Laparoscopic Resection Combined with a Transsacral Approach for a Recurrent Tailgut Cyst with a Refractory Fistula.

Tailgut cyst is a rare cystic disease of the anterior sacral surface and the remains of an embryonic tail gut. Tailgut cysts have a potential for malignancy, and complete resection with an adequate surgical margin is necessary. Even if incomplete resection does not result in recurrence of malignant disease, there is a risk of local infection leading to refractory fistulas. The optimal treatment for such refractory recurrent lesions has not been reported. We describe a case in which the combination of laparoscopic and transsacral approaches was effective for resecting a recurrent refractory fistula after incomplete resection of a tail gut cyst.

Perioperative and Postoperative Continuous Nutritional Counseling Improves Quality of Life of Gastric Cancer Patient Undergoing Gastrectomy.

Post-gastrectomy syndrome (PGS) and body weight loss (BWL) decrease quality of life (QOL) and survival of the patient undergoing gastrectomy. We have introduced perioperative and post-discharge continuous nutritional counseling (CNC) to prevent BWL and improve QOL after gastrectomy. In the present study, we evaluated the effect of CNC on QOL using the Post-gastrectomy Syndrome Assessment Scale-45 (PGSAS-45). Eighty-three patients with gastric cancer (GC) who underwent curative gastrectomy between March 2018 and July 2019 were retrospectively analyzed. Patients received either pre-discharge nutritional counseling alone (control group, n = 45) or CNC (CNC group, n = 38) after gastrectomy. QOL at 12 months after gastrectomy was compared between the two groups. In QOL assessment, change in body weight (-7.98% vs. -12.77%, p = 0.0057), ingested amount of food per meal (7.00 vs. 6.07, p = 0.042) and ability for working (1.89 vs. 2.36, p = 0.049) were significantly better in CNC group than control group. Multiple regression analysis showed that CNC was a significantly beneficial factor for abdominal pain subscale (p = 0.028), diarrhea subscale (p = 0.047), ingested amount of food per meal (p = 0.012), Ability for working (p = 0.031) and dissatisfaction at the meal (p = 0.047). Perioperative and postoperative CNC could improve QOL in the patient undergoing gastrectomy in addition to preventing postoperative BWL.

Near-infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Patient-Derived Xenografts using a Humanized anti-Fibroblast Activation Protein Antibody.

Esophageal cancer remains a highly aggressive malignancy with a poor prognosis, despite ongoing advancements in treatments such as immunotherapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a crucial role in driving the aggressiveness of esophageal cancer. In a previous study utilizing human-derived xenograft models, we successfully developed a novel cancer treatment that targeted CAFs with near-infrared photoimmunotherapy (NIR-PIT), as an adjuvant therapy. In this study, we sought to translate our findings toward clinical practice by employing patient-derived xenograft (PDX) models and utilizing humanized monoclonal antibodies, specifically Sibrotuzumab, which is anti-human fibroblast activation protein (FAP) antibody and already being investigated in clinical trials as monotherapy. PDX models derived from esophageal cancer patients were effectively established, preserving the expression of key biomarkers such as EGFR and FAP, as observed in primary tumors. The application of FAP-targeted NIR-PIT using Sibrotuzumab, conjugated with the photosensitizer IR700DX, exhibited precise binding and selective elimination of FAP-expressing fibroblasts in vitro. Notably, in our in vivo investigations using both cell line-derived xenograft and PDX models, FAP-targeted NIR-PIT led to significant inhibition of tumor progression compared to control groups, all without inducing adverse events such as weight loss. Immunohistological assessments revealed a substantial reduction in CAFs exclusively within the tumor microenvironment of both models, further supporting the efficacy of our approach. Thus, our study demonstrates the potential of CAF-targeted NIR-PIT employing Sibrotuzumab as a promising therapeutic avenue for clinical treatment of esophageal cancer patients.

