Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancerrelated death globally. Clinical guidelines for HCC have been established and revised by many ...countries and regions. We summarized and compared the treatment algorithms in the updated HCC guidelines established by Japan, China, Hong Kong, the Asian-Pacific Association for the Study of the Liver, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver and European Organization for Research and Treatment of Cancer. Variations in treatment algorithms between the guidelines is inevitable, considering the differences in the prevalence and etiology of HCC, local clinical practice, and medical and insurance systems between countries or regions, and this might be confusing for practitioners worldwide. A comprehensive understanding of the guidelines that are globally available might be useful for future improvement of each guideline.
Programmed cell death 1 (PD-1) blockade therapy can result in dramatic responses in some patients with cancer. However, about 15% of patients receiving PD-1 blockade therapy experience rapid tumor ...progression, a phenomenon termed "hyperprogressive disease" (HPD). The mechanism(s) underlying HPD has been difficult to uncover because HPD is challenging to reproduce in animal models. Near-infrared photoimmunotherapy (NIR-PIT) is a method by which specific cells in the tumor microenvironment (TME) can be selectively depleted without disturbing other cells in the TME. In this study, we partially depleted CD8+ T cells with NIR-PIT by targeting the CD8β antigen thereby temporarily changing the balance of T-cell subsets in two different syngeneic tumor models. PD-1 blockade in these models led to rapid tumor progression compared with controls. CD3ε+CD8α+/CD3ε+CD4+FoxP3+ (Teff/Treg) ratios in the PD-1 and NIR-PIT groups were lower than in controls. Moreover, in a bilateral tumor model, low-dose CD8β-targeted NIR-PIT with anti-PD-1 blockade showed rapid tumor progression only in the tumor exposed to NIR light. In this experiment CD8β-targeted NIR-PIT in the exposed tumor reduced local CD8+ T cells resulting in a regulatory T-cell (Treg)-dominant TME. In conclusion, this reports an animal model to simulate the Treg-dominant TME, and the data generated using the model suggest that HPD after PD-1 blockade therapy can be attributed, at least in part, to imbalances between effector T cells and Tregs in the TME.
Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that utilizes an antibody-photoabsorber-conjugate (AbPC) combined with NIR light. The AbPC is injected and binds to ...the tumor whereupon NIR light irradiation causes a photochemical reaction that selectively kills cancer cells. NIR-PIT is ideal for surface-located skin cancers such as melanoma. However, there is concern that the pigment in melanoma lesions could interfere with light delivery, rendering treatment ineffective. We investigated the efficacy of CD29- and CD44-targeted NIR-PIT (CD29-PIT and CD44-PIT, respectively) in the B16 melanoma model, which is highly pigmented. While CD29-PIT and CD44-PIT killed B16 cells in
vitro and in
vivo, CD29-PIT suppressed tumor growth more efficiently. Ki67 expression showed that cells surviving CD29-PIT were less proliferative, suggesting that CD29-PIT was selective for more proliferative cancer cells. CD29-PIT did not kill immune cells, whereas CD44-PIT killed both T and NK cells and most myeloid cells, including DCs, which could interfere with the immune response to NIR-PIT. The addition of anti-CTLA4 antibody immune checkpoint inhibitor (ICI) to CD29-PIT increased the infiltration of CD8 T cells and enhanced tumor suppression with prolonged survival. Such effects were less prominent when the anti-CTLA4 ICI was combined with CD44-PIT. The preservation of immune cells in the tumor microenvironment (TME) after CD29-PIT likely led to a better response when combined with anti-CTLA4 treatment. We conclude that NIR-PIT can be performed in pigmented melanomas and that CD29 is a promising target for NIR-PIT, which is amenable to combination therapy with other immunotherapies.
Adhesion formation is a critical issue in surgery, particularly in hepatectomy. The present study aimed to develop a bilayer adhesion barrier comprising alginate (Alg) of different molecular weight ...(Mw). It was expected that a slowly dissolving layer remains on the cut surface, functioning as a physical barrier, whereas a rapidly dissolving layer widely distributes in the peritoneal cavity to prevent de novo adhesions.
Bilayer Alg sponges were fabricated using low Mw Alg for the upper layer and high Mw Alg for the bottom layer. The dissolution behavior of each layer was evaluated in vitro in peritoneum-like environments. We constructed a Pean crush hepatectomy-induced adhesion model in rats. The effects of the bilayer sponge on cut surface and de novo adhesions were separately evaluated in terms of their extent and grade.
