Frequency of Positive Familial Criteria in Patients with Adenocarcinoma of the Esophageal-Gastric Junction and Stomach: First Prospective Data in a Caucasian Cohort.

OBJECTIVES: Current prospective studies investigating the frequency of hereditary criteria in a Caucasian population for adenocarcinoma of the esophagogastric junction (AEG) and stomach (GC) are missing. Genetic testing criteria (screening criteria) for hereditary diffuse gastric cancer (HDGC) were updated in 2020, but do not address patients with intestinal histology (familial intestinal gastric cancer FIGC). Thus, we prospectively screened patients residing in Berlin newly diagnosed with AEG or GC for hereditary criteria to gain insights into the frequency of HDGC. METHODS: Prospective documentation of familial/clinical parameters in patients residing in Berlin with AEG or GC over three years was conducted. Besides HDGC criteria from 2015 and revised 2020, we also documented patients fulfilling these criteria but with intestinal type gastric cancer (FIGC). Statistical analysis was performed using X2-test. RESULTS: One hundred fifty-three patients were finally included (92 GC; male: 50 (n.s.); 61 AEG; male: 47; p = 0.007). Hereditary criteria for HDGC were detected in 9/92 (9.8%) (2015 criteria) and in 14/92 (15.2%) (2020 criteria) of GC patients (AEG: 2015 criteria 3/61 (4.9%) versus 4/61 according to 2020 criteria (6.5%)). Patients fulfilling hereditary criteria but with intestinal histology (FIGC) increased from 8.7% (2015) to 14.1%, respectively (2020) (AEG: 3.2% (2015) versus 6.6% (2020)). Hereditary criteria including intestinal histology were found in 29.3% (GC) and 13.1% (AEG) (p = 0.03) according to the 2020 criteria. CONCLUSIONS: HDGC criteria were found in 15.2% of GC patients according to the 2020 criteria. Percentage increased to 29.3% including patients with intestinal histology among the GC group, and was 13.1% in cases with AEG. These data indicate that family history seems to be of utmost importance in GC to further detect potential hereditary genetic risks. This equally applies for patients with intestinal subtype GC.

Implication of FDG-PET/CT in patients with potentially operable colorectal lung metastases.

OBJECTIVES: This prospective study assessed the role of F-18-FDG-PET/CT in clinical staging for patients with colorectal cancer planned for pulmonary metastasectomy by thoracotomy or video-assisted surgery. PATIENTS AND METHODS: In addition to conventional imaging, we performed 86 F-18-FDG-PET/CT studies in 76 patients with potentially resectable metastatic colorectal lung metastases. We then investigated the effect that PET/CT had on further clinical management. Based on the results from the 47 thoracotomies performed, we compared the number of pulmonary metastases discovered after histologic examination with the number predicted by the conventional computed tomography (CT) as an independent part of the F-18-FDG-PET/CT examination and by the F-18-FDG-PET component. RESULTS: F-18-FDG-PET/CT led to changes in treatment regime and diagnostic planning in many patients. In five patients PET/CT revealed previously undetected local recurrence of the primary colorectal cancer, in four patients hepatic metastases, in three patients bone metastases, in two patients soft-tissue metastases, and in three patients histologically preoperatively proven N2 or N3 station lymph node involvement. These all constituted exclusion criteria, and consequently the previously planned pulmonary metastasectomy was not performed. The sensitivity and positive predictive value (PPV) for detection of pulmonary metastases were 84.2% and 36.4% for CT and 75.0% and 61.6% for F-18-FDG-PET study. The calculated sensitivity, specificity, PPV, and NPV of F-18-FDG-PET/CT for detecting thoracic lymph node involvement were 85.7%, 93.0%, 66.7%, and 97.5%, respectively. Furthermore, we found that F-18-FDG-PET/CT may predict thoracic lymph node involvement based on the SUV of pulmonary nodules. CONCLUSIONS: F-18-FDG-PET/CT has a clear role in the diagnostic workup for pulmonary metastatic colorectal cancer and may save patients from futile surgery. It cannot, however, be relied on to detect all possible pulmonary and nodal metastases, which surgeons must always consider when making treatment decisions.

Prognostic value of cytokeratin-positive bone marrow cells of gastric cancer patients.

