesotheliomas. Fortunately this forms only a small group of mesothelial malignancy. In common epithelioid and biphasic variants calretinin, thrombomodulin, CK5/6, HBME-1 are sensitive positive markers whereas CEA and BerEP4 are negative markers of malignant mesotheliomas.

Pathological determinants of survival in node-negative oesophageal cancer.

BACKGROUND: Many studies have analysed prognostic factors following oesophagectomy, but few have examined survival determinants in node-negative (N0) oesophageal cancer. The prognostic significance of a number of histological variables following surgical resection of N0 oesophageal cancer was studied. METHODS: The case notes of 219 patients undergoing potentially curative oesophagectomy for N0 squamous cell carcinoma or adenocarcinoma of the oesophagus were reviewed. Details of the patient's sex, age at operation, histological type, longitudinal tumour length, tumour (T) stage, circumferential resection margin involvement, tumour grade, presence of vascular invasion, perineural invasion, Barrett's metaplasia, and survival were noted. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Univariate analysis revealed three factors that correlated with poor prognosis: T stage (P = 0.024), adenocarcinoma (P = 0.033) and degree of differentiation (P = 0.001). Multivariate analysis revealed that all three were significant independent adverse prognostic indicators. CONCLUSION: Surgical resection of node-negative oesophageal cancer is associated with diverse long-term outcomes. This diversity of outcome is not reflected in the tumour node metastasis (TNM)-based staging system. The utility of the TNM system in predicting prognosis after surgical resection is open to question.

Spectrum of cutaneous appendage tumors at Aga Khan University Hospital.

OBJECTIVE: To determine the frequency of various types of cutaneous appendage tumors in our practice. METHOD: This is a partly retrospective and partly prospective study conducted at the Department of Pathology, Histopathology Section, The Aga Khan University Hospital, Karachi between 1st January 1997 and 31st December 2001. RESULTS: One hundred sixty six skin appendage tumors were diagnosed during the study period. 87.3% were benign, while 12.6% were malignant. Male female ratio was almost equal. Mean age was 41.72 years. 37.34% showed eccrine differentiation, 14.45% showed apocrine differentiation and 41.56% showed pilosebaceous differentiation, 6.62% exhibited mixed differentiation. The 5 commonest tumors were pilomatricoma, nodular hidradenoma (eccrine acrospiroma), syringocystadenoma papilleferum, eccrine poroma and eccrine spiradenoma. The commonest malignant tumors were porocarcinoma and sebaceous carcinoma. Pilomatricoma were common in children. CONCLUSION: Most of our findings roughly correlate with the western published data. However, commonest site for eccrine poromas in our study was head and neck. Also, not a single case of eccrine spiradenoma was seen in the first two decades of life. These findings differ significantly from western data.

Prognostic significance of circumferential resection margin involvement following oesophagectomy for cancer.

The factors affecting long-term survival following oesophagectomy for oesophageal cancer are poorly understood. We examined the significance of microscopic tumour involvement at the circumferential resection margin (CRM) on postoperative survival following oesophagectomy. The case notes of 329 patients who underwent a potentially curative oesophagectomy for squamous or adenocarcinoma were reviewed retrospectively. As part of the procedure, all patients underwent an en-bloc resection of their periesophageal tissue. The presence of tumour either at, or within, 1 mm of the CRM was recorded and correlated with their TNM and survival data. A total of 67 patients (20%) were noted to have a positive CRM, of which 40 cases (12%) had tumour at the resection margin and the remainder had tumour within 1 mm of the margin. Univariate analysis showed no statistically significant association between survival and either category of CRM involvement. Multivariate analysis showed that only T-stage, nodal status and tumour grade were prognostic markers. In conclusion, the presence of microscopic tumour at the CRM following an en-bloc oesophagectomy is not a significant prognostic marker.