The Alg sponge layer with low Mw dissolved faster than that with high Mw in vitro. One week after the hepatectomy, although no significant decrease in adhesion extent on the cut surface was observed in rats that received Seprafilm and Interceed, treatment with Alg bilayer sponge significantly decreased the adhesion extent to 38% of that without treatment. Moreover, a significant decrease in de novo adhesion extent was observed in the Alg bilayer sponge compared with the Interceed group.
The Alg bilayer sponge was effective for preventing both cut surface and de novo adhesions in the rat Pean crush hepatectomy model. The simple yet functional design of the Alg bilayer sponge can facilitate its use in future clinical practice.
Near infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that employs a monoclonal antibody (mAb) conjugated to a photo-absorber dye, IRDye700DX, which is ...activated by 690 nm light. Cancer cell-targeted NIR-PIT induces rapid necrotic/immunogenic cell death (ICD) that induces antitumor host immunity including re-priming and proliferation of T cells. Interleukin-15 (IL-15) is a cytokine that activates natural killer (NK)-, B- and T-cells while having minimal effect on regulatory T cells (Tregs) that lack the IL-15 receptor. Here, we hypothesized that IL-15 administration with cancer cell-targeted NIR-PIT could further inhibit tumor growth by increasing antitumor host immunity. Three syngeneic mouse tumor models, MC38-luc, LL/2, and MOC1, underwent combined CD44-targeted NIR-PIT and short-term IL-15 administration with appropriate controls. Comparing with the single-agent therapy, the combination therapy of IL-15 after NIR-PIT inhibited tumor growth, prolonged survival, and increased tumor infiltrating CD8+ T cells more efficiently in tumor-bearing mice. IL-15 appears to enhance the therapeutic effect of cancer-targeted NIR-PIT.
Arterial blood supply to the pancreas from accessary middle colic artery Ito, Kyoji; Takemura, Nobuyuki; Inagaki, Fuyuki ...
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... et al.,
July 2019, 2019-Jul, 2019-07-00, 20190701, Letnik:
19, Številka:
5
Journal Article
Recenzirano
An accessory middle colic artery (AMCA) is an aberrant artery feeding the splenic flexure of the colon. Little is known about the branching pattern of an AMCA. We aimed to evaluate the branching ...pattern of the AMCA from the superior mesenteric artery (SMA) with special reference to the pancreatic artery using multidetector-row computed tomography (MDCT) before surgery.
We investigated 112 patients who underwent contrast-enhancement MDCT before surgical resection of the pancreas between January 2015 and July 2018. The pancreatic branch from the AMCA was divided into the dorsal pancreatic artery (DPA) and the inferior pancreaticoduodenal artery (IPDA). The branching level and angle of the AMCA from the SMA were also evaluated.
The AMCA was present in 27.7% of patients (n = 31/112). The AMCA branching pattern was classified into four types: type A, no branch from the AMCA (n = 20); type B, a common trunk with the DPA (n = 6); type C, a common trunk with the IPDA (n = 3); and type D, a common trunk with the DPA and IPDA (n = 2). The AMCA with the IPDA (types C and D) branched more proximally compared to the AMCA without the IPDA (P = 0.04). The AMCA branched vertically from the SMA in most cases (n = 24/31, 77.4%).
The AMCA had a pancreatic branch in 8.9% (10/112) of cases. Special attention should be paid to its branching pattern in pancreatic and colon surgery.
Indocyanine green (ICG) is a fluorescent dye that selectively accumulates in primary hepatocellular carcinoma (HCC) as well as in extrahepatic metastases of HCC. Reported here is a case of ...metachronous lymph node (LN) metastases from HCC that were resected using ICG fluorescence navigation. A man in his 70s was referred to this department for suspected LN metastasis from HCC. Computed tomography revealed an enlarged suprapancreatic LN. After a laparotomy, an ICG fluorescence imaging system intraoperatively revealed strong fluorescence of this LN, which was then easily resected. An examination after the removal of the LN revealed fluorescence from the adjacent lymphatic tissue as well, so an additional resection was performed. Pathologically, both LNs were confirmed to be metastases from HCC. In this case, some lymphatic tissue metastases from HCC could not be identified prior to surgery, but intraoperative use of ICG fluorescence navigation facilitated their complete removal.
