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A 66-year-old man was diagnosed with inoperable advanced gastric cancer with liver and peritoneal metastases. The patient underwent SOX therapy as primary chemotherapy; subsequently, liver and peritoneal metastases disappeared. However, lung metastasis was detected later, and weekly paclitaxel(PTX)combined with ramucirumab(RAM)chemotherapy was initiated; subsequently, lung metastasis and advanced gastric cancer disappeared. During remission, lung metastasis was detected again. Although weekly PTX combined with RAM chemotherapy was reinitiated, a progressive disease status was achieved. As tertiary chemotherapy, nivolumab therapy(240 mg/body, every 2 weeks)was initiated for 20 courses over 11 months. This therapy was significantly effective, which aid the patient to achieve a complete response. The patient survived and is healthy for 5 years due to chemotherapy administration alone.

Purpose: A diagnostic and treatment strategy for appendiceal tumors (ATs) has not been established. We aimed to evaluate our treatment strategy for ATs including laparoscopic surgery (LS) and to identify preoperative malignancy predictors. Methods: A total of 51 patients were retrospectively reviewed. Data including tumor markers and imaging findings were compared between carcinoma and non-carcinoma patients. Validity of planned operation was evaluated based on pathological diagnosis. Results: Twenty-five patients were diagnosed with carcinoma, 13 with low-grade mucinous neoplasm, and 13 with other diseases. Symptoms were more commonly present in carcinoma patients than in non-carcinoma patients (68.0% vs. 23.1%, p=0.001). Elevated CEA and CA19-9 were more frequently observed in carcinoma patients than in non-carcinoma patients (pp=0.04, respectively). Five carcinoma patients had malignancy on biopsy, compared with zero non-carcinoma patients. Significant differences were noted in the percentages of carcinoma and non-carcinoma patients with solid enhanced mass (41.7% vs. 0%, pp=0.03) on imaging. Although the sensitivity was not high, the specificity and positive predictive value of these findings were 100%. Forty-two patients (82.4%) underwent LS as minimally invasive exploratory tool and/or radical operation, of whom 2 were converted to open surgery for invasion of adjacent organ. None of the patients had intraoperative complications or postoperative mortality. Conclusion: Clinical symptoms, elevated tumor markers, and worrisome features of solid enhanced mass and tumor wall irregularity on imaging can be malignancy predictors. For management of AT patients, LS is feasible and useful for diagnosis and treatment.

Mechanical small bowel obstruction (SBO) is a common postoperative complication, and most cases are caused by postoperative adhesions. We herein report a case of SBO with superior mesenteric vein occlusion caused by a metal staple after laparoscopic appendectomy. A 35-year-old Japanese woman presented to our department with severe upper abdominal pain and vomiting. She had undergone laparoscopic appendectomy using a linear stapler 7 years before. Abdominal CT showed mild small intestinal dilation with mesenteric edema and volvulus of the small bowel mesentery. Moreover, occlusion of the superior mesenteric vein was observed. Emergency exploratory laparoscopy revealed a strangulated SBO caused by a free unformed staple. The obstruction was released by a laparoscopic technique without bowel resection. The number of laparoscopic surgeries has recently been increasing, and complications specific to laparoscopic surgery have been recognized. All spilled and unformed staples should be removed to the greatest extent possible during laparoscopic operations.

This study aimed at investigating the function and significance of CD110 expression in pancreatic cancer. We performed immunohistochemical staining for CD110 expression in tumor samples from 86 patients with pancreatic cancer. We evaluated clinical outcomes and other clinicopathological factors to determine the significance of CD110 on survival and liver metastasis. We examine thrombopoietin–CD110 signaling in cancer cell extravasation in vitro and in vivo. We investigated the effects of CD110 knockdown on liver metastasis in a splenic xenograft mouse model. CD110 expression in cancer cells was associated with low-histological-grade invasive ductal carcinoma, and patients with high CD110 expression had poorer prognosis (P = 0.0003). High CD110 expression was an independent predictor of liver metastasis (P = 0.0422). Knockdown of CD110 expression significantly attenuated cell migration and invasion. Treatment with thrombopoietin promoted pancreatic cancer cell extravasation. In the presence of thrombopoietin, CD110 increased cell viability through the activation of the ERK–MYC signaling pathway. Knockdown of CD110 expression inhibited liver metastases in the mouse model. CD110 promotes pancreatic cancer progression and it may serve as a predictive factor for liver metastasis.

Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.

Specific cell populations leading the local invasion of cancer are called "leading cells". However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.

