Publications by authors named "Shuhei Okuyama"

38 Publications

Clarithromycin As an Alternative and Prophylactic Agent in a Hematopoietic Stem Cell Transplantation Patient.

Am J Case Rep 2021 Jun 15;22:e931731. Epub 2021 Jun 15.

Medical Mycology Research Center, Chiba University, Chiba, Japan.

BACKGROUND Nocardia infections have rarely been reported in hematopoietic stem cell transplantation (HSCT) patients, who usually receive the prophylactic use of sulfamethoxazole/trimethoprim (ST) against Pneumocystis jiroveci. However, the ST prophylaxis, sensitive to Nocardia species, sometimes induces renal toxicities. Therefore, alternative prophylactic or therapeutic drugs are required for nocardiosis in HSCT patients. CASE REPORT A 34-year-old Japanese man with acute mixed phenotypic leukemia with t(9; 22) received allogenic peripheral blood HSCT from a haplo-identical sibling donor. He developed graft versus host disease (GVHD) with grade II, and was treated with prednisolone and cyclosporine A with concurrent ciprofloxacin, fluconazole, valacyclovir, and ST. However, the prophylactic ST was ceased because of its renal toxicity. He developed a pulmonary nodular lesion with elevated ß-D-glucan and Aspergillus galactomannan antigen. Repeated blood and sputum culture isolated no pathogens. Voriconazole treatment administered once improved these lesions and laboratory findings. One month later, he presented with right pleuritic chest pain and multiple ring-enhancing cavitation lesions along the ribs. A needle biopsy demonstrated Nocardia elegans, which is an extremely rare infection induced by Nocardia species, in the cavitation lesions, shown by 16S rRNA gene sequencing. He was started on doripenem and liposomal amphotericin B, and a subsequent treatment kept him free from Nocardia elegans infection, without any adverse effects, while continuing the cyclosporine A and prednisolone treatment for chronic GVHD. CONCLUSIONS Clarithromycin has fewer adverse effects than ST. This case suggests that clarithromycin is an appropriate alternative and prophylactic therapy for patients with nocardiosis and ST toxicities.
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http://dx.doi.org/10.12659/AJCR.931731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216568PMC
June 2021

Endoscopic near-infrared photoimmunotherapy in an orthotopic head and neck cancer model.

Cancer Sci 2021 Jun 8. Epub 2021 Jun 8.

Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Near-infrared photoimmunotherapy (NIR-PIT) is a cell selective cancer therapy that uses an antibody-photoabsorber (IRDye700DX, IR700) conjugate (APC) and NIR light. NIR-PIT targeting epidermal growth factor receptor (EGFR) in head and neck cancer (HNC) was conditionally approved in Japan in 2020. APC-bound tumors can be detected using endoscopic fluorescence imaging, whereas NIR light can be delivered using endoscopic fiber optics. The aims of this study were: (1) to assess the feasibility of endoscopic NIR-PIT in an orthotopic HNC model using a CD44-expressing MOC2-luc cell line; and (2) to evaluate quantitative fluorescence endoscopic imaging prior to and during NIR-PIT. The results were compared in 3 experimental groups: (1) untreated controls, (2) APC injection without light exposure (APC-IV), and (3) APC injection followed by NIR light exposure (NIR-PIT). APC injected groups showed significantly higher fluorescence signals for IR700 compared with the control group prior to therapeutic NIR light exposure, and the fluorescence signal significantly decreased in the NIR-PIT group after light exposure. After treatment, the NIR-PIT group showed significantly attenuated bioluminescence compared with the control and the APC-IV groups. Histology demonstrated diffuse necrotic death of the cancer cells in the NIR-PIT group alone. In conclusion, endoscopically delivered light combined with quantitative fluorescence imaging can be used to "see and treat" HNC. This method could also be applied to other types of cancer approachable with endoscopy.
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http://dx.doi.org/10.1111/cas.15013DOI Listing
June 2021

Safety and Effectiveness of Endoscopic Band Ligation for Colonic Diverticular Bleeding in Elderly Patients.

Digestion 2021 Feb 8:1-7. Epub 2021 Feb 8.

Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan.

Introduction: Colonic diverticulosis increases with age, leading to a higher risk of colonic diverticular bleeding (CDB) in the elderly. As life expectancy continues to increase, the need for endoscopic hemostasis for CDB in the elderly can also be expected to increase. However, there have been no reports to date on the feasibility of endoscopic hemostasis for elderly CDB patients. Several recent studies have addressed the effectiveness of endoscopic band ligation (EBL) for CDB. In this study, we evaluate the safety and effectiveness of EBL in elderly CDB patients compared to younger CDB patients.

Methods: We retrospectively analyzed the medical records of consecutive patients treated with EBL for the first time at a tertiary referral center between March 2011 and November 2017. Patients were grouped according to age into those at least 75 years old (the Elderly) and those <75 years old (the Nonelderly). Patient characteristics, technical success, and complications were compared between the two groups.