Disialoganglioside (GD2) is a subtype of glycolipids that is highly expressed in tumors of neuroectodermal origins, such as neuroblastoma and osteosarcoma. Its limited expression in normal tissues ...makes GD2 a potential target for precision therapy. Several anti-GD2 monoclonal antibodies are currently in clinical use and have had moderate success. Near-infrared photoimmunotherapy (NIR-PIT) is a cancer therapy that arms antibodies with IRDye700DX (IR700) and then exposes this antibody–dye conjugate (ADC) to NIR light at a wavelength of 690 nm. NIR light irradiation induces a profound photochemical response in IR700, resulting in protein aggregates that lead to cell membrane damage and death. In this study, we examined the feasibility of GD2-targeted NIR-PIT. Although GD2, like other glycolipids, is only located in the outer leaflet of the cell membrane, the aggregates formation exerted sufficient physical force to disrupt the cell membrane and kill target cells in vitro. In in vivo studies, tumor growth was significantly inhibited after GD2-targeted NIR-PIT, resulting in prolonged survival. Following GD2-targeted NIR-PIT, activation of host immunity was observed. In conclusion, GD2-targeted NIR-PIT was similarly effective to the conventional protein-targeted NIR-PIT. This study demonstrates that membrane glycolipid can be a new target of NIR-PIT.
Near‐infrared photoimmunotherapy (NIR‐PIT) is a cancer treatment that utilizes antibody‐photoabsorber (IR700) conjugates to selectively kill target cells by exposing them to NIR light. Cytotoxic ...T‐lymphocyte antigen 4 (CTLA4) is a major immune checkpoint ligand mediating antitumor immune suppression. Local depletion of CTLA4 expressing cells in the tumor bed with NIR‐PIT could enhance antitumor immune responses by both blocking the CTLA4‐axis and depleting immune suppressive cells. The aim of this study is to evaluate the antitumor efficacy of CTLA4‐targeted NIR‐PIT using four murine tumor models, MC38‐luc, LL/2‐luc, MOC2‐luc, and MOC2. The CTLA4‐targeted NIR‐PIT depletes intratumoral CTLA4 expressing cells which are mostly regulatory T cells. In vivo CTLA4‐targeted NIR‐PIT yields complete responses in 80% of MC38‐luc, 70% of LL/2‐luc, and 40% of MOC2‐luc tumors prolonging survival in all cases. After CTLA4‐targeted NIR‐PIT, activation and infiltration of CD8+ T cells within the tumor microenvironment is observed. In conclusion, CTLA4‐targeted NIR‐PIT can effectively treat tumors by blocking the CTLA4‐axis as well as by eliminating CTLA4‐expressing immune suppressor cells, resulting in T cell mediated antitumor immunity. Local CTLA4‐expressing cell depletion in tumor beds using NIR‐PIT could be a promising new cancer immunotherapy for safely treating a variety of tumor types.
CTLA4 is a major immune checkpoint ligand mediating antitumor immune suppression. Antitumor therapeutic efficacy is described, after locally depleting intratumoral CTLA4 expressing cells by a specific cell‐elimination biotechnology, near‐infrared photoimmunotherapy. This treatment dramatically enhances T cell mediated antitumor host immunity in mice that can be easily applied to human patients.
Background
In hepatectomy, the preservation of portal perfusion and venous drainage in the remnant liver is important for securing postoperative hepatic function. Right hepatectomy is generally ...indicated when a hepatic tumor involves the right hepatic vein (RHV). However, if a sizable inferior RHV (IRHV) exists, hepatectomy with preservation of the IRHV territory may be another option. In this case, we verified the clinical feasibility of anatomical bisegmentectomy 7 and 8 with RHV ligation, averting the right hepatic parenchyma from venous congestion, utilizing the presence of the IRHV.
Case presentation
A 70-year-old man was presented with a large hepatic tumor infiltrating the RHV on computed tomography during a medical checkup. The patient was diagnosed with hepatocellular carcinoma (HCC), T2N0M0, stage III. Right hepatectomy was first considered, but multi-detector computed tomography (MDCT) also revealed a large IRHV draining almost all of segments 5 and 6, suggesting that IRHV-preserving liver resection may be another option. The calculated future remnant liver volumes were 382 mL (26.1% of the total volume) after right hepatectomy and 755 mL (51.7% of the total volume) after anatomical bisegmentectomy 7 and 8; therefore, we scheduled IRHV-preserving anatomical bisegmentectomy 7 and 8 considering the prevention of postoperative liver failure and increased chance of performing repeat resections in cases of recurrence. Preoperative three-dimensional simulation using MDCT clearly revealed the portal perfusion area and venous drainage territories by the RHV and IRHV. There was an issue with invisibility of the anatomical resection line of segments 7 and 8, which was completely dissolved by intraoperative ultrasonography using Sonazoid and the portal dye injection technique with counter staining. The postoperative course in the patient was uneventful, without recurrence of HCC, for 30 months after hepatectomy.
Conclusions
IRHV-preserving anatomical bisegmentectomy 7 and 8 is a safe and feasible procedure utilizing the three-dimensional simulation of the portal perfusion area and venous drainage territories and the portal dye injection technique.
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