Pancreatic cancer is characterized by increased hyperplasia of fibrotic tissue, termed desmoplasia, and lymph node metastasis is an independent prognostic factor in this disease. However, there are no reports focused on desmoplasia in pancreatic cancer lymph node metastases. The present study evaluated a range of factors and investigated their association with poor prognosis in pancreatic cancer cases with lymph node metastasis, including the degree of desmoplasia in lesions. To identify the poor prognostic factors associated with lymph node metastasis, the present study retrospectively reviewed the clinical data of 65 patients with lymph node metastases that underwent surgical pancreatic cancer resection between 2007 and 2012 at a single institution. The investigation focused on the degree of fibrosis in metastatic lesions in 216 lymph nodes, and investigated associations with prognosis or clinicopathological findings. The ratios of the fibrotic area in metastatic lymph node lesions were evaluated and classified into three categories, high (≥70%), moderate (10–70%) and low (

Cancer‑associated fibroblasts (CAFs) promote the progression of pancreatic ductal adenocarcinoma (PDAC) via tumor‑stromal interactions. Neutrophil extracellular traps (NETs) are extracellular DNA meshworks released from neutrophils together with proteolytic enzymes against foreign pathogens. Emerging studies suggest their contribution to liver metastasis in several types of cancer. Herein, in order to investigate the role of NETs in liver metastasis in PDAC, the effects of NET inhibitors on spontaneous PDAC mouse models were evaluated. It was demonstrated that DNase I, a NET inhibitor, suppressed liver metastasis. For further investigation, further attention was paid to liver micrometastasis and an experimental liver metastasis mouse model was used that was generated by intrasplenic tumor injection. Furthermore, DNase I also suppressed liver micrometastasis and notably, CAFs accumulated in metastatic foci were significantly decreased in number. In vitro experiments revealed that pancreatic cancer cells induced NET formation and consequently NETs enhanced the migration of hepatic stellate cells, which was the possible origin of CAFs in liver metastasis. On the whole, these results suggest that NETs promote liver micrometastasis in PDAC via the activation of CAFs.

Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.

The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, inflammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis identified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pancreatic parenchyma.

A patient in his 70s was diagnosed with sigmoid colon cancer[pT3pN1cM1(PUL1), pStage IV ]for which he underwent sigmoid colectomy and received S-1 adjuvant therapy for the lung metastases. The patient received a total of 10 courses of S- 1, administered orally on days 1-14 of a 21-day cycle. The lung metastases showed a complete response, and the patient completed the S-1 chemotherapy. No recurrence of lung metastases was detected up to 6 months later.

Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. Interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction. Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruction and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs.

Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.

Background Salinomycin has cytotoxic effects on various types of malignancy and induces autophagy. However, it has not been clarified whether autophagy induced by salinomycin treatment has a protective or cytotoxic role. We investigated whether salinomycin affects autophagy in pancreatic cancer cells and whether autophagy induced by salinomycin treatment has a protective or cytotoxic role in these cells. Methods We investigated the effect of salinomycin using three pancreatic cancer cell lines. We investigated effect on proliferation and the CD133 positive fraction using flow cytometry. In addition, we monitored the change in autophagic activity after salinomycin treatment using fluorescent immunostaining, western blotting, and flow cytometry. Finally, knockdown of ATG5 or ATG7 by siRNA was used to investigate the impact of autophagy inhibition on sensitivity to salinomycin. Results Salinomycin suppressed the proliferation of pancreatic cancer cells in a concentration dependent manner, and reduced the CD133 positive fraction. Salinomycin enhanced autophagy activity in these cells in a concentration dependent manner. Autophagy inhibition made pancreatic cancer cells more sensitive to salinomycin. Conclusions Our data provide the first evidence indicating that autophagy induced by salinomycin have a protective role in pancreatic cancer cells. A new therapeutic strategy of combining salinomycin, autophagy inhibitors, and anticancer drugs could hold promise for pancreatic cancer treatment.

In 1955, Gottschalk and Hedlund introduced in their book that Jones constructed a minimal homeomorphism whose minimal set is connectd but not path-connected and contains infinitely many arcs. However the homeomorphism is defined only on this set. In 1991, Walker first constructed a homeomorphism of $S^1\times \mathbf{R}$ with such a minimal set. In this paper, we will show that Walker's homeomorphism cannot be a diffeomorphism (Theorem 2). Furthermore, we will construct a $C^\infty$ diffeomorphism of $S^1\times \mathbf{R}$ with a compact connected but not path-connected minimal set containing arcs (Theorem 1) by using the approximation by conjugation method.