Results: EBL was performed in 153 patients during the study period (49 Elderly patients and 104 Nonelderly patients). Elderly patients were less likely to be male (p < 0.001) and had lower hemoglobin levels on admission (p < 0.001). Bleeding on the right side of the splenic flexure was observed more frequently in the Nonelderly (p = 0.002). Charlson Comorbidity Index (CCI) and use of antithrombotic agents were significantly higher in the Elderly (p < 0.001 and p < 0.001, respectively). Active bleeding tended to be observed more frequently in the Elderly (p = 0.054), while the difference was not significant. There were no significant differences in the shock index, procedure time, or units of packed red blood cells transfused between the 2 groups. No significant differences in the technical success rate (97.1 vs. 98%, p = 0.76), early rebleeding rate (10.2 vs. 14.4%, p = 0.47), or other complications (2 vs. 1%, p = 0.58) were observed. Perforation and abscess formation were not observed in either group. Female gender, left-sidedness, higher CCI, and lower hemoglobin level were all significantly more frequently observed in the Elderly on multiple logistic regression analysis.

Discussion/conclusion: EBL may be similarly safe and effective for the treatment of CDB in the elderly as in the nonelderly.
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http://dx.doi.org/10.1159/000513310DOI Listing
February 2021

Association between the frequency of daily tooth brushing and development of nonalcoholic fatty liver disease.

Dig Dis 2021 Feb 3. Epub 2021 Feb 3.

Background & Aims: This study aimed to evaluate the association between the frequency of daily tooth brushing and the development of nonalcoholic fatty liver disease (NAFLD).

Methods: A retrospective longitudinal study was conducted from 2005 to 2012 at the Center for Preventive Medicine at St. Luke's International Hospital, Japan. Data on all participants who underwent a health checkup during the study period were collected. NAFLD was diagnosed by abdominal ultrasonography, and all participants who were diagnosed with NALFD at the time of their initial visit, consumed alcohol in any amount, or had received only one health checkup were excluded. The questionnaire for the frequency of daily tooth brushing was conducted as part of health checkups. The primary outcome was the risk of developing NAFLD according to the frequency of daily tooth brushing (1-2 times a day, or 3 times a day) compared to those who brush teeth once or less than once a day.

Results: Data were collected from 25,804 people. A total of 3,289 (12.7%) participants developed NAFLD. The mean age was 45.2 years, and 6,901 (26.7%) of the participants were male. The risk of developing NAFLD significantly decreased with increased frequency of daily tooth brushing. Adjusted odds ratios (ORs) are as follows: Brushing teeth 1-2 times a day (OR: 0.85, 95% CI: 0.77-0.95), and 3 times a day (OR: 0.74, 95% CI: 0.67-0.82).

Conclusions: Frequent tooth brushing was shown to significantly reduce the risk of developing NAFLD. .
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http://dx.doi.org/10.1159/000514930DOI Listing
February 2021

The association between non-alcoholic fatty liver disease (with or without metabolic syndrome) and extrahepatic cancer development.

J Gastroenterol Hepatol 2021 Jul 13;36(7):1971-1978. Epub 2020 Dec 13.

Department of Medicine, St. Luke's International Hospital, Tokyo, Japan.

Background And Aim: This study was designed to determine whether non-alcoholic fatty liver disease (NAFLD), with or without metabolic syndrome (MetS), is a risk factor for cancer development.

Methods: We conducted a retrospective longitudinal study at the Center for Preventive Medicine, St. Luke's International Hospital. Among all participants who underwent a health checkup between 2005 and 2019, cancer development tendencies were compared between those who were diagnosed with NAFLD and those who were not. Further evaluation was conducted among NAFLD-diagnosed participants with versus without MetS in the same manner. Those with a history of a specific liver disease, any type of cancer, or alcohol consumption in any amount at the time of the initial visit were excluded from the study.

Results: Data were collected from 30 172 participants who underwent health checkups, among whom 4394 (14.6%) had NAFLD. Over the 14-year follow-up period, 2086 participants (6.9%) developed cancer. Participants with NAFLD had a higher incidence of digestive organ neoplasms (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.07-1.67), especially in the stomach (OR: 1.40, 95% CI: 1.02-1.94) and small intestine (OR: 2.80, 95% CI: 0.87-8.96), than did those without NAFLD. Participants with NAFLD and MetS had significantly lower rates of neoplasms in respiratory and intrathoracic organs (OR: 0.35 95% CI: 0.14-0.88) and male genital organs (OR: 0.46 95% CI: 0.24-0.87) than did individuals without NAFLD.

