Lipegfilgrastim for prophylaxis of chemotherapy-induced neutropenia in Dutch patients.

BACKGROUND: Chemotherapy (CT)-induced neutropenia and febrile neutropenia (FN) can lead to changes in the treatment plan, potentially worsening the cancer outcome. This study evaluated the effect of the glycopegylated granulocyte-colony stimulating factor lipegfilgrastim, used as primary (PP) or secondary prophylaxis (SP), on treatment modifications in adult patients receiving cytotoxic CT with or without biological/targeted therapy (BT) for solid and haematological tumours. METHODS: This phase 4, prospective, observational study was conducted in eight centres in the Netherlands, in 2015-2017. Other study objectives were to characterise the population of cancer patients receiving lipegfilgrastim, to evaluate the incidence of CT-induced neutropenic events, and to assess safety. RESULTS: Of 142 patients, 73.94% had breast cancer and 55.63% received CT in the adjuvant setting. Most patients received lipegfilgrastim as PP (74.65%) and were at low (34.51%) or high risk (39.44%) of FN. CT dose delays were recorded for 22.64% and 36.11% of patients receiving lipegfilgrastim for PP and SP, respectively. CT dose reductions were recorded for 2.11% of patients; no CT dose omissions and one BT dose omission occurred. FN and grade III/IV neutropenia were reported for 5.63% and 9.86% of patients, respectively; associated hospitalisations were rare. The most frequently lipegfilgrastimrelated adverse events (AE) were myalgia, bone pain, and back pain. Serious AEs (55) were reported for 30 (21.13%) patients. There were two deaths, unrelated to lipegfilgrastim administration. CONCLUSION: Administration of lipegfilgrastim in routine clinical practice in the Netherlands results in limited CT/BT dose modifications and low incidence of neutropenic events, with no new safety concerns.

Molecular evidence of field cancerization in a patient with 7 tumors of the aerodigestive tract.

Exposure of the mucosa of the upper aerodigestive tract to carcinogens can induce genetic changes resulting in various independent clones of neoplastic growth, a concept defined as "field cancerization." The risk of developing multiple tumors in this compartment of the body is well established. We studied 6 distinct tumors of the upper aerodigestive tract of a single patient for loss of heterozygosity (LOH), microsatellite instability (MSI), p53 mutations, and K-ras codon 12 point mutations. We detected a unique pattern of LOH and p53 mutations in all 6 tumors. No tumor showed a K-ras mutation or MSI. The results support the mechanism of "field cancerization" and illustrate the potential power of molecular techniques to elucidate pathogenesis.

Atypical melanocytic proliferation associated with squamous cell carcinoma in situ of the esophagus.

We present the case of a 64-year-old woman who underwent a transhiatal esophagectomy subsequent to the presence of high-grade dysplasia of the esophageal squamous epithelium in repeated biopsies. In the resection specimen chronic esophagitis and multifocal carcinoma in situ of the squamous epithelium were diagnosed, associated with a diffuse intraepithelial proliferation of melanocytic cells. While melanocytic hyperplasia (melanocytosis) has previously been recognized as an occasional reactive lesion that can accompany esophageal inflammation and invasive squamous carcinoma, the present case was unusual because of its cytonuclear and architectural atypia in the melanocytic cell population, resembling features of a melanoma in situ in the absence of manifest invasive malignant melanoma. The disappearance of the melanocytic lesion during follow-up supports its nonneoplastic nature, however. This case illustrates that 'malignant features' in esophageal melanocytosis should be interpreted with caution.

Helicobacter pylori and Epstein-Barr virus infection and the p53 tumour suppressor pathway in gastric stump cancer compared with carcinoma in the non-operated stomach.

AIM: To evaluate similarities and differences between gastric stump cancer and conventional carcinoma in the non-operated stomach. METHODS: 26 stump carcinomas were compared with 24 conventional stomach cancers. Stage, histological type, and demographics were comparable in the two groups. Expression of p53 and p21-Waf1/Cip1 was evaluated by immunohistochemical staining. Helicobacter pylori infection was evaluated by examining haematoxylin-eosin stained slides and immunohistochemistry. Epstein-Barr virus infection was evaluated by RNA in situ hybridisation. RESULTS: Expression of p53 and p21-Waf1/Cip1 was similar in both groups and positive in more than half of the patients. H pylori infection was observed in six stump carcinomas and 17 conventional carcinomas in the intact stomach (p < 0.01). RNA in situ hybridisation (EBER1-ISH) for Epstein-Barr virus was positive in nine stump carcinomas and two carcinomas in the non-operated stomach (p < 0.05). CONCLUSIONS: There appear to be aetiological differences between stump carcinoma and cancer in the intact stomach. Further study of these differences may improve our understanding of gastric carcinogenesis in general.

Pancreatic cancer after remote peptic ulcer surgery.