Background & Aims Pancreatic stellate cells (PSCs) change from a quiescent to activated state in the tumor environment and secrete extracellular matrix (ECM) molecules and cytokines to increase the aggressiveness of tumors. However, it is not clear how PSCs are activated to produce these factors, or whether this process can be inhibited. PSCs have morphologic and functional similarities to hepatic stellate cells, which undergo autophagy to promote fibrosis and tumor growth. We investigated whether autophagy activates PSCs, which promotes development of the tumor stroma and growth of pancreatic tumors in mice. Methods We used immunofluorescence microscopy and immunohistochemistry to analyze pancreatic tumor specimens from 133 patients who underwent pancreatectomy in Japan from 2000 to 2009. PSCs were cultured from pancreatic tumor tissues or tissues of patients with chronic pancreatitis; these were analyzed by immunofluorescence microscopy, immunoblots, quantitative reverse transcription polymerase chain reaction, and in assays for invasiveness, proliferation, and lipid droplets. Autophagy was inhibited in PSCs by administration of chloroquine or transfection with small interfering RNAs. Proteins were knocked down in immortalized PSCs by expression of small hairpin RNAs. Cells were transplanted into pancreatic tails of nude mice, and tumor growth and metastasis were quantified. Results Based on immunohistochemical analyses, autophagy was significantly associated with tumor T category ( P = .018), histologic grade ( P = .001), lymph node metastases ( P P = .009), perilymphatic invasion ( P = .001), and perivascular invasion ( P = .003). Autophagy of PSCs was associated with shorter survival times of patients with pancreatic cancer. PSC expression of microtubule-associated protein 1 light chain 3, a marker of autophagosomes, was associated with poor outcomes (shorter survival time, disease recurrence) for patients with pancreatic cancer (relative risk of shorter survival time, 1.56). Immunoblots showed that PSCs from pancreatic tumor samples expressed higher levels of markers of autophagy than PSCs from chronic pancreatitis samples. Inhibitors of autophagy increased the number of lipid droplets of PSCs, indicating a quiescent state of PSCs, and reduced their production of ECM molecules and interleukin 6, as well as their proliferation and invasiveness in culture. PSCs exposed to autophagy inhibitors formed smaller tumors in nude mice ( P = .001) and fewer liver metastases ( P = .018) with less peritoneal dissemination ( P = .018) compared to PSCs not exposed to autophagy inhibitors. Conclusions Autophagic PSCs produce ECM molecules and interleukin 6 and are associated with shorter survival times and disease recurrence in patients with pancreatic cancer. Inhibitors of PSC autophagy might reduce pancreatic tumor invasiveness by altering the tumor stroma.

A patient in his 70s was diagnosed with rectal cancer (pT3, pN1, cM0, and pStage IIIa) for which he underwent low anterior resection of the rectum and received adjuvant therapy with UFT/LV. Multiple liver, lung, and para-aortic lymph node metastases were detected after 6 months, and the patient then received a total of 24 courses of FOLFOX4 plus bevacizumab instead of UFT/LV. The liver and para-aortic lymph node metastases showed a complete response (CR), and the lung metastases markedly diminished. Therefore, the patient completed the FOLFOX4 plus bevacizumab chemotherapy regimen. After 2 years, a recurrence of the initial liver metastases was detected. A CR on radiological imaging does not correspond to a pathological CR. Therefore, a careful follow-upis required even when a CR on radiological imaging is achieved.

Let ’t be a nonsingular flow on a 3-dimensional manifold M. Denote by P : PX ! M the projectivized bundle of the quotient bundle of TM by the line bundle tangent to’t. The derivative of’t induces a flow t on PX, called the projective flow of ’t. In this paper, we consider the dynamical properties of t restricted to 1 P (M) for a minimal set M of’t, under the condition that the restriction of t to 1 P (M) has exactly two minimal sets N1 and N2. If’t has no dominated splitting over M, we find two types of orbits of t in the domain between N1 and N2: one is “bounded below” and the other is “bounded above”. As an application we prove that, if’t is further assumed to be almost periodic on the minimal set, there is a dense orbit in that domain.