Conclusions: Non-alcoholic fatty liver disease is associated with the development of gastrointestinal malignancies, while MetS is a negative risk factor for lung and prostate cancer.
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http://dx.doi.org/10.1111/jgh.15350DOI Listing
July 2021

Negative correlation of high serum bilirubin with cancer development in adults without hepatobiliary disease.

Eur J Cancer Prev 2021 Jan;30(1):69-75

Medicine, St. Luke's International Hospital.

Background And Aims: This study aimed to evaluate whether serum bilirubin levels were associated with cancer development in a population without liver disease.

Methods: A retrospective longitudinal study was performed by including participants who underwent a health checkup at St. Luke's International Hospital in Tokyo from 2005 to 2019. We excluded those with liver diseases or prior history of cancer at baseline. All participants were classified into four groups according to their total bilirubin (T-Bil) level: very low (<0.5 mg/dl), low (≥0.5 mg/dl, <1.0 mg/dl), intermediate (≥1.0 mg/dl, <1.5 mg/dl), and high (≥1.5 mg/dl). Our primary outcome was to observe cancer development. This study received IRB approval (19-R041).

Results: A total of 77 855 patients were included. During a median follow-up of 1751 days, 5110 participants developed some type of cancer during the study period. Compared to the very-low group, odds ratio (OR) for developing any type of cancer in a concentration-dependent manner decreased as the T-Bil category shifted to higher groups: OR 0.89, 95% confidence interval (CI) 0.79-1.01 for low group; OR 0.81, 95% CI 0.71-0.94 for intermediate group, and OR 0.80, 95% CI 0.65-0.99 for high group. In terms of secondary outcome, neoplasms of the female genital organs showed the same trend; OR 0.69, 95% CI 0.51-0.93 for low group; OR 0.63, 95% CI 0.44-0.92 for intermediate group, and OR 0.52, 95% CI 0.24-1.09 for high group.

Conclusion: Increased serum bilirubin negatively correlated with cancer development in a concentration-dependent manner, especially for neoplasms of the female genital organs.
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http://dx.doi.org/10.1097/CEJ.0000000000000643DOI Listing
January 2021

Impact of comorbidity and relative dose intensity on outcomes in diffuse large B-cell lymphoma patients treated with R-CHOP.

J Cancer Res Clin Oncol 2020 Nov 10;146(11):2995-3002. Epub 2020 Jun 10.

Department of Hematology, Yamagata Prefectural Central Hospital, 1800, Aoyagi, Yamagata, 990-2292, Japan.

Background: Comorbidity and relative dose intensity (RDI) have been associated with survival in diffuse large B-cell lymphoma (DLBCL) patients, but both relationships remain unaddressed in the same patients.

Methods: A retrospective review of consecutive DLBCL patients treated from January 2010 to October 2018 was performed. Data for the clinical characteristics of the patients, including the Charlson Comorbidity Index (CCI) and RDI, on their outcomes were evaluated.

Results: A total of 211 patients with a median age of 72 years (range 19-90 years) were analyzed. CCI ≥ 2 was associated with poor event-free survival (EFS) and overall survival (OS). RDI < 70% was associated with worse EFS and OS. A multivariate analysis revealed that RDI < 70% was only a poor risk factor for the reduction of OS in elderly DLBCL patients (65 years <) and independent from the presence of CCI. The relationship between CCI and RDI in elderly patients was analyzed in four groups, based on CCI ≥ 2 or less and RDI ≥ 70% or less. The group with CCI ≥ 2 and RDI < 70% had a poorer OS and EFS, as compared to the other three groups. The group with CCI < 2 and RDI ≥ 70% had a superior OS but an identical EFS, as compared to the two groups with CCI < 2 and RDI < 70% and CCI ≥ 2 and RDI ≥ 70%.

Conclusions: CCI ≥ 2 was associated with a poorer outcome, but maintaining RDI ≥ 70% may improve the outcome, especially in elderly DLBCL patients.
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http://dx.doi.org/10.1007/s00432-020-03279-7DOI Listing
November 2020

Effectiveness of risk scoring systems in predicting endoscopic treatment in colonic diverticular bleeding.

J Gastroenterol Hepatol 2020 May 9;35(5):815-820. Epub 2019 Dec 9.

Division of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan.

Background And Aims: The identification of stigmata of recent hemorrhage (SRH) in colonic diverticular bleeding (CDB) enables an endoscopic treatment and can improve the clinical outcome. However, SRH identification rate remains low. This study aims to investigate whether NOBLADS and Strate scoring systems are useful for predicting SRH identification rate of CDB pre-procedurally via colonoscopy.

Methods: In this single-center retrospective observational study, 302 patients who experienced their first episode of CDB from April 2008 to March 2018 were included. Patients were classified into SRH-positive and SRH-negative groups. The primary outcome was SRH identification rate. The secondary outcomes were active bleeding in SRH and early rebleeding rates. The usefulness of the NOBLADS and Strate scores as predicted values of SRH identification was evaluated using the area under the receiver operating characteristic curve.