Fibroblast activation protein-targeted near-infrared photoimmunotherapy depletes immunosuppressive cancer-associated fibroblasts and remodels local tumor immunity.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a critical role in tumor immunosuppression. However, targeted depletion of CAFs is difficult due to their diverse cells of origin and the resulting lack of specific surface markers. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that leads to rapid cell membrane damage. METHODS: In this study, we used anti-mouse fibroblast activation protein (FAP) antibody to target FAP+ CAFs (FAP-targeted NIR-PIT) and investigated whether this therapy could suppress tumor progression and improve tumor immunity. RESULTS: FAP-targeted NIR-PIT induced specific cell death in CAFs without damaging adjacent normal cells. Furthermore, FAP-targeted NIR-PIT treated mice showed significant tumor regression in the CAF-rich tumor model accompanied by an increase in CD8+ tumor infiltrating lymphocytes (TILs). Moreover, treated tumors showed increased levels of IFN-γ, TNF-α, and IL-2 in CD8+ TILs compared with non-treated tumors, suggesting enhanced antitumor immunity. CONCLUSIONS: Cancers with FAP-positive CAFs in their TME grow rapidly and FAP-targeted NIR-PIT not only suppresses their growth but improves tumor immunosuppression. Thus, FAP-targeted NIR-PIT is a potential therapeutic strategy for selectively targeting the TME of CAF+ tumors.

Robot-assisted laparoscopic surgery for rectal cancer in a patient with a horseshoe kidney: A case report.

A 52-year-old, Japanese man presented to the hospital with a complaint of anal bleeding, and detailed examination resulted in a diagnosis of locally advanced rectal cancer. The patient underwent total neoadjuvant therapy followed by short-course radiation therapy and consolidation chemotherapy, which provided a partial response. After preoperative contrast-enhanced computed tomography showed a horseshoe kidney, robot-assisted, precise, laparoscopic, low anterior resection with D3 dissection and ileostomy construction was performed. The horseshoe renal isthmus was elevated surrounding the inferior mesenteric artery, and the left ureter and seminal vessels ran in front of the kidney. The hypogastric nerve traveled ventral to the horseshoe kidney. With robotic surgery, it was possible to perform more precise surgery while recognizing vascular and nerve anatomy in a rectal cancer patient with a horseshoe kidney due to good three-dimensional visibility and articulated forceps manipulation.

Epidural versus patient-controlled intravenous analgesia on pain relief and recovery after laparoscopic gastrectomy for gastric cancer: randomized clinical trial.

BACKGROUND: Epidural analgesia (EDA) is a main modality for postoperative pain relief in major open abdominal surgery within the Enhanced Recovery After Surgery protocol. However, it remains unclear whether EDA is an imperative modality in laparoscopic gastrectomy (LG). This study examined non-inferiority of patient-controlled intravenous analgesia (PCIA) to EDA in terms of postoperative pain and recovery in patients who underwent LG. METHODS: In this open-label, non-inferiority, parallel, individually randomized clinical trial, patients who underwent elective LG for gastric cancer were randomized 1:1 to receive either EDA or PCIA after surgery. The primary endpoint was pain score using the Numerical Rating Scale at rest 24 h after surgery, analysed both according to the intention-to-treat (ITT) principle and per protocol. The non-inferiority margin for pain score was set at 1. Secondary outcomes were postoperative parameters related to recovery and adverse events related to analgesia. RESULTS: Between 3 July 2017 and 29 September 2020, 132 patients were randomized to receive either EDA (n = 66) or PCIA (n = 66). After exclusions, 64 patients were included in the EDA group and 65 patients in the PCIA group for the ITT analysis. Pain score at rest 24 h after surgery was 1.94 (s.d. 2.07) in the EDA group and 2.63 (s.d. 1.76) in the PCIA group (P = 0.043). PCIA was not non-inferior to EDA for the primary endpoint (difference 0.69, one side 95% c.i. 1.25, P = 0.184) in ITT analysis. Postoperative parameters related to recovery were similar between groups. More EDA patients (21 (32.8%) versus 1 (1.5%), P < 0.001) developed postoperative hypotension as an adverse event. CONCLUSIONS: PCIA was not non-inferior to EDA in terms of early-phase pain relief after LG.Registration number: UMIN000027643 (https://www.umin.ac.jp/ctr/index-j.htm).

