We report the surgical case of advanced esophageal cancer with cirrhosis in a patient who has been cancer-free for 6 years after overcoming anastomotic leakage, purulent osteomyelitis, cervical lymph node recurrence, and systemic edema. A 69-year-old woman visited our hospital and presented with the complaint of a food sticking sensation. Endoscopic findings showed a type 3 tumor in the middle thoracic esophagus. Esophagectomy was subsequently performed. Histopathological findings revealed poorly differentiated squamous cell carcinoma, Mt, 17×15 mm, type 3, pT3, pIM0, pPM0, pDM0, pRM0, pN2(7/18), pStage Ⅲ, and liver cirrhosis(F4, A1-2). Postoperative suture failure was observed; however, it conservatively improved in approximately 2 months. The patient had lower back pain since approximately 6 weeks after the surgery, and she was diagnosed with purulent spondylitis and was administered antibiotics. The patient was subsequently discharged 67 days after the surgery. One course of 5-FU+CDDP was administered as postoperative adjuvant chemotherapy. However, renal function deteriorated, and chemotherapy was discontinued. Four months after the surgery, cervical echography revealed recurrence in the left cervical lymph node, and docetaxel(DTX)was administered. Five DTX doses were administered, because of which the left cervical lymph nodes markedly shrunk. Moreover, the sixth dose of DTX resulted in febrile neutropenia and a large amount of abdominal pleural effusion. Consequently, the patient was hospitalized. Tolvaptan treatment was extremely effective, and the thoracic ascites disappeared. Esophageal cancer has not recurred, and the patient is being observed at an outpatient clinic 6 years after the surgery.

Stage Ⅳ gastric cancer(GC)with ovarian metastasis showed poor prognosis and its treatment strategy remains unclear. Recent studies identified the favorable prognostic effect of conversion surgery in Stage Ⅳ GC following intensive chemotherapy. We report here a case with advanced GC and ovarian metastasis, who underwent conversion surgery for them followed by chemotherapy and had a long-term survival. We reviewed the literatures in order to discuss clinical significance of our treatment strategy.

With the advancement of endoscopic resection(ER)of colorectal cancer, surgical resection after ER has been increasing. This study evaluated the effects of initial ER on short- and long-term outcomes in T1b colorectal cancer. This retrospective cohort study enrolled patients with pathological T1b colorectal cancer who underwent colorectal surgical resection between 2008 and 2018. A total of 239 eligible patients were divided into 2 groups: patients initially treated using surgical resection with lymph node dissection(LND)(surgery alone, n=142)and patients treated using initial ER and additional surgical resection with LND(surgery after ER, n=97). No significant differences were observed in short-term outcomes(ie, operative time, blood loss, or postoperative complications)or the long-term outcomes(ie, recurrence rate, overall survival rate, or recurrence free survival rate)between groups.

In Japan, the standard treatment for squamous cell anal cancer(SCAC)has not been established. Herein, we report a case of SCAC that completely responded to chemoradiotherapy(CRT).

A 55-year-old man was referred for surgery after colonoscopy revealed type 3 advanced lower rectal cancer in the lower rectum. CT and MRI scan showed no distant metastasis but on the left side of the rectum, there was a 34×30 mm large mass suspicious of lymph node metastasis, which had left-sided wall pelvic fascia invasion. We performed preoperative chemoradiotherapy(CRT)to ensure a secure surgical margin. As a result, the tumor volume was reduced and robot-assisted rectal amputation and bilateral lateral lymph node dissection were performed using a combined transperineal speculum approach. The pathological results showed that circumferential resection margin of 3 mm was secured. The lymph nodes on the left side of the rectum were mostly fibrotic and the tumor component had almost disappeared. Preoperative CRT is useful for securing the surgical margin. The multidisciplinary treatment including extended surgery enabled the curative resection of even highly advanced rectal cancer.

The risk factors for recurrence in patients with pStage Ⅱ colorectal cancer still remains controversial. The aim of this study was to investigate the risk factors for recurrence after surgery in patients with pStage Ⅱ colorectal cancer.

Adenocarcinoma of the rete testis is a rare malignant tumor with poor prognosis. We report a case of adenocarcinoma of the rete testis. A 55-year-old man became aware of discomfort in the right scrotum. Negative results were obtained for the serum markers AFP, β-human chorionic gonadotropin (β-HCG), and LDH. Computed tomography (CT) showed enhancement of the right testis. Radical orchiectomy was performed. Immunohistochemical examination of the resected specimen showed positive results for CEA, and adenocarcinoma of the rete testis was diagnosed. Serum CEA level was elevated. CT showed swelling of the para-aortic lymph nodes. Retroperitoneal lymph node dissection (RPLND) was performed, and serum CEA then normalized. The patient developed penile metastases 4 months after RPLND, and serum CEA level again increased. Total penile resection was performed. TIP (Paclitaxel, Ifosfamide, Cisplatin) therapy was started after lung metastasis and increased serum CEA were identified. CT after 2 cycles of TIP therapy revealed disappearance of lung metastasis and normalization of serum CEA. Five months later, CT showed recurrence of lung metastases.