BACKGROUND: Peptic ulcer surgery may carry an increased risk for pancreatic cancer development. Molecular analysis of K-ras codon 12, frequently mutated in conventional pancreatic cancers, might provide insight into the aetiological mechanisms. METHODS: The relative risk of pancreatic cancer was computed by multivariate and person-year analysis in a cohort of 2633 patients who had undergone gastrectomy. Lung cancer risk was analysed as an indirect means of assessing smoking behaviour. K-ras codon 12 mutational analysis was performed on 15 postgastrectomy pancreatic cancers. RESULTS: There was an overall increased risk of pancreatic carcinoma of 1.8 (95% confidence interval, 1.3 to 2.6) five to 59 years postoperatively, which gradually increased to 3.6 at 35 years or more after surgery (chi(2) test for trend, p < 0.05). Multivariate analysis indicated that parameters other than postoperative interval did not influence the risk. Lung cancer risk was significantly increased after surgery, but no time trend was observed. The spectrum and prevalence of K-ras codon 12 mutations were comparable to conventional pancreatic cancer. CONCLUSIONS: Remote partial gastrectomy is associated with an increased risk of pancreatic cancer. Postgastrectomy and non-postgastrectomy pancreatic cancers may share similar aetiological factors, such as smoking. However, the neoplastic process in patients who have undergone gastrectomy appears to be accelerated by factors related to the surgery itself.

Epstein-Barr virus in gastric carcinomas and gastric stump carcinomas: a late event in gastric carcinogenesis.

BACKGROUND: To determine at what stage during gastric carcinogenesis Epstein-Barr virus (EBV) enters the gastric epithelial cells, the presence of EBV was investigated in two pathogenetically related but distinct forms of adenocarcinoma of the stomach-gastric carcinoma of the intact stomach (GCIS) and gastric stump carcinoma (GSC)-and their presumed precursor lesions. PATIENTS AND METHODS: Eleven patients with EBV positive GCIS and eight patients with EBV positive GSC, demonstrated by the highly sensitive EBV encoded RNA 1/2 (EBER1/2) RNA in situ hybridisation (RISH) technique, were studied. Paraffin wax embedded tissue available from preoperative gastric biopsies and tumour adjacent tissue from the resection specimens containing normal gastric mucosa, inflamed gastric mucosa, and preneoplastic lesions (intestinal metaplasia and dysplasia) was investigated by EBER1/2 RISH, in addition to EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1 (LMP-1) immunohistochemistry (IHC). RESULTS: In both GCIS and GSC and their precursor lesions EBER1/2 transcripts were restricted to the carcinoma cells. In addition, positivity of EBNA-1 IHC was also restricted to the tumour cells. IHC for LMP-1 was negative in all cases tested. CONCLUSIONS: The absence of EBER1/2 transcripts in preneoplastic gastric lesions (intestinal metaplasia and dysplasia) and their presence in two distinct types of gastric carcinoma strongly suggest that EBV can only infect neoplastic gastric cells and thus is a late event in gastric carcinogenesis.

Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome.

AIM: To investigate whether mutations in the STK11/LKB1 gene and genes implicated in the colorectal adenoma-carcinoma sequence are involved in Peutz-Jeghers syndrome (PJS) related tumorigenesis. METHODS: Thirty nine polyps and five carcinomas from 17 patients (from 13 families) with PJS were analysed for loss of heterozygosity (LOH) at 19p13.3 (STK11/LKB1 gene locus), 5q21 (APC gene locus), 18q21-22 (Smad4 and Smad2 gene locus), and 17p13 (p53 gene locus), and evaluated for immunohistochemical staining of p53. In addition, mutational analysis of K-ras codon 12, APC, and p53 and immunohistochemistry for Smad4 expression were performed on all carcinomas. RESULTS: LOH at 19p was seen in 15 of the 39 polyps and in all carcinomas (n = 5). Interestingly, six of the seven polyps from patients with cancer had LOH, compared with nine of the 31 polyps from the remaining patients (p = 0.01). In one polyp from a patient without a germline STK11/LKB1 mutation, no LOH at 19p or at three alternative PJS candidate loci (19q, 6p, and 6q) was found. No LOH at 5q was observed. However, mutational analysis revealed an APC mutation in four of the five carcinomas. LOH at 17p was not seen in polyps or carcinomas; immunohistochemistry showed expression of p53 in one carcinoma and focal expression in three polyps. At subsequent sequence analysis, no p53 mutation was found. One carcinoma had an activating K-ras codon 12 mutation and another carcinoma showed 18q LOH; however, no loss of Smad4 expression was seen. CONCLUSIONS: These results provide further evidence that STK11/LKB1 acts as a tumour suppressor gene, and may be involved in the early stages of PJS tumorigenesis. Further research is needed to see whether LOH in PJS polyps could be used as a biomarker to predict cancer. Differences in molecular genetic alterations noted between the adenoma-carcinoma sequence and PJS related tumours suggest the presence of a distinct pathway of carcinogenesis.

K-ras mutations in gastric stump carcinomas and in carcinomas from the non-operated stomach.