Results: There were 126 and 176 patients in the SRH-positive and SRH-negative groups, respectively. The area under the receiver operating characteristic curve for SRH identification using the NOBLADS score was 0.74 (95% confidence interval, 0.69-0.80) and that using the Strate score was 0.74 (95% confidence interval, 0.68-0.79). Active bleeding and early rebleeding rates increased according to each score. By setting the cut-off of the NOBLADS score to four points, treatment was possible in 70.2% (66/94) patients. Addition of extravasation at computed tomography to a NOBLADS score of ≧ 4 points allowed treatment of all patients (24/24).

Conclusions: Severity scoring in acute lower gastrointestinal bleeding was effective for predicting SRH identification in CDB. We suggest that combination of these scorings and CT findings could offer a new therapeutic strategy.
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http://dx.doi.org/10.1111/jgh.14901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318164PMC
May 2020

Near-infrared photoimmunotherapy through bone.

Cancer Sci 2019 Dec 22;110(12):3689-3694. Epub 2019 Oct 22.

Molecular Imaging Program, National Institutes of Health, National Cancer Institute, Bethesda, MD, USA.

Near-infrared photoimmunotherapy (NIR-PIT) is a molecularly targeted cancer phototherapy that is based on injecting a conjugate of a silicon-phthalocyanine derivative, IRdye 700DX (IR700), and a monoclonal antibody that targets an expressed antigen on the cancer cell surface. Subsequent local exposure to NIR light results in the rapid and highly selective immunogenic cell death of targeted cancer cells. Because many cancers grow in bones through which light does not penetrate well, the goal of this study was to determine if NIR-PIT can effectively treat cancers in bone. A bovine rib was used as a bone sample. Because the sample's NIR light transmittance was shown to be approximately 4.52% in preliminary tests, it was hypothesized that a maximum radiation dosage of 128 and 1500 J/cm would be sufficient to induce cell death in in vitro target cells and in vivo mouse tumor models, respectively. Cell viability was measured through bioluminescence studies comparing relative luciferase activity, as well as a cytotoxicity assay. In the in vitro model, tumor cell viability was significantly decreased after 64 and 128 J/cm NIR light irradiation through the bone. An in vivo mouse tumor model also showed that 1500 J/cm NIR light irradiation through the bone significantly reduced tumor viability at both 24 and 48 hours posttreatment compared to the control group (P = .026 and .040 respectively). Therefore, despite limitations in light transmission, NIR-PIT nevertheless is capable of effectively treating cancers within bone.
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http://dx.doi.org/10.1111/cas.14203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890452PMC
December 2019

Characterization of reemergent anti-B red blood cell antibodies in a patient with recurrent acute myeloid leukemia with ABO-incompatible allogeneic peripheral blood stem cell transplantation.

Transfusion 2019 11 10;59(11):3319-3323. Epub 2019 Sep 10.

Department of Laboratory Medicine, Yamagata Prefectural Central Hospital, Yamagata, Japan.

Background: Isohemagglutinins against ABO antigens absent on both recipient and donor red blood cells (RBCs) increase or decrease after ABO-incompatible hematopoietic stem cell transplantation (HSCT). However, few reports have described the changes in the isohemagglutinin titers and the characteristics in patients with recurrent hematologic conditions after ABO-incompatible HSCT.

Case Report: A 59-year-old female with acute erythroid leukemia received a peripheral blood stem cell transplant from her HLA-haploidentical daughter. The patient was typed as group O with anti- A (4+) and B (4+) isohemagglutinins, while the donor was typed as group B. The bone marrow cells achieved complete donor cell chimerism on Day 13 after HSCT. On Day 120, the patient showed 97% B RBC type with persistent anti-A (3+) and without anti-B antibodies. On Day 375, her leukemia relapsed, and recipient type O RBCs and anti-B antibodies sequentially reemerged. However, clinicolaboratory hemolysis and erythroid aplasia were not detected in the patient.

Results: The post-HSCT sera agglutinated the allo B RBCs, but not the donor B RBCs, while the pre-HSCT sera agglutinated both RBCs. The burst-forming/colony-forming units of erythroid formation from the donor peripheral blood stem cells were impaired by only the pre-HSCT sera and not by the post-HSCT sera.

Conclusion: To our knowledge, this is the first report investigating the characteristic changes of isohemagglutinins between the pre- and post-HSCT sera in a patient with recurrent acute myeloid leukemia. The present study suggests that the plasma cells producing anti-donor B RBCs in the patient have been selectively eliminated or induced into an anergic state by the post-HSCT immunologic reconstruction.
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http://dx.doi.org/10.1111/trf.15510DOI Listing
November 2019

Host Immunity Following Near-Infrared Photoimmunotherapy Is Enhanced with PD-1 Checkpoint Blockade to Eradicate Established Antigenic Tumors.