A nonsingular flow $\varphi_t$ on a $3$-manifold induces a flow on the plane bundle orthogonal to $\varphi_t$ by the derivative. This flow also induces a flow $\psi_t$ on its projectivized bundle $PX$, which is called the projective flow. In this paper, we will investigate this projective flow in order to understand the original flow $\varphi_t$, in particular, under the condition that $\varphi_t$ is minimal and $\psi_t$ has more than one minimal sets: If the projective flow $\psi_t$ has more than two minimal sets, then we will show that $\varphi_t$ is topologically equivalent to an irrational flow on the $3$-torus. In the case when $\psi_t$ has exactly two minimal sets, then we obtain several properties of the minimal sets of $\psi_t$. In particular, we construct two $C^\infty$ sections to $PX$ which separate these minimal sets (and hence $PX$ is a trivial bundle) if $\varphi_t$ is not topologically equivalent to an irrational flow on the $3$-torus. As an application of this characterization, the chain recurrent set of the projective flow is shown to be the whole $PX$.

One of substantial problems in dynamical systems is to characterize the topological types of minimal sets. In this paper, we are concerned with locally connected minimal sets of surface homeomorphisms. In the case of a homeomorphism of a closed orientable surface dieren t from the torus, we obtain that its locally connected minimal set is either a nite set or a nite disjoint union of simple closed curves. On the other hand, there is a homeomorphism of the torus with a locally connected minimal set which is neither a nite set nor a nite disjoint union of simple closed curves nor the whole torus. We will show that, if such a minimal set exists, then the minimal set is unique and it satises conditions similar to those of the Sierpi nski curve.

A non-singular C 1 vector field X of a closed 3-manifold M generating a flow \( \varphi_t \) induces a flow of the bundle N X orthogonal to X. This flow further induces a flow \( P \varphi_t \) of the projectivized bundle of N X. In this paper, we assume that the projectivized bundle is a trivial bundle, and study the lift \( \angle\varphi_t \) of \( P \varphi_t \) to the infinite cyclic covering \( M \times \mathbb{R}\). We prove that the flow \( \angle\varphi_t \) is not minimal, and construct an example of \( \varphi_t \) such that \( \angle\varphi_t \) has a dense orbit. If \( \varphi_t \) is almost periodic and minimal, then \( \angle\varphi_t \) is shown to be classified into three cases: (1) All the orbits of \( \angle\varphi_t \) are bounded. (2) All the orbits of \( \angle\varphi_t \) are proper. (3) \( \angle\varphi_t \) is transitive.

A total of 47 cases of malignant schwannoma of the stomach appeared in the Japanese literature including seven operated cases in our clinic were clinically surveyed. Limited to our seven cases, gastric malignant schwannomas represented 0.3% of all gastric cancers and 8.5% of all gastric sarcomas in our clinic. In the cumulative series, the male-to-female ratio was equal and the age at hospitalization was 56.1 in an average. In over half of these cases, the tumor occurred at upper 1/3 region of the stomach and the endogastric type was most common, reached 44% in a frequency. Deep ulceration with central necrosis in the tumor was seen in 56.4%. Both submucosal tumor without any further description and Leiomyosarcoma were main preoperative diagnosis, each occupied 36%. Acurate preoperative diagnosis as malignant shcwannoma was made in only 11.6%. Immunohistochemical staining for S-100 protein in biopsied or removed materials revealed positive in 87.1%, suggesting the usefulness of this examination. Metastasis on laparotomy was found in 23.8% in the liver, 9.5% in lymph nodes and 4.8% in the peritoneum. Of the own seven patients, curative resection was feasible in four patients and the remaining three patients died of progression of the residual tumor within postoperative 2 years. Therefore, an effort for curative resection should be made at present and otherwise intra- or postoperative chemotherapy would be necessary in advanced cases.

Let $f$ be an orientation preserving homeomorphism of $S^2$ which has a (nontrivial) continuum $X$ as a minimal set. Then there are exactly two connected components of $S^2\setminus X$ which are left invariant by $f$ and all the others are wandering. The Carath\'eodory rotation number of an invariant component is irrational., Comment: 16 pages, 15 figures

Using methods and results of decomposition theory we construct minimal actions of groups of homeomorphisms of some classical fractals (the Sierpi\'nski carpet and its generalizations, and the Menger curve) with positive entropy. Suspending these group actions we get minimal foliated spaces which have positive geometric entropy and are modelled on these fractals.

The Ruelle invariants for non-singular flows of a 3-dimensional manifold and diffeomorphisms of the disc are described by invariant fiber measures, which are families of probability measures on the fibers of the projectivized bundle invariant under the holonomies among almost all fibers. The dynamical properties of invariant fiber measures are also given, which show the benefit of this description.

For any diffeomorphism f of the two torus T^2 isotopic to the identity, the Ruelle invariant {\mathcal R}_\mu(f) is shown to vanish for some f -invariant probability measure \mu .