Near-infrared photoimmunotherapy (NIR-PIT) employs molecularly targeted antibodies conjugated with a photoabsorbing silicon-phthalocyanine dye derivative which binds to cancer cells. Application of ...NIR light following binding of the antibody–photoabsorber conjugates (APCs) results in ligand release on the dye, dramatic changes in solubility of the APC–antigen complex, and rapid, irreversible cell membrane damage of cancer cells in a highly selective manner, resulting in a highly immunogenic cell death. Clinically, this process results in edema after treatment mediated by reactive oxygen species (ROS). Based on the chemical and biological mechanism of NIR-PIT cytotoxicity and edema formation, in order to minimize acute inflammatory edema without compromising therapeutic effects, l-sodium ascorbate (l-NaAA) was administered to quench harmful ROS and accelerate the ligand release reaction. l-NaAA suppressed acute edema by reducing ROS after NIR-PIT yet did not alter the therapeutic effects. NIR-PIT could be performed safely under existence of l-NaAA without side effects caused by unnecessary ROS production.
Hepatectomy for gastric cancer liver metastases (GCLM) has a 5-year survival rate of 9-42%; however, indications for hepatectomy remain unclear. Many researchers have reported prognostic factors for ...GCLM after hepatectomy, but surgical indications vary according to the literature. Furthermore, the indication for optimal candidates for neoadjuvant chemotherapy and intensive chemotherapy is also unclear. To understand the indications for surgery and chemotherapy intended for hepatectomy for GCLM, a new treatment algorithm was created based on previously reported evidence from the viewpoint of hepatic surgeons.
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.
Near infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that induces necrotic/immunogenic cell death. It employs a monoclonal antibody (mAb) conjugated ...to a photo-absorber dye, IRDye700DX, which is activated by NIR light. Tumor-targeting NIR-PIT is also at least partly mediated by a profound immune response against the tumor. Cytotoxic T-lymphocyte antigen-4 (CTLA4) is widely recognized as a major immune checkpoint protein, which inhibits the immune response against tumors and is therefore, a target for systemic blockade. We investigated the effect of combining tumor-targeted NIR-PIT against the cell-surface antigen, CD44, which is known as a cancer stem cell marker, with a systemic CTLA4 immune checkpoint inhibitor in three syngeneic tumor models (MC38-luc, LL/2, and MOC1). CD44-targeted NIR-PIT combined with CTLA4 blockade showed greater tumor growth inhibition with longer survival compared with CTLA4 blockade alone in all tumor models. NIR-PIT and CTLA4 blockade produced more complete remission in MOC1 tumors (44%) than NIR-PIT and programmed cell death protein 1 (PD-1) blockade (8%), which was reported in our previous paper. However, the combination of NIR-PIT and CTLA4 blockade was less effective in MC38-luc tumors (11%) than the combination of NIR-PIT and PD-1 blockade (70%). Nonetheless, in many cases ineffective results with NIR-PIT and PD-1 blockade were reversed with NIR-PIT and CTLA4 blockade.
Targeted near-infrared (NIR) fluorescence probes are playing a significant role in biomedical imaging because NIR penetrates deeper into tissues and is associated with reduced autofluorescence ...compared to visible light fluorescence probes. Long-wavelength emitting 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) is an attractive platform for synthesizing NIR fluorophores because of its high photostability, high molar absorption coefficient, and sharp absorption and emission spectra. However, its lipophilicity hampers the conjugation chemistry necessary to add targeting moieties. In this study, we synthesized a novel NIR BODIPY derivative, NMP14. Substitutions of ethylene-bridged pyrrole units at the 3- or 5-position of the parent BODIPY chromophore result in a red shift of more than 200 nm. However, NMP14 cannot be conjugated to antibodies because of its hydrophobicity. Therefore, we synthesized NMP13 by adding short poly(ethylene glycol) to NMP14 and successfully conjugated NMP13 to cetuximab and trastuzumab. In vitro microscopic studies showed that NMP13 conjugated antibodies were activated after internalization and lysosomal processing, which means that NMP13 acts as an activatable probe only turning on after cellular internalization. After the administration of NMP13 conjugated antibodies, mice tumors were detected with high tumor to background ratios for a long period. These results suggest that NMP13 has potential as an activatable fluorescence probe for further clinical applications.
Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastasis (PM) from colorectal cancer (CRC) has been reported to substantially improve the prognosis ...and the quality of life of patients in comparison to systemic chemotherapy or palliative approaches. This study aimed to demonstrate the safety and feasibility of hepatectomy for metachronous liver metastases from CRC following CRS and HIPEC for PM on the basis of three case reports.
We describe three cases involving patients who underwent hepatectomy for metachronous liver metastases from CRC after CRS and HIPEC for PM. All patients underwent CRS and HIPEC after primary tumor resection, and hepatectomy was performed for the metachronous liver metastases after CRS and HIPEC. The hepatectomy procedures for cases 1, 2, and 3 were left hemihepatectomy and partial resection of S5, posterior sectionectomy, and left-lateral sectionectomy and partial resection of S5 and S8, respectively. Although adhesion of surrounding organs to the liver surface was observed on a broad level, dissections and hepatectomy could be performed safely. No recurrence was detected in cases 1 and 2 after hepatectomy. In case 3, liver metastases were detected from the time of the initial diagnosis of the primary tumor, and complete remission was achieved once with systemic chemotherapy. Although we performed hepatectomy for the recurrence of liver metastases after complete remission, early re-recurrence was observed after hepatectomy.
Hepatectomy for metachronous liver metastases after CRS and HIPEC for PM could be a multi-modality treatment option for CRC recurrence.