Cancer Immunol Res 2019 03 25;7(3):401-413. Epub 2019 Jan 25.

Molecular Imaging Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Near-infrared photoimmunotherapy (NIR-PIT) induces immunogenic cell death but has mostly failed to induce durable antitumor responses in syngenic tumor mouse models. We hypothesized that adaptive immune resistance could be limiting durable responses after treatmemt with NIR-PIT. We investigated the effects of combining NIR-PIT targeting cell-surface CD44 and PD-1 blockade in multiple syngeneic tumor models. In two of three models, NIR-PIT monotherapy halted tumor growth, enhanced dendritic cell tumor infiltration, and induced tumor antigen-specific T-cell responses absent at baseline. The addition of PD-1 blockade reversed adaptive immune resistance, resulting in both enhanced preexisting tumor antigen-specific T-cell responses and enhanced T-cell responses induced by NIR-PIT. Enhanced immune responses correlated with shared tumor antigen expression, suggesting that antigenicity is a major determinant of response to combination NIR-PIT and PD-1 blockade. Combination treatment induced complete rejection of MC38 tumors treated with NIR-PIT, as well as untreated, distant tumors. Accordingly, tumor antigen-specific T-cell responses were measured in both treated and untreated tumors, validating the development of systemic antitumor immunity. Mice that cleared tumors resisted subsequent tumor challenge, indicating the presence of systemic immune memory. Cumulatively, these results demonstrate reversal of adaptive immune resistance following induction of innate and adaptive immunity by NIR-PIT, resulting in high rates of tumor rejection and/or significant tumor growth control in antigenic syngeneic models of cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237708PMC
March 2019

Giant cellulitis-like Sweet syndrome as an initial clinical presentation of acute myeloblastic leukemia with t(6;9)(p23;q34): DEK-CAN and internal duplications of FMS-like tyrosine kinase 3.

Ann Hematol 2019 Mar 18;98(3):787-788. Epub 2019 Jan 18.

Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, 990-2292, Japan.

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http://dx.doi.org/10.1007/s00277-019-03613-1DOI Listing
March 2019

Photoinduced Ligand Release from a Silicon Phthalocyanine Dye Conjugated with Monoclonal Antibodies: A Mechanism of Cancer Cell Cytotoxicity after Near-Infrared Photoimmunotherapy.

ACS Cent Sci 2018 Nov 6;4(11):1559-1569. Epub 2018 Nov 6.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1088, United States.

Photochemical reactions can dramatically alter physical characteristics of reacted molecules. In this study, we demonstrate that near-infrared (NIR) light induces an axial ligand-releasing reaction, which dramatically alters hydrophilicity of a silicon phthalocyanine derivative (IR700) dye leading to a change in the shape of the conjugate and its propensity to aggregate in aqueous solution. This photochemical reaction is proposed as a major mechanism of cell death induced by NIR photoimmunotherapy (NIR-PIT), which was recently developed as a molecularly targeted cancer therapy. Once the antibody-IR700 conjugate is bound to its target, activation by NIR light causes physical changes in the shape of antibody antigen complexes that are thought to induce physical stress within the cellular membrane leading to increases in transmembrane water flow that eventually lead to cell bursting and necrotic cell death.
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http://dx.doi.org/10.1021/acscentsci.8b00565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276043PMC
November 2018

Near infrared photoimmunotherapy using a fiber optic diffuser for treating peritoneal gastric cancer dissemination.

Gastric Cancer 2019 05 31;22(3):463-472. Epub 2018 Aug 31.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Background: Peritoneal dissemination (PD) of abdominal malignancies is a common form of metastasis and its presence signals a poor prognosis. New treatment is required for patients with PD. Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). In this study, we investigate in vitro and in vivo efficacy of trastuzumab (tra)-IR700DX NIR-PIT on a human epidermal growth factor receptor type 2 (HER2)-positive gastric cancer cell line.

Methods: NIR-PIT effects were investigated in vitro and in vivo. Disseminated peritoneal implants mice were separated into 5 groups: (1) no treatment; (2) tra-IR700 i.v. only; (3) NIR light only; (4) NIR-PIT; (5) repeated NIR-PIT. The peritoneal cavity was irradiated with NIR light using a fiber optic diffuser delivered through the catheter.

Results: Specific binding and cell-specific killing was observed after NIR-PIT in vitro. In the in vivo study, fluorescence endoscopy showed high tumor accumulation of tra-IR700 within tumors. Significantly prolonged survival was achieved in the three treatment groups (tra-IR700 i.v. only, NIR-PIT, and repeated NIR-PIT groups) compared with control and NIR light only group (p < 0.05 for tra-IR700 i.v. only, p < 0.01 for NIR-PIT, and p < 0.0001 for repeated NIR-PIT). Moreover, most prolonged survival was shown for the repeated NIR-PIT group (p < 0.0001 vs tra-IR700 i.v. only, p < 0.01 vs NIR-PIT).