PD-L1-expressing cancer-associated fibroblasts induce tumor immunosuppression and contribute to poor clinical outcome in esophageal cancer.

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity.

The oncogenic function of PLAGL2 is mediated via ASCL2 and IGF2 and a Wnt-independent mechanism in colorectal cancer.

Colorectal cancer (CRC) tumorigenesis and progression are linked to common oncogenic mutations, especially in the tumor suppressor APC, whose loss triggers the deregulation of TCF4/ß-Catenin activity. CRC tumorigenesis is also driven by multiple epimutational modifiers such as transcriptional regulators. We describe the common (and near-universal) activation of the zinc finger transcription factor and Let-7 target PLAGL2 in CRC and find that it is a key driver of intestinal epithelial transformation. PLAGL2 drives proliferation, cell cycle progression, and anchorage-independent growth in CRC cell lines and nontransformed intestinal cells. Investigating effects of PLAGL2 on downstream pathways revealed very modest effects on canonical Wnt signaling. Alternatively, we find pronounced effects on the direct PLAGL2 target genes IGF2, a fetal growth factor, and ASCL2, an intestinal stem cell-specific bHLH transcription factor. Inactivation of PLAGL2 in CRC cell lines has pronounced effects on ASCL2 reporter activity. Furthermore, ASCL2 expression can partially rescue deficits of proliferation and cell cycle progression caused by depletion of PLAGL2 in CRC cell lines. Thus, the oncogenic effects of PLAGL2 appear to be mediated via core stem cell and onco-fetal pathways, with minimal effects on downstream Wnt signaling.NEW & NOTEWORTHY A Let-7 target called PLAGL2 drives oncogenic transformation via Wnt-independent pathways. This work illustrates the robust effects of this zinc finger transcription factor in colorectal cancer (CRC) cell lines and nontransformed intestinal epithelium, with effects mediated, in part, via the direct target genes ASCL2 and IGF2. This has implications for the role of PLAGL2 in activation of onco-fetal and onco-stem cell pathways, contributing to immature and highly proliferative phenotypes in CRC.

Conventional Cancer Therapies Can Accelerate Malignant Potential of Cancer Cells by Activating Cancer-Associated Fibroblasts in Esophageal Cancer Models.

Esophageal cancer is one of the most aggressive tumors, and the outcome remains poor. One contributing factor is the presence of tumors that are less responsive or have increased malignancy when treated with conventional chemotherapy, radiotherapy, or a combination of these. Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Focusing on conventional cancer therapies, we investigated how CAFs acquire therapeutic resistance and how they affect tumor malignancy. In this study, low-dose chemotherapy or radiotherapy-induced normal fibroblasts showed enhanced activation of CAFs markers, fibroblast activation protein, and α-smooth muscle actin, indicating the acquisition of malignancy in fibroblasts. Furthermore, CAFs activated by radiotherapy induce phenotypic changes in cancer cells, increasing their proliferation, migration, and invasion abilities. In in vivo peritoneal dissemination models, the total number of tumor nodules in the abdominal cavity was significantly increased in the co-inoculation group of cancer cells and resistant fibroblasts compared to that in the co-inoculation group of cancer cells and normal fibroblasts. In conclusion, we demonstrated that conventional cancer therapy causes anti-therapeutic effects via the activation of fibroblasts, resulting in CAFs. It is important to select or combine modalities of esophageal cancer treatment, recognizing that inappropriate radiotherapy and chemotherapy can lead to resistance in CAF-rich tumors.

Laparoscopic and Endoscopic Cooperative Surgery for Gastric Submucosal Tumor Near Esophagogastric Junction With Sliding Hiatal Hernia.