A 75-year-old woman was admitted to our hospital with suspected gastrointestinal perforation and underwent emergency surgery. Bladder perforation was revealed during the surgery, and she was referred to our department. We detected a tumor on the apex of the bladder and performed partial resection of the bladder. Based on histopathological examination, a diagnosis of urachal cancer was established. Gemcitabine and cisplatin (GC) therapy was administered as an adjuvant therapy because of the high risk of peritoneal dissemination. She had the purulent spondylitis and gluteus medius abscess at the first course of GC therapy. We stopped GC therapy within the first course due to the adverse events and decreased performance status. Computed tomography revealed tumor recurrence in the pelvis three months after discontinuation of GC therapy. As the companion diagnostics revealed MSI-High, we administrated pembrolizumab. She was taking prednisolone 5 mg for SLE, but stable disease was observed after 5 courses of pembrolizumab. However, pembrolizumab was discontinued for eight months due to the stent graft insertion for the common iliac artery aneurysm. She had progressive disease after eight months interval of treatment. We restarted pembrolizumab but she was hospitalized for tumor fever after a total of eight courses. The patient died a month later. This seems to be the first case wherein pembrolizumab was administered for urachal cancer with MSI-High.

(Objectives)The usefulness of partial nephrectomy for renal tumors has been highlighted in various guidelines. Since 2006, we have been actively performing laparoscopic partial nephrectomy for renal tumors. We investigated the postoperative recurrence of renal tumors diagnosed as renal cell carcinoma after laparoscopic partial nephrectomy. (Patients and methods)From August 2006 to March 2020, 320 patients who underwent laparoscopic partial nephrectomy at our hospital and were pathologically diagnosed with renal cancer were included. A retrospective statistical study was conducted to analyze the postoperative recurrence. (Results)Postoperative recurrence was observed in 11 patients (3.4%). The median time to recurrence was 12 months (3-26 months), non-distant metastasis was observed in four cases (1.3%), and distant metastasis was observed in seven cases (2.2%). No statistically significant difference was found in the factors related to recurrence, in this study. (Conclusions)In this study, no statistically significant factors were found, but the higher the clinical stage, the higher the recurrence rate.

(Purpose) This study examined the usefulness of positron emission tomography (PET) / computed tomography (CT) in the diagnosis of metastasis in patients with urothelial carcinoma. (Materials and methods) The subjects were patients who were newly diagnosed with urothelial carcinoma in our department on whom we performed CT and PET/CT to search for metastasis. (Results) The median age of the 92 subjects was 71 years, and bladder and upper tract urotherial cancer were underlying diseases in 41 (46%) and 51 (54%) patients, respectively. In 66 (72%) of the 92 cases, no metastasis was observed by CT, while PET/CT revealed metastasis in 9 (14%). The 57 (86%) patients in whom both CT and PET/CT showed no metastasis underwent radical surgery, while 2 patients (4%) exhibited pathological lymph node metastasis.Of the 26 patients in whom CT revealed metastasis, PET/CT showed no metastasis in 3 (12%), and the absence of pathological metastasis was confirmed in all patients. Of the 23 patients found to have metastasis in both CT and PET/CT, metastasis that could not be identified by CT was discovered by performing PET/CT in 10 (43%) patients.PET/CT showed significantly higher diagnostic accuracy than CT alone (p< 0.01), with sensitivities of 94.1% and 67.6%, specificities of 100% and 94.8%, and positive diagnosis rates of 97.8% and 84.7%, respectively. (Conclusions) PET/CT in patients with urothelial cancer revealed that metastases that cannot be diagnosed by CT alone are found at a significant frequency. Since these metastases can affect treatment choices in patients with urothelial cancer, PET/CT is considered to be useful in diagnosing patients with urothelial cancer.

In the development of drug delivery system (DDS)-based anticancer drugs, the techniques for the intratumor mapping and quantification of active pharmaceutical ingredients (API) in pharmaceuticals must be pivotal for predicting pharmacological effects and adverse events. X-ray fluorescence spectrometry (XRF) is a potent analytical tool for mapping/quantifying platinum pharmaceutics such as oxaliplatin (l-OHP) and its liposomal formulation. In recent studies, we employed XRF to visualize the intratumor micro-distribution of l-OHP in a tumor-bearing model mouse intravenously injected with either free l-OHP or l-OHP liposomes. The intratumor distribution of l-OHP within tumor sections could be determined by XRF to detect platinum atoms. After treatment with the liposomal formulation, the l-OHP was localized near the tumor vessels and, via repeated injections, increasingly accumulated in tumors by a much greater degree than treatment with free l-OHP. The repeated injections of l-OHP liposomes improved the vascular permeability via inducing the apoptosis of tumor cells near the tumor vessels, which should improve the tumor microenvironment and enhance the intratumor accumulation of repeated doses of l-OHP liposomes. The proposed process was also used to visualize the intratumor distribution of l-OHP in rectal cancer specimens resected from a patient who had received l-OHP-based preoperative chemotherapy. We further revealed that neutralization of an acidic tumor microenvironment via oral administration with NaHCO3 could improve the therapeutic efficacy of weakly basic anticancer agent-encapsulating liposomes. Collectively, mapping/quantifying the intratumor API in DDS drugs and/or improving the tumor microenvironment would be an effective means to accelerate the clinical development of DDS-based anticancer drugs.

