Non-CpG sites preference in G:C > A:T transition of TP53 in gastric cancer of Eastern Europe (Poland, Romania and Hungary) compared to East Asian countries (China and Japan).

AIM: Mutation spectrum of TP53 in gastric cancer (GC) has been investigated world-widely, but a comparison of mutation spectrum among GCs from various regions in the world are still sparsely documented. In order to identify the difference of TP53 mutation spectrum in GCs in Eastern Europe and in East Asia, we sequenced TP53 in GCs from Eastern Europe, Lujiang (China), and Yokohama, Kanagawa (Japan) and identified the feature of TP53 mutations of GC in these regions. SUBJECTS AND METHOD: In total, 689 tissue samples of GC were analyzed: 288 samples from East European populations (25 from Hungary, 71 from Poland and 192 from Romania), 268 from Yokohama, Kanagawa, Japan and 133 from Lujiang, Anhui province, China. DNA was extracted from FFPE tissue of Chinese, East European cases; and from frozen tissue of Japanese GCs. PCR products were direct-sequenced by Sanger method, and in ambiguous cases, PCR product was cloned and up to 8 clones were sequenced. We used No. NC_000017.11(hg38) as the reference sequence of TP53. Mutation patterns were categorized into nine groups: six base substitutions, insertion, deletion and deletion-insertion. Within G:C > A:T mutations the mutations in CpG and non-CpG sites were divided. The Cancer Genome Atlas data (TCGA, ver.R20, July, 2019) having somatic mutation list of GCs from Whites, Asians, and other ethnicities were used as a reference for our data. RESULTS: The most frequent base substitutions were G:C > A:T transition in all the areas investigated. The G:C > A:T transition in non-CpG sites were prominent in East European GCs, compared with Asian ones. Mutation pattern from TCGA data revealed the same trend between GCs from White (TCGA category) vs Asian countries. Chinese and Japanese GCs showed higher ratio of G:C > A:T transition in CpG sites and A:T > G:C mutation was more prevalent in Asian countries. CONCLUSION: The divergence in mutation spectrum of GC in different areas in the world may reflect various pathogeneses and etiologies of GC, region to region. Diversified mutation spectrum in GC in Eastern Europe may suggest GC in Europe has different carcinogenic pathway of those from Asia.

Maspin-related Orchestration of Aggressiveness of Gastric Cancer.

BACKGROUND AND STUDY AIM: Although some hypotheses have been postulated on the genesis of gastric cancer (GC), the origin of this disease remains unclear. The aim of this study was to develop a hypothesis about gastric carcinogenesis based on our experience in the field of GC and on published reports on about 28 studies in the field of subcellular maspin expression in GC. In 180 cases of GC, the clinicopathologic features were correlated with the results obtained after paired immunohistochemical stains (tumor/normal mucosa) with 15 antibodies: E-cadherin, HER-2, VEGF, CD31, CD105, COX-2, maspin, bax, bcl-2, p53, Ki67, MLH-1, MSH-2, Mena protein, and vimentin. RESULTS: Cytoplasmic maspin was observed in foveolar cells with intestinal metaplasia, whereas mixed (combined nuclear-cytoplasmic) expressions were more characteristic of the intramucosal foci of signet-ring cells and dysplastic cells. The tumor cells that expressed cytoplasmic maspin were mostly intestinal type bax/COX-2/Mena/E-cadherin-positive differentiated adenocarcinomas with nodular growth and more superficial invasion. The nuclear shift of maspin was more frequent in HER-2/p53-positive intestinal type adenocarcinomas with diffuse architecture at the invasion front, as well as for node-positive poorly cohesive carcinomas. Loss of maspin expression induced a higher risk of distant metastases, without differences in the survival rate. CONCLUSIONS: In GC with associated metaplasia, cytoplasmic maspin is predominant; the nuclear shift induces local aggressiveness and risk of node metastases, whereas total loss can indicate a risk of distant metastases. In GC without associated metaplasia, nuclear expression of maspin is retained, indicating a more aggressive behavior.

Geographic particularities in incidence and etiopathogenesis of sporadic gastric cancer.

It is known that geographical differences in the prevalence and etiopathogenesis of gastric cancer exist across the world. Eastern Europe and East Asia are two of the largest endemic areas of gastric cancer in the world, yet there are few studies comparing its features in these two regions. Based on our experience and literature data, we performed a review that is mainly focused on the etiology and pathogenesis of sporadic gastric cancer and its geographic particularities. Geographic prevalence of specific Helicobacter pylori strains is also synthesized. The pathogenesis of gastric cancer in patients from countries of the authors, respectively Japan, Romania, Hungary and Poland, is particularly examined.

Aberrant metastatic behavior and particular features of early gastric cancer.