The usefulness of laparoscopic and endoscopic cooperative surgery (LECS) for gastric submucosal tumors in the cardiac region has been reported in recent years. However, LECS for submucosal tumors at the esophagogastric junction with hiatal sliding esophageal hernia has not been reported, and its validity as a treatment method is unknown. The patient was a 51-year-old man with a growing submucosal tumor in the cardiac region. Surgical resection was indicated because a definitive diagnosis of the tumor was not determined. The lesion was a luminal protrusion tumor, located on the posterior wall of the stomach 20 mm from the esophagogastric junction, and had a maximum diameter of 16.3 mm on endoscopic ultrasound examination. Because of the hiatal hernia, the lesion could not be detected from the gastric side by endoscopy. Local resection was considered to be feasible because the resection line did not extend into the esophageal mucosa and the resection site could be less than half the circumference of the lumen. The submucosal tumor was resected completely and safely by LECS. The tumor was diagnosed as a gastric smooth muscle tumor finally. Nine months after surgery, a follow-up endoscopy showed reflux esophagitis. LECS was a useful technique for submucosal tumors of the cardiac region with hiatal hernia, but fundoplication might be considered for preventing backflow of gastric acid.

Impact of cancer-associated fibroblasts on survival of patients with ampullary carcinoma.

Background: Cancer-associated fibroblasts (CAFs) reportedly enhance the progression of gastrointestinal surgery; however, the role of CAFs in ampullary carcinomas remains poorly examined. This study aimed to investigate the effect of CAFs on the survival of patients with ampullary carcinoma. Materials and methods: A retrospective analysis of 67 patients who underwent pancreatoduodenectomy between January 2000 and December 2021 was performed. CAFs were defined as spindle-shaped cells that expressed α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP). The impact of CAFs on survival, including recurrence-free (RFS) and disease-specific survival (DSS), as well as prognostic factors associated with survival, was analyzed. Results: The high-α-SMA group had significantly worse 5-year RFS (47.6% vs. 82.2%, p = 0.003) and 5-year DSS (67.5% vs. 93.3%, p = 0.01) than the low-α-SMA group. RFS (p = 0.04) and DSS (p = 0.02) in the high-FAP group were significantly worse than those in the low-FAP group. Multivariable analyses found that high α-SMA expression was an independent predictor of RFS [hazard ratio (HR): 3.68; 95% confidence intervals (CI): 1.21-12.4; p = 0.02] and DSS (HR: 8.54; 95% CI: 1.21-170; p = 0.03). Conclusions: CAFs, particularly α-SMA, can be useful predictors of survival in patients undergoing radical resection for ampullary carcinomas.

Overcoming cancer-associated fibroblast-induced immunosuppression by anti-interleukin-6 receptor antibody.

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation.

Dual-targeted near-infrared photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in the tumor microenvironment.

Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT, targeting cancer cells and CAFs, could be a therapeutic strategy. A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, P < 0.001 and P = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. We demonstrated the relationship between EGFR/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-targeted NIR-PIT might be a promising therapeutic strategy for cancer treatment.

Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (Telomelysin) with radiotherapy in oesophageal cancer patients unfit for standard treatments.

PURPOSE: OBP-301 (Telomelysin) is an attenuated type-5 adenovirus that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 sensitises human cancer cells to ionising radiation by inhibiting DNA repair, and radiation enhances coxsackievirus and adenovirus receptor-mediated OBP-301 infection on the contrary. We assessed OBP-301 with radiotherapy in oesophageal cancer patients unfit for standard chemoradiation treatments. METHODS: A phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed oesophageal cancer patients deemed unfit to undergo surgery or chemotherapy. Study treatment consisted of OBP-301 administration by intratumoural needle injection using a flexible endoscope on days 1, 18 and 32. Radiotherapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. RESULTS: Of the 13 patients, 7, 3 and 3 patients were treated with 1010, 1011 and 1012 virus particles, respectively. Study group comprised 10 males and 3 females, with a median age of 82 years (range, 53-91 years). All patients developed a transient, self-limited lymphopenia. Distribution studies revealed transient virus shedding in the plasma. Eight patients had local complete response (CR); all of them exhibited no pathologically viable malignant cells in biopsy specimens, and 3 patients had a partial response. The objective response rate was 91.7%. The clinical CR rate was 83.3% in stage I and 60.0% in stage II/III. Histopathological examination revealed massive infiltration of CD8+ cells and increased PD-L1 expression. CONCLUSION: Multiple courses of endoscopic intratumoural OBP-301 injection with radiotherapy are feasible and provide clinical benefits in patients with oesophageal cancer unfit for standard treatments.

Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer.

Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

Safety of Surgical Treatment for Elderly Patients with Gallbladder Carcinoma.

Gallbladder carcinoma (GBC) is a common malignancy with a poor prognosis. With the average life expectancy increasing globally, the incidence of GBC is predicted to increase as well. We investigated the safety and feasibility of surgical treatment for elderly patients with GBC. We retrospectively compared clinical pathological data and treatment outcomes in 45 consecutive GBC patients (23 patients ≥ 75 years [elderly group] and 22 patients < 75 years [younger group]) who underwent curative resection at the Iwakuni Center from January 2008 to December 2017. The proportion of preoperative comorbidities and anticoagulant use was significantly higher in the elderly group. The American Society of Anesthesiologists score was higher in the elderly versus the younger group, and the elderly group had significantly shorter operation times. Reduced activities of daily living was more common in the elderly versus younger group. The percentage of radical resection and overall 3-year survival (66.6% younger vs. 64.4% elderly) were similar between the groups. Controlling Nutritional Status (CONUT) score ≥ 3 and R0 resection were identified as prognostic factors for overall survival rate among all patients. After careful patient selection.

Photoimmunotherapy for cancer-associated fibroblasts targeting fibroblast activation protein in human esophageal squamous cell carcinoma.

Cancer-associated fibroblasts (CAFs) are strongly implicated in tumor progression, including in the processes of tumorigenesis, invasion, and metastasis. The targeting of CAFs using various therapeutic approaches is a novel treatment strategy; however, the efficacy of such therapies remains limited. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a novel targeted therapy employing a cell-specific mAb conjugated to a photosensitizer, has been introduced as a new type of phototherapy. In this study, we have developed a novel NIR-PIT technique to target CAFs, by focusing on fibroblast activation protein (FAP), and we evaluate the treatment efficacy in vitro and in vivo. Esophageal carcinoma cells exhibited enhanced activation of fibroblasts, with FAP over-expressed in the cytoplasm and on the cell surface. FAP-IR700-mediated PIT showed induced rapid cell death specifically for those cells in vitro and in vivo, without adverse effects. This novel therapy for CAFs, designed as local control phototherapy, was safe and showed a promising inhibitory effect on FAP+ CAFs. PIT targeting CAFs via the specific marker FAP may be a therapeutic option for CAFs in the tumor microenvironment in the future.

Pancreatic Ductal Adenocarcinoma in Remnant Pancreas after Pancreaticoduodenectomy for Acinar Cell Carcinoma: A Case Report.

We report a case of a pancreatic ductal adenocarcinoma (PDAC) in the remnant pancreas of a 78-year-old man after pancreaticoduodenectomy for acinar cell carcinoma, a relatively rare pancreatic neoplasm. After diagnosis of pancreatic carcinoma, subtotal stomach-preserving pancreaticoduodenectomy was performed. The pathological diagnosis was acinar cell carcinoma of the pancreas (disease stage IA, pT1, pN0, M0), without regional lymph node invasion. Cancer antigen 19-9 levels gradually increased during the 22 months after surgery, and computed tomography showed two solid tumors, 1.1 and 2.1 cm in diameter, at the site of the remnant pancreas. Endoscopic ultrasound fine-needle aspiration revealed pancreatic ductal adenocarcinoma. The tumor cells were not immunoreactive for trypsin. Both tumors were diagnosed as PDAC of the remnant pancreas. The patient declined curative resection, and chemoradiotherapy was started as alternative treatment. The patient died 28 months after surgery. Because this is an extremely rare case, additional cases and studies are needed in order to clarify its pathogenesis.

A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness.

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.