Conclusion: NIR-PIT using a fiber optic diffuser to deliver light is a promising candidate for the treatment of disseminated peritoneal metastases and could be readily translated to humans.
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http://dx.doi.org/10.1007/s10120-018-0871-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400986PMC
May 2019

Near infrared photoimmunotherapy targeting bladder cancer with a canine anti-epidermal growth factor receptor (EGFR) antibody.

Oncotarget 2018 Apr 10;9(27):19026-19038. Epub 2018 Apr 10.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Anti-epidermal growth factor receptor (EGFR) antibody therapy is used in EGFR expressing cancers including lung, colon, head and neck, and bladder cancers, however results have been modest. Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate which is activated by NIR light. NIR-PIT is in clinical trials in patients with recurrent head and neck cancers using cetuximab-IR700 as the conjugate. However, its use has otherwise been restricted to mouse models. This is an effort to explore larger animal models with NIR-PIT. We describe the use of a recombinant canine anti-EGFR monoclonal antibody (mAb), can225IgG, conjugated to the photo-absorber, IR700DX, in three EGFR expressing canine transitional cell carcinoma (TCC) cell lines as a prelude to possible canine clinical studies. Can225-IR700 conjugate showed specific binding and cell-specific killing after NIR-PIT on EGFR expressing cells . In the study, can225-IR700 conjugate demonstrated accumulation of the fluorescent conjugate with high tumor-to-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 µg of can225-IR700 i.v. only; (3) NIR light exposure only; (4) 100 µg of can225-IR700 i.v., NIR light exposure. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups ( < 0.001), and significantly prolonged survival was achieved ( < 0.001 vs. other groups) in the treatment groups. In conclusion, NIR-PIT with can225-IR700 is a promising treatment for canine EGFR-expressing cancers, including invasive transitional cell carcinoma in pet dogs, that could provide a pathway to translation to humans.
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http://dx.doi.org/10.18632/oncotarget.24876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922375PMC
April 2018

Endoscopic near infrared photoimmunotherapy using a fiber optic diffuser for peritoneal dissemination of gastric cancer.

Cancer Sci 2018 Jun 29;109(6):1902-1908. Epub 2018 May 29.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC) which is activated by near infrared light. Here, we describe the efficacy of endoscopic NIR-PIT using the APC trastuzumab-IR700DX (tra-IR700) in the setting of human epidermal growth factor 2 positive (HER2 + ) gastric carcinoma with peritoneal disseminations. In this in vivo study, fluorescence endoscopy showed high tumor accumulation of tra-IR700 within disseminated peritoneal implants. Mice with disseminated peritoneal gastric cancer were separated into 4 groups: (i) control (no treatment); (ii) tra-IR700 i.v. only; (iii) NIR light only; and (iv) endoscopic NIR-PIT. NIR light irradiation was carried out through a fiber optic diffuser under endoscopic guidance. In vivo bioluminescence images showed significantly greater therapeutic effect in the endoscopic NIR-PIT group than that in the control groups (P < .01 vs other control groups). Histological analysis showed diffuse cancer cell death in NIR-PIT-treated tumors. In conclusion, NIR-PIT with NIR light delivered via an endoscopic fiber optic diffuser is a promising method for the treatment of peritoneal dissemination of gastric cancer. Moreover, this technique could be readily used in other types of cancers with peritoneal dissemination provided that suitable antibodies could be found.
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http://dx.doi.org/10.1111/cas.13621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989863PMC
June 2018

Interstitial near-infrared photoimmunotherapy: effective treatment areas and light doses needed for use with fiber optic diffusers.

Oncotarget 2018 Feb 27;9(13):11159-11169. Epub 2018 Jan 27.

National Institutes of Health, National Cancer Institute, Molecular Imaging Program, Bethesda, Maryland 20892-1088, United States.

Near-infrared photoimmunotherapy (NIR-PIT), a promising cancer therapy utilizing an antibody-photoabsorber conjugate (APC) and NIR light, which induces rapid necrotic cell death only in APC-bound cells. Effective NIR-PIT in mouse models has been achieved using superficial light illumination (SLI) with light emitting diodes (LEDs) or lasers, but in the clinical setting, fiber optic diffusers have been employed to deliver light to deeper tumors. However, the performance of NIR light in tissue delivered by fiber optic diffusers is poorly understood. Here, we investigated NIR-PIT using a cylindrical fiber optic diffuser in a mouse model of A431 tumors. NIR-PIT with 100 J/cm, the same light dose used in clinical trials of NIR-PIT, was applied after insertion of the diffuser within the tumor bed, and then both bioluminescence and fluorescence imaging were analyzed to assess the therapeutic efficacy. The diffuser can deliver adequate NIR light dose for effective NIR-PIT to the A431 tumor at a distance of approximately 1 cm around the light source at 100 J/cm. At 50 J/cm NIR light effective NIR-PIT was reduced to a distance of 5 - 7 mm diameter around the light source. These results indicate that the energy of interstitial light (measured in Joules/cm) administered via a fiber diffuser determines the depth of effective NIR-PIT around the diffuser and determines the spacing at which such diffusers should be placed to entirely cover the tumor. Thermal measurements demonstrate that interstitial light for NIR-PIT does not cause damage to the skin overlying the diffuser.
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http://dx.doi.org/10.18632/oncotarget.24329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834257PMC
February 2018