In this paper, we have focused on the metastatic behavior of EGC and its particularities. The main factors that are currently considered as predictors of the metastatic behavior and that are used in the therapeutic decision (endoscopic resection vs surgical removal) are the tumor size (upper or bellow 2 cm), depth of infiltration, angiolymphatic invasion, the presence or absence of ulceration, and histologic type (undifferentiated vs differentiated carcinomas). However, most of the metastatic cases were published as case reports or case series. This is the reason why a proper estimation of metastatic risk in EGC is not well known. To date, 79 cases presenting bone metastases, three reports of brain metastases, and one EGC that was associated with skin metastasis were published. However, occult metastasis, lymph node micrometastasis, and skip metastasis can also occur and should be identified. Making a synthesis of the literature data that is correlated with our experience, we finally proposed the inclusion of the six Japanese subgrouping system, tumor size, angiolymphatic invasion, and micrometastasis as components of the pTNM staging system, which should be particularly adapted for EGC.

Single skip metastasis in sentinel lymph node: In an early gastric cancer.

Lymph node status is considered a key prognostic and predictive factor in patients with gastric cancer (GC). Although there is a practical approach to the intraoperative detection of sentinel lymph nodes (SLNs), such a procedure is not included in the European surgical protocol. In this report, we present a practical approach to SLN mapping in a representative case with early gastric cancer (EGC). A 74-year-old female was hospitalized with an endoscopically observed, superficially ulcerated tumor located in the antral region. Subtotal gastrectomy with D2 lymphadenectomy and SLN mapping was performed by injecting methylene blue dye into the peritumoral submucosal layer. An incidentally detected blue-stained lymph node located along the middle colic artery was also removed. This was detected 40 min after injection of the methylene blue. Histopathologic examination showed a pT1b-staged well-differentiated HER-2-negative adenocarcinoma. All of the 41 LNs located at the first, third, and fifth station of the regional LN compartments were found to be free of tumor cells. The only lymph node with metastasis was located along the middle colic artery and was considered a non-regional lymph node. This incidentally identified skip metastasis indicated stage IV GC. A classic chemotherapy regimen was given, and no recurrences were observed six months after surgery. In this representative case, low-cost SLN mapping, with a longer intraoperative waiting time, totally changed the stage of the tumor in a patient with EGC.

Hereditary diffuse gastric cancer--An overview.

The incidence of gastric cancer varies by up to ten fold throughout the world, and the geographic distribution of hereditary cases is not well explored. Familial clustering is seen in 10% of cases, and approximately 3% of all gastric cancers develop due to hereditary diffuse gastric cancer (HDGC). In this review, the characteristics of HDGC are presented according to molecular particularities, geographic distribution, and other parameters. Based on our experience and the data from the literature, we discuss the possibility of applying a mutation signature (spectrum) study and adductomic approaches to a comparative carcinogenesis of HDGC. We also provide a comprehensive, up-to-date review of genetic counseling and criteria for screening and surveillance of eligible families.

Gastric cancer in young vs old Romanian patients: immunoprofile with emphasis on maspin and mena protein reactivity.

Increasing number of early-onset gastric carcinomas (GCs) and controversial results regarding the differences among young and older patients with this type of cancer are the reasons why correlation of clinicopathological factors with molecular markers is necessary. The aim of our study was to compare the demographic, clinical and immunohistochemical (IHC) aspects in Romanian patients with GC diagnosed below and above 45 years old. In 191 samples provided from patients with GC, the clinicopathological parameters were correlated with a panel of 15 antibodies: E-cadherin, HER-2, VEGF, CD31, CD105, COX-2, maspin, bax, bcl-2, p53, Ki67, MLH-1, MSH-2, mena protein and vimentin. Compared to the conventional cases, GCs diagnosed below 45 years old were more frequently located at the gastroesophageal junction and presented a higher percentage of lymph node metastases. The diffuse type E-cadherin/mena/p53/Ki67/bax-negative cases that displayed nuclear maspin positivity were also more frequently in younger patients. The intestinal type early-onset GCs were the most angiogenic ones, the apoptotic rate being lower than in the intestinal type GCs of the aged. Compared to the conventional cases, in the early-onset GCs the nuclear maspin-mediated antiproliferative activity is more intense in diffuse type while the mena-dependent tumor cell proliferation is more characteristic for intestinal type GCs.

Mixed adenoneuroendocrine carcinoma of gastrointestinal tract: report of two cases.