BACKGROUND: Epithelial cells in the bone marrow of patients with gastric cancer suggest tumor dissemination; however, their prognostic implications are controversial. We prospectively evaluated the correlation of bone marrow findings, recurrence rate, and disease-free survival after long-term follow-up. METHODS: Bone marrow were aspirated from both iliac crests and stained with monoclonal cytokeratin (CK)-18 antibody in 209 patients before their initial operation. Patients were followed up for a median of 56 months. RESULTS: Overall, 39 (19%) of 209 patients and 15 (14%) of 109 R0-resected patients had CK-positive cells. CK-positive patients had more local, regional, and distant recurrence than CK-negative patients (P < .05). We found a significantly shorter disease-free survival (P < .05) in the patients with >2 CK-positive cells per 2 x 10(6) bone marrow cells (mean, 35 months) than in patients with 2 CK-positive cells per 2 x 10(6) bone marrow cells was an independent prognostic factor for tumor-related death (P < .05). CONCLUSIONS: Not only the mere presence of CK-positive epithelial cells in bone marrow, but also the cell number, correlates with prognosis. Our findings suggest that classifying CK-positive bone marrow cells in these patients will facilitate future studies.

Gastric cancer surgery in elderly patients.

BACKGROUND: To investigate the value of individual risk-adapted therapy in geriatric patients, we performed a consecutive analysis of 363 patients undergoing potentially curative surgery for gastric cancer. PATIENTS AND METHODS: All patients underwent extensive preoperative workup to assess surgical risk. The following criteria were evaluated in 3 age groups (<60 years, 60-75 years, and >75 years): comorbidity, tumor characteristics, type of resection, postoperative morbidity and mortality, recurrence rate, overall survival, and disease-free survival. RESULTS: There was an increased rate of comorbidity in the higher age groups (51% vs 76% vs 83%; P<0.05). Cardiovascular and pulmonary diseases were most common. There was a decrease in the rate of both total gastrectomy (74%, 54%, 46%; P<0.05) and D2 lymphadenectomy (78%, 53%, 31%; P<0.05). The 30-day mortality in the 3 age groups was 0%, 1%, and 8%, respectively (P<0.05). There was only a slight difference in tumor recurrence rate (35%, 37%, and 27%; P=0.437), with no significant difference in 5-year cancer-related survival (61%, 53%, 61%; P=0.199). CONCLUSIONS: Patient selection and risk-adapted surgery in elderly patients can result in acceptable therapeutic results comparable to younger patients. Limited surgery in elderly gastric cancer patients with high comorbidity does not necessarily compromise oncological outcome.

Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity.

Platelet-derived growth factor receptor alpha (PDGFRalpha) and c-Kit are receptor tyrosine kinases. Both are targets of the tyrosine kinase inhibitor imatinib mesylate which is approved for treatment of some cancers. In order to assess the role of PDGFRalpha and c-Kit in malignant peripheral nerve sheath tumours (MPNST) we examined human tumours for structural alterations, protein and ligand expression. We investigated 34 MPNST, 6 corresponding plexiform neurofibromas (pNF) and 1 MPNST cell culture from 31 patients for mutations and polymorphisms in PDGFRA (exon 2-21) and KIT (exon 9, 11, 13, 17). PDGFRA was amplified in seven tumours from six patients and MPNST cell culture S462. KIT was amplified in five tumours from four patients and in the cell culture. Two MPNST carried somatic PDGFRA mutations in exons coding for the extracellular domain. In addition we detected several polymorphisms in PDGFRA. No point mutations or polymorphisms were detected in the four KIT exons analysed. PDGFRalpha expression was present in 21 of 28 MPNST patients (75%) and the MPNST cell culture. Expression analysis of PDGFRalpha ligands in MPNST and neurofibromas revealed that PDGF-A was more widely expressed than PDGF-B. Focal c-Kit expression was detected in 2 of 29 (7%) MPNST patients. Imatinib treatment of MPNST cell culture S462 exerted a growth inhibitory effect and prevented PDGF-AA induced PDGFRalpha phosphorylation. In summary, PDGFRA, PDGF and KIT dysregulation as well as growth inhibition of cell culture S462 by imatinib may suggest that MPNST patients benefit from treatment with imatinib.

Subclassification of nerve sheath tumors by gene expression profiling.

Nerve sheath tumors are the most common tumors of Neurofibromatosis type 1 (NF1) patients. Dermal neurofibromas develop in nearly all NF1-patients, whereas plexiform neurofibromas are only observed in one-third of the patients. NF1-patients have about a 10% lifetime risk for developing malignant pheripheral nerve sheath tumors (MPNST). The origin of these tumors is thought to be the Schwann cell lacking functional neurofibromin. However, additional genetic alterations are likely to modulate tumor biology and to contribute to individual nerve sheath tumor entities. To gain insight into the molecular events and to determine whether these tumors can be classified according to gene expression profiles, we performed expression analysis applying cDNA array technology. Nine dermal neurofibromas, 7 plexiform neurofibromas, ten MPNST and two MPNST cell cultures were examined. All tumors but 6 sporadic MPNST were obtained from NF1-patients. We detected significant differences in gene expression patterns between neurofibromas and MPNST and between dermal neurofibromas and plexiform neurofibromas. Tumor class prediction agreed in all but one case with histological and clinical classification. NF1-associated and sporadic MPNST could not be distinguished by their gene expression patterns. We present a panel of discriminating genes that may assist subclassification of nerve sheath tumors.