Near Infrared Photoimmunotherapy with Combined Exposure of External and Interstitial Light Sources.

Mol Pharm 2018 09 21;15(9):3634-3641. Epub 2018 Feb 21.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States.

Near infrared photoimmunotherapy (NIR-PIT) is a new target-cell-specific cancer treatment that induces highly selective necrotic/immunogenic cell death after systemic administration of a photoabsorber antibody conjugate and subsequent NIR light exposure. However, the depth of NIR light penetration in tissue (approximately 2 cm) with external light sources limits the therapeutic effects of NIR-PIT. Interstitial light exposure using cylindrical diffusing optical fibers can overcome this limitation. The purpose in this study was to compare three NIR light delivery methods for treating tumors with NIR-PIT using a NIR laser system at an identical light energy; external exposure alone, interstitial exposure alone, and the combination. Panitumumab conjugated with the photoabsorber IRDye-700DX (pan-IR700) was intravenously administered to mice with A431-luc xenografts which are epithelial growth factor receptor (EGFR) positive. One and 2 days later, NIR light was administered to the tumors using one of three methods. Interstitial exposure alone and in combination with external sources showed the greatest decrease in bioluminescence signal intensity. Additionally, the combination of external and interstitial NIR light exposure showed significantly greater tumor size reduction and prolonged survival after NIR-PIT compared to external exposure alone. This result suggested that the combination of external and interstitial NIR light exposure was more effective than externally applied light alone. Although external exposure is the least invasive means of delivering light, the combination of external and interstitial exposures produces superior therapeutic efficacy in tumors greater than 2 cm in depth from the tissue surface.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400989PMC
September 2018

Avoiding thermal injury during near-infrared photoimmunotherapy (NIR-PIT): the importance of NIR light power density.

Oncotarget 2017 Dec 11;8(68):113194-113201. Epub 2017 Aug 11.

National Institutes of Health, National Cancer Institute, Molecular Imaging Program, Bethesda, Maryland, 20892, United States.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly-established cancer treatment which employs the combination of an antibody-photoabsorber conjugate (APC) and NIR light. When NIR light is absorbed by APC-bound tissues, a certain amount of heat is generated locally. For the most part this results in a subclinical rise in skin temperature, however, excessive light exposure may cause non-specific thermal damage. In this study, we investigated the potential for thermal damage caused by NIR-PIT by measuring surface temperature. Two sources of light, laser and light emitting diode (LED), were compared in a mouse tumor model. First, we found that the skin was heated rapidly by NIR light regardless of whether laser or LED light sources were used. Air cooling at the surface reduced the rise in temperature. There were no associations between the rise of skin temperature and tumor volume of the treated tumor, or APC concentration. Second, we investigated the extent of thermal damage to the skin at various light doses. We detected burn injuries 1 day after NIR-PIT, when the NIR light was at a power density higher than 600 mW/cm. Successful treatments at lower power density could be achieved if the total light energy absorbed by the tumor was the same, i.e. by extending the duration of light exposure. In conclusion, this study demonstrates that thermal injury after NIR-PIT can be avoided by either employing a cooling system or by lowering the power density of the light source and prolonging the exposure time such that the total energy is constant. Thus, thermal damage is preventable side effect of NIR-PIT.
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http://dx.doi.org/10.18632/oncotarget.20179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762583PMC
December 2017

meningitis in a diffuse large B-cell lymphoma patient with CD4-positive lymphocytopenia and persistent oligoclonal CD8-positive lymphocytes in the peripheral blood.

Int J Clin Exp Pathol 2018 1;11(1):455-461. Epub 2018 Jan 1.

Medical Mycology Research Center, Chiba University Chuo-Ku, Chiba, Japan.