Near‐infrared photoimmunotherapy (NIR‐PIT) is a novel cancer therapy that employs a combination of infrared light and tumor‐targeted monoclonal antibody‐photoabsorber conjugates to cause both direct ...tumor necrosis and immunogenic cell death. NIR‐PIT may have potential in the perioperative setting before surgery, and therefore it is important to know the effect of NIR‐PIT on wound healing. Fifty mice were implanted with subcutaneous xenografts of N87 human gastric cancer cells, and tumors were excised after reaching a predetermined size. After excision, 30 mice were split into three groups: Controls, NIR‐PIT 1 day prior to surgery and NIR‐PIT 3 days prior to surgery. The quantity of reactive oxygen species (ROS) in each wound was measured on Postoperative Days 2 and 4, and mice were monitored weekly for 4 weeks for evidence of local tumor recurrence as well as clinical evidence of wound healing complications (eg, dehiscence, infection). The remaining 20 mice (10 controls, 10 treated with NIR‐PIT 1 day prior to surgery) were sacrificed on either Postoperative Day 7 or 14, the skin around wounds were excised, and tensile strength was measured with a digital force gauge. There were no significant differences between treatment and control groups with respect to wound ROS levels, wound tensile strength, local tumor recurrence, or postoperative complication rates (P > .05). In conclusion, neoadjuvant (pre‐operative) NIR‐PIT shows no evidence of adverse wound healing effects, and it is likely a safe adjunctive treatment to surgery. Postoperative use of NIR‐PIT merits investigation.
Near‐infrared photoimmunotherapy (NIR‐PIT), which is now under world‐wide phase 3 trial including in Japan, may be useful in the perioperative setting either before or after tumor excision that should be rational because NIR‐PIT could minimize tumor volume and initiate host antitumor immunity for safe and successful outcome. In order to apply this neoadjuvant NIR‐PIT before the surgery, only the concern of surgeons is if wound healing is hampered by preoperative NIR‐PIT. Therefore, in this study, in order to respond high demands from many surgeons, the effect of NIR‐PIT on wound healing was measured using reactive oxygen species monitoring and wound tensile strength measurements and shown to have no difference between treatment and control mice.
Intercellular signaling through the cell-surface receptor Notch plays important roles in a variety of developmental processes
as well as in pathogenesis of some human cancers and genetic disorders. ...However, the mechanisms by which Notch signals are
transduced into cells still remain elusive. Here we investigated the signaling mechanisms for Notch in the cell fate control
of neural progenitor cells. We show that Deltex-1 (DTX1), a mammalian homolog of Drosophila Deltex, mediates a Notch signal to block differentiation of neural progenitor cells. We found that a significant fraction
of DTX1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300. Through
its binding to p300, DTX1 inhibited transcriptional activation by the neural-specific helix-loop-helix-type transcription
factor MASH1, and this mechanism is likely responsible for the differentiation inhibition of neural progenitor cells. Our
results further suggest that DTX1 regulates transcription independently of the previously characterized Notch signaling pathway
involving RBP-J and HES1/HES5. Thus, DTX1 serves as an important signaling component downstream of Notch that regulates transcription
in the nucleus.
Acalculous cholecystitis is a rare but life-threatening disease, but its pathogenesis is not fully revealed yet. We experienced two acalculous cholecystitis cases associated with aortic dissection. ...In Case 1, acalculous cholecystitis occurred just after the exacerbation of the aortic dissection. Laparotomy showed necrotized cholecystitis with fresh thrombi formation. Case 2 developed acalculous cholecystitis on the 65th hospital day of aortic dissection. Laparotomy revealed the perforation of the gallbladder. Histological study revealed fibrosis and hemosiderosis in the subserosal layer. The histological findings of these two patients are quite different: Case 1 is acute ischemic and Case 2 is chronic ischemic. While a few cases of acute ischemic cholecystitis have been reported previously, chronic acalculous cholecystitis (CAC) has not been documented. History of aortic dissection could be a risk factor of acute and CAC due to relatively decreased splanchnic blood flow.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Percutaneous transhepatic gallbladder aspiration (PTGBA) and percutaneous transhepatic gallbladder drainage (PTGBD) are often the first-line treatments for acute cholecystitis, instead of ...surgical cholecystectomy. This retrospective study aimed to compare the treatment outcomes of PTGBA and PTGBD and evaluate the risks of treatment failure among patients undergoing PTGBA before surgical cholecystectomy.
Methods
We retrospectively reviewed 99 patients who underwent PTGBA or PTGBD as the first-line treatment before surgical cholecystectomy, between January 2014 and December 2019. Patient characteristics, computed tomography (CT) findings, and post-treatment outcomes were compared between the PTGBA and PTGBD groups. Additionally, risk factors, including CT findings for PTGBA failure, were assessed using multivariate univariate analysis with a backward selection model.
Results
Acute cholecystitis was not controlled in 21 of 47 (44.7%) patients in the PTGBA group and one of 52 patients (1.9%) in the PTGBD group (
P
< .001). Subsequent multiple logistic regression analysis identified the contrast effect of the gallbladder bed in the arterial phase of contrast-enhanced CT (odds ratio OR 9.17, 95% confidence interval CI 2.08–40.4,
P
= 0.003) and onset within 3 days (odds ratio OR 6.29, 95% confidence interval CI 1.37–29.0,
P
= 0.018) as independent risk factors for PTGBA failure.
Conclusions
PTGBA is more prone to failure than PTGBD; however, it is a simpler gallbladder drainage treatment method without the need for X-ray fluoroscopy and catheter management after the procedure. Evaluating the risk of PTGBA failure using CT findings and onset date would help us choose a drainage approach more effectively.
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