Prevalence of familial pancreatic cancer in Germany.

Based on several case-control studies, it has been estimated that familial aggregation and genetic susceptibility play a role in up to 10% of patients with pancreatic cancer, although conclusive epidemiologic data are still lacking. Therefore, we evaluated the prevalence of familial pancreatic cancer and differences to its sporadic form in a prospective multicenter trial. A total of 479 consecutive patients with newly diagnosed, histologically confirmed adenocarcinoma of the pancreas were prospectively evaluated regarding medical and family history, treatment and pathology of the tumour. A family history for pancreatic cancer was confirmed whenever possible by reviewing the tumour specimens and medical reports. Statistical analysis was performed by calculating odds ratios, regression analysis with a logit-model and the Kaplan-Meier method. Twenty-three of 479 (prevalence 4.8%, 95% CI 3.1-7.1) patients reported at least 1 first-degree relative with pancreatic cancer. The familial aggregation could be confirmed by histology in 5 of 23 patients (1.1%, 95% CI 0.3-2.4), by medical records in 9 of 23 patients (1.9%, 95% CI 0.9-3.5) and by standardized interviews of first-degree relatives in 17 of 23 patients (3.5%, 95% CI 2.1-5.6), respectively. There were no statistical significant differences between familial and sporadic pancreatic cancer cases regarding sex ratio, age of onset, presence of diabetes mellitus and pancreatitis, tumour histology and stage, prognosis after palliative or curative treatment as well as associated tumours in index patients and families, respectively. The prevalence of familial pancreatic cancer in Germany is at most 3.5% (range 1.1-3.5%) depending on the mode of confirmation of the pancreatic carcinoma in relatives. This prevalence is lower than so far postulated in the literature. There were no significant clinical differences between the familial and sporadic form of pancreatic cancer.

Body mass index does not affect systematic D2 lymph node dissection and postoperative morbidity in gastric cancer patients.

BACKGROUND: The extent of standard lymph node dissection (D1, D2, or D3) in gastric cancer patients is still controversial. Several prospective European trials attained contradictory results. A generally increased body mass index (BMI) of the European patients was assumed to be one of the major causes for postoperative morbidity. METHODS: We evaluated the effect of BMI on the quality of routine D2 lymph node dissection and on postoperative morbidity in patients with gastric cancer who underwent a potentially curative total gastrectomy. A total of 199 consecutive gastric cancer patients who underwent a total gastrectomy and a routine D2 lymph node dissection between 1992 and 2001 were included in the study. According to BMI, they were assigned to three groups: group A, with BMI <25 kg/m(2) (normal body weight); group B, with BMI of 25 to 30 kg/m(2) (overweight); and group C, with BMI >30 kg/m(2) (obesity). Parameters such as complete histopathological staging, intraoperative blood loss, length of operation, and surgical and nonsurgical morbidity were recorded and correlated within the different groups. RESULTS: No significant differences were found with regard to the number of examined lymph nodes, blood loss, length of operation, surgical complications, or length of stay in the intensive care unit. CONCLUSIONS: In contrast to comparable Japanese studies, our analysis reveals that even for overweight patients, a standard D2 lymph node dissection is justified without significantly increased morbidity.

Analysis of DLC-1 expression in human breast cancer.

The chromosome region 8p12-p22 shows frequent allelic loss in many neoplasms, including breast cancer (BC). The DLC-1 gene, located on 8p21-p22, might be a candidate tumor suppressor gene in this region. To evaluate the involvement of DLC-1 in breast carcinogenesis we studied DLC-1 mRNA expression in a panel of 14 primary human BC and the corresponding normal breast cells as well as 8 BC cell lines. Low levels or absence of DLC-1 mRNA were observed in 57% of primary BC and 62.5% of BC cell lines, respectively. We could not find any correlation between DLC-1 mRNA expression and deletions at the DLC-1 locus. Transfection of the gene into DLC-1 deficient T-47D cells raised the DLC-1 mRNA level and resulted in inhibition of cell growth and reduced colony-forming capacity. Our results indicate a role of DLC-1 in BC carcinogenesis.