Nocardiosis, sometimes presenting with multiple granulomatous lesions, is a rare opportunistic infection occurring in immunocompromised patients. However, its immunological features remain largely unaddressed. We investigated the immunological characteristics of human nocardiosis and examined the component cells of the granulomatous lesions. A 66-year-old man with diffuse large B-cell lymphoma presented with fever and multiple nodules in the lung during chemotherapy. The blood culture formed white colonies, but their characterization was difficult by routine microbiological laboratory methods. Matrix-assisted laser desorption ionization-time of flight mass spectrometry identified the colonies as . Meanwhile, the patient suddenly experienced an epileptic seizure without a brain abscess. His cerebrospinal fluid (CSF) showed neutrophilic pleocytosis (108/mm). The conventional agar culturing failed to isolate colonies, but culturing with brain-heart infusion agar generated colonies. These colonies were completely concordant with those from the blood, as confirmed by 16S rRNA gene sequencing. Therefore, the patient had developed meningitis through sepsis induced by . His CD4-positive T-lymphocyte counts were low, and oligoclonal CD8-positive αβ T-lymphocytes were present in the blood prior to the first and after three cycles of chemotherapy. He had bone marrow granulomatous lesions comprising lymphoma and CD8-positive αβ T-cells. Treatment with sulfamethoxazole/trimethoprim relieved all of his symptoms. The combined analysis by microbiological and molecular methods determined the cause of his epileptic seizure. His immunological characteristics, including low CD4-positive or CD8-positive αβ T-lymphocytes, may have contributed to the unusual clinical presentations by , which rarely involves the central nervous system.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957946PMC
January 2018

Dynamic changes in the cell membrane on three dimensional low coherent quantitative phase microscopy (3D LC-QPM) after treatment with the near infrared photoimmunotherapy.

Oncotarget 2017 Nov 1;8(61):104295-104302. Epub 2017 Nov 1.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States of America.

Near infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer therapy that relies on the binding of a near-infrared antibody photoabsorber conjugate (APC) to a cancer cell. Subsequent exposure to NIR light selectively induces rapid necrotic cell death on target-expressing cells with minimal off-target effects. When treated with NIR-PIT, targeted cells become swollen, develop blebs and burst within minutes of light exposure. Detailed spatial and temporal morphological changes of the cellular membrane of targeted cells treated with NIR-PIT have not been fully explored with state-of-the-art microscopic methods. In this study, we investigated the morphologic and kinetic effects of PIT on two types of cells, a spindle-shaped 3T3/Her cell and a spheric-shaped MDA-MB468 cell, after NIR-PIT using three-dimensional low-coherent quantitative phase microscopy (3D LC-QPM). Adhesive cells treated with NIR-PIT demonstrated region-specific cell membrane rupture occurring first on the distal free edge of the cell near the site of adhesion, in a process that was independent of cell shape. The results show that the peripheral portions of the cell membrane near the site of adhesion are particularly vulnerable to the effects of NIR-PIT, likely because these sites exhibit higher baseline surface tension.
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http://dx.doi.org/10.18632/oncotarget.22223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732807PMC
November 2017

Molecularly Targeted Cancer Combination Therapy with Near-Infrared Photoimmunotherapy and Near-Infrared Photorelease with Duocarmycin-Antibody Conjugate.

Mol Cancer Ther 2018 03 13;17(3):661-670. Epub 2017 Dec 13.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that uses an antibody-photoabsorber conjugate (APC). However, the effect of NIR-PIT can be enhanced when combined with other therapies. NIR photocaging groups, based on the heptamethine cyanine scaffold, have been developed to release bioactive molecules near targets after exposure to light. Here, we investigated the combination of NIR-PIT using panitumumab-IR700 (pan-IR700) and the NIR-releasing compound, CyEt-panitumumab-duocarmycin (CyEt-Pan-Duo). Both pan-IR700 and CyEt-Pan-Duo showed specific binding to the EGFR-expressing MDAMB468 cell line In studies, additional injection of CyEt-Pan-Duo immediately after NIR light exposure resulted in high tumor accumulation and high tumor-background ratio. To evaluate the effects of combination therapy , tumor-bearing mice were separated into 4 groups: (i) control, (ii NIR-PIT, (iii) NIR-release, (iv) combination of NIR-PIT and NIR-release. Tumor growth was significantly inhibited in all treatment groups compared with the control group ( < 0.05), and significantly prolonged survival was achieved ( < 0.05 vs. control). The greatest therapeutic effect was shown with NIR-PIT and NIR-release combination therapy. In conclusion, combination therapy of NIR-PIT and NIR-release enhanced the therapeutic effects compared with either NIR-PIT or NIR-release therapy alone. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935585PMC
March 2018

Epstein-Barr virus clonality and plasmacytosis in a patient with atypical angioimmunoblastic T cell lymphoma.

Ann Hematol 2018 Mar 30;97(3):537-539. Epub 2017 Nov 30.

Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, 990-2292, Japan.

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http://dx.doi.org/10.1007/s00277-017-3189-1DOI Listing
March 2018

Evaluation of Early Therapeutic Effects after Near-Infrared Photoimmunotherapy (NIR-PIT) Using Luciferase-Luciferin Photon-Counting and