Epithelial-mesenchymal transition (EMT) is an important program in epithelial cancer cells to acquire the motility and invasion, which promotes cancer metastasis to remote organs. EMT is induced by various secreted factors, such as transforming growth factor-β (TGF-β) and epidermal growth factor (EGF). TGF-β ligand activates Smad-dependent and -independent pathways by binding to TGF-β receptors. In Smad-dependent pathway, the activated TGF-β receptor phosphorylates Smad2/3 and accelerates its association with Smad4, leading to their nuclear translocation. Smad2/3-4 complex promotes the expression of EMT-inducing transcription factors, such as Snail and Slug. In Smad-independent pathway, mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are activated and required for TGF-β-induced EMT. Smad-independent pathway is similar to downstream of receptor tyrosine kinases, and therefore EGFR signaling is known to induce EMT synergize with TGF-β signaling. We explored a new mechanism of EGFR-mediated activation of TGF-β signaling and found that c-Abl kinase activates TGF-β signaling. Based on our proteomic analysis, we identified several TGF-β signaling molecules as nuclear c-Abl substrates, including transcriptional intermediary factor 1-γ (TIF1γ/TRIM33/Ectodermin), a suppressor of TGF-β signaling. c-Abl-mediated phosphorylation of TIF1γ inhibits its binding to Smad3, thereby increasing Smad3's transcriptional activity and promoting EMT. TIF1γ phosphorylation is also involved in the EGFR-caused aberrant activation of TGF-β signaling, suggesting that EGFR/c-Abl pathway activates TGF-β signaling through phosphorylation of nuclear substrates and promotes EMT. Our findings provide new insights into the activation machinery of TGF-β signaling, and further studies are required to clarify the clinical significance of the EGFR/c-Abl pathway in cancer metastasis.

P-type ion pumps (P-type ATPases) are involved in various fundamental biological processes. For example, the gastric proton pump (H+,K+-ATPase) and sodium pump (Na+,K+-ATPase) are responsible for secretion of gastric acid and maintenance of cell membrane potential, respectively. In this review, we summarize three topics of our studies. The first topic is gastric H+,K+-ATPase associated with Cl--transporting proteins (Cl-/H+ exchanger ClC-5 and K+-Cl- cotransporter KCC4). In gastric parietal cells, we found that ClC-5 is predominantly expressed in intracellular tubulovesicles and that KCC4 is predominantly expressed in the apical membrane. Gastric acid (HCl) secretion may be accomplished by the two different complexes of H+,K+-ATPase and Cl--transporting protein. The second topic focuses on the Na+,K+-ATPase α1-isoform (α1NaK) associated with the volume-regulated anion channel (VRAC). In the cholesterol-enriched membrane microdomains of human cancer cells, we found that α1NaK has a receptor-like (non-pumping) function and that binding of low concentrations (nM level) of cardiac glycosides to α1NaK activates VRAC and exerts anti-cancer effects without affecting the pumping function of α1NaK. The third topic is the Na+,K+-ATPase α3-isoform (α3NaK) in human cancer cells. We found that α3NaK is abnormally expressed in the intracellular vesicles of attached cancer cells and that the plasma membrane translocation of α3NaK upon cell detachment contributes to the survival of metastatic cancer cells. Our results indicate that multiple functions of P-type ion pumps are generated by different membrane environments and their associated proteins.

Plasma medicine is a rapidly expanding new field of interdisciplinary research that combines physics, chemistry, biology, and medicine. Non-thermal atmospheric pressure plasma (NTAPP) has recently been applied to living cells and tissues, and has emerged as a novel technology for medical applications, such as wound healing, blood coagulation, and cancer treatment. NTAPP was found to affect cells indirectly through the treatment of cells with previously prepared medium irradiated by NTAPP, termed plasma-activated medium (PAM). The treatment of culture media with NTAPP results in the generation of a large amount of reactive oxygen species and reactive nitrogen species, and their derived species. We found that PAM triggered a spiral apoptotic cascade in the mitochondrial-nuclear network in A549 cancer cells. This process induced the depletion of total cellular NAD+ and elevations in intracellular calcium ion, ultimately leading to cell death. We also detected the production of hydroxyl radical and elevations in intracellular ferrous ions in PAM-treated cells. The elevations observed in ferrous ions may have been due to their release from the intracellular iron store, ferritin. However, difficulties are associated with applying PAM to the clinical phase because culture media cannot be used for medical treatments. The anti-tumor activity of plasma-activated Ringer's solution was significantly stronger than that of PAM. At the end, we herein demonstrated the advantages of the combined application of plasma-activated acetate Ringer's solution and hyperthermia, a heat treatment at 42℃, for A549 cancer cell death and elucidated the underlying mechanisms.