BACKGROUND/AIMS: Partial gastrectomy is a well-established pre-malignant condition. It is postulated that in the gastric stump an accelerated neoplastic process takes place, similar to that of (intestinal type) adenocarcinoma from the non-operated stomach. K-ras codon 12 mutation is one of the most frequent oncogenic alterations in human solid neoplasms. It is rare in conventional gastric carcinoma and has not been studied in gastric stump carcinoma. The aim of this study was to compare the prevalence of K-ras codon 12 point mutations in gastric stump carcinomas with those in conventional carcinomas from the non-operated stomach. METHODOLOGY: Twenty-four gastric stump carcinomas were compared with 26 conventional gastric carcinomas. Stage, histology, and demographics were comparable in both groups. Mutations in codon 12 of the K-ras gene were examined with a polymerase chain reaction (PCR)-based method and subsequent dot blot hybridization with mutation-specific probes. The results of Helicobacter pylori infection, Epstein-Barr virus infection and p53 immunohistochemistry were partially known from a previous study. RESULTS: In one of the gastric stump carcinomas as well as in one of the conventional gastric carcinomas a K-ras codon 12 point mutation was found. p53 immunohistochemistry results were comparable in both groups. Interestingly, Helicobacter pylori infection rate and Epstein-Barr virus in situ hybridization for EBER1, as previously studied, appeared were significantly different in the two groups. CONCLUSIONS: K-ras codon 12 point mutations are rare in both gastric stump carcinomas and conventional gastric carcinomas. This supports the postulated hypothesis that the pathways of carcinogenesis in both gastric stump carcinoma and conventional gastric carcinoma share common features. However, these groups differ in infection rate of Helicobacter pylori and of Epstein-Barr virus, which suggests that some neoplastic stimuli differ as well.

Remote partial gastrectomy as a risk factor for pancreatic cancer: potential for preventive strategies.

BACKGROUND: Pancreatic cancer is the fifth leading cause of cancer death mainly because of an advanced disease stage at the time of diagnosis. Patients with a remote partial gastrectomy for benign ulcer disease may constitute a high risk group for pancreatic cancer; an increased index of suspicion could potentially lead to early detection in these patients. METHODS: The risk of developing pancreatic cancer following partial gastrectomy was evaluated by reviewing the literature. Furthermore, the risk of pancreatic cancer in an Amsterdam cohort of 2633 postgastrectomy patients has recently been assessed. The presence and type of K-ras codon 12 mutations in 15 postgastrectomy pancreatic cancer cases were also determined and compared to the conventional spectrum of these mutations in sporadic pancreatic cancer. RESULTS: After a follow-up time of 20 years or more since peptic ulcer surgery, the relative risk reported in the literature varies from 1.65 to 5-fold. In the Amsterdam cohort of 2633 postgastrectomy patients an overall increased risk of 1.8 was observed. The risk gradually increases to 3.6 after a postoperative interval of 35 years or more. A comparable frequency and type of K-ras codon 12 mutations was found in the postgastrectomy pancreatic cancer cases as reported in sporadic pancreatic cancer in non-operated patients, suggesting a similar carcinogenesis in the two groups and indicating a potential utility of this molecular marker for surveillance strategies. CONCLUSIONS: Patients who underwent peptic ulcer surgery are at higher risk of developing subsequent pancreatic cancer, especially after a prolonged (> 20 yrs) postoperative interval. An increased index of suspicion may contribute to early detection in these patients. The similar K-ras codon 12 mutation pattern in conventional and postgastrectomy pancreatic cancers makes this a suitable target for molecular diagnosis in these patients.

Comparison of cyclooxygenase 2 expression in adenocarcinomas of the gastric cardia and distal oesophagus.

BACKGROUND: Adenocarcinomas of the gastric cardia and distal oesophagus are at present often considered as one clinical entity because of their comparable increasing incidence, prognosis, and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. AIMS: The aim of this study was to analyse expression of cyclooxygenase 2 (COX-2) in cardia carcinomas, and correlate this expression with clinicopathological parameters and survival. The results were compared with the prognostic value of COX-2 found for Barrett carcinomas. METHODS: Tumour sections of 134 consecutive patients undergoing potentially curative surgery for an adenocarcinoma of the gastric cardia and substantially invading the distal oesophagus were immunohistochemically stained using a COX-2 monoclonal antibody. Specimens were blindly scored based on intensity and extent of COX-2 immunopositivity. RESULTS: COX-2 expression was negative to weak in 59% ("COX-2 low") and moderate to strong in 41% ("COX-2 high") of tumours. This was significantly lower than in Barrett carcinomas (p<0.0001). COX-2 expression was not correlated with any clinicopathological parameter. A correlation between elevated COX-2 expression and reduced survival, as described for Barrett carcinomas, was not identified for cardiac carcinomas. CONCLUSIONS: There is a difference in COX-2 expression with respect to intensity and prognostic significance between adenocarcinomas of the gastric cardia and distal oesophagus. This suggests a different pathogenesis and different genetic constitution of these two cancers. Based on these findings, the role of selective COX-2 inhibitors in the treatment of adenocarcinomas of the gastric cardia is less promising than in Barrett carcinomas.