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare tumor of the gastrointestinal tract that consists of a dual adenocarcinomatous and neuroendocrine differentiation, each component representing at least 30% of the tumor. To date, only seven cases have been reported in the cecum, and less than 40 in the stomach. Our first case was diagnosed in a 74-years-old female as a polypoid lesion of the cecum with direct invasion in the transverse colon, without lymph node metastases. The second case was diagnosed in the stomach of a 46-years-old male as a polypoid tumor of the antral region that invaded the pancreas and presented metastases in 22 regional lymph nodes. The metastatic tissue was represented by the glandular component. In both cases, the tumor consisted of a moderately-differentiated tubular adenocarcinoma (with mucinous component in Case 1) intermingled with neuroendocrine carcinoma. Ki67 index was lower than 20% in Case 1, respectively higher than 20% in Case 2. The neuroendocrine component was marked by synaptophysin and neuron specific enolase, being negative for Keratins 7/20. The neuroendocrine component represented 60% in Case 1, and 40% in Case 2, respectively. The glandular components were marked by carcinoembryonic antigen, maspin and keratin 20/7 (Case 1/2). Both cases were proved to be microsatellite stable. Independently by the localization and tumor stage, MANECs appear to be highly malignant tumors, with high risk for distant metastases. The aggressiveness seems to depend on the endocrine component, independent of its proportion. The neuroendocrine component could be a dedifferentiated adenocarcinoma with a neuroendocrine phenotype.

Giant gastrointestinal stromal tumor of the stomach: a challenging diagnostic and therapeutically approach.

Gastrointestinal stromal tumors (GISTs) are rare but challenging tumors regarding the diagnosis and therapy. The symptomatology depends on the tumor size and location, and can be totally non-specific, as in the present case. We present the case of a 76-year-old female that was hospitalized with postprandial nausea and vomiting. Bulging of the posterior wall of the stomach was seen at endoscopically examination and confirmed by the computed tomography. Surgical resection of the 120×100 mm-sized tumor that involved the posterior gastric wall and gastrocolic ligament, was performed; the posterior wall of the stomach was also partially excised. Histological examination revealed a 120×95×70 mm nodular tumor with solid aspect and large necrotic and hemorrhagic area on cut section. The tumor cells were marked by c-KIT, DOG-1, smooth muscle actin and MSH-2 and were negative for Ki67, maspin, E-cadherin, S-100, and keratin AE1÷AE3. The resection margins were free of tumor cells. No recurrences were reported three years after surgical intervention; no postoperative chemotherapy was performed. This case highlights that a well-conducted trans-disciplinary approach can have real benefits, even in borderline-operable giant potentially-malignant GISTs. New criteria to establish the malignant potential of GIST should be explored.

Clinical significance of carcinoembryonic antigen expression of acellular mucin pools after preoperative chemoradiotherapy of rectal carcinoma.

INTRODUCTION: Although several studies have shown that the presence of acellular mucin pools in surgical specimens with rectal carcinomas examined after preoperative chemoradiotherapy indicated complete response to therapy, the proper meaning of these pools has yet to be elucidated. The aims of this study were to analyze the immunoprofile of acellular mucin pools and to review the relevant literature. METHODS: In 30 consecutive rectal cancers that were preoperatively treated with chemoradiotherapy, the clinicopathologic features were correlated with the immunoexpression of AE1/AE3 keratin and carcinoembryonic antigen (CEA). RESULTS: Acellular mucin pools were present in all the cases, independently by their preoperative histological aspect. In remnant tumors (n=20), they were present at the invasion front and were marked by CEA. In cases without remnant tumor cells (n=10), they also displayed CEA positivity. In 2 of the 10 cases, isolated tumor cells were identified after multilevel sectioning of paraffin-embedded blocks. CONCLUSIONS: The presence of acellular mucin pools in surgical specimens of rectal cancers cannot be interpreted as an indicator of complete response to radiotherapy if at least 10 multilevel sections are performed in at least three tumor blocks per case, and CEA negativity is not proved.

Lethal cardiotoxicity, steatohepatitis, chronic pancreatitis, and acute enteritis induced by capecitabine and oxaliplatin in a 36-year-old woman.

A 36-year-old female was hospitalized with symptoms suggesting intestinal occlusion. She was diagnosed with adenocarcinoma of the ampulla of Vater (pT4N0 stage) and underwent cephalic duodenopancreatectomy 8 months ago. Five cycles of postoperative chemotherapy were administrated using capecitabine and oxaliplatin (CAPOX or XELOX), the last one being completed 1 month ago. During the present hospitalization, because of normal computed tomography and ultrasound abdominal examination, rehydration and antibiotherapy were administrated. However, 4 days after hospital admission, the patient died. At autopsy and histological examination, we found a severe myocardial sclerosis with large scarring areas, severe steatohepatitis, chronic pancreatitis with large fibrotic areas, and acute enteritis. Alcohol consumption was denied. The patient died due to associated heart, liver and pancreatic failure. This multiorgan toxicity and death following CAPOX regimen had not yet been reported in the literature. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6472150549833105.

Quantum transport enhancement by time-reversal symmetry breaking.

Quantum mechanics still provides new unexpected effects when considering the transport of energy and information. Models of continuous time quantum walks, which implicitly use time-reversal symmetric Hamiltonians, have been intensely used to investigate the effectiveness of transport. Here we show how breaking time-reversal symmetry of the unitary dynamics in this model can enable directional control, enhancement, and suppression of quantum transport. Examples ranging from exciton transport to complex networks are presented. This opens new prospects for more efficient methods to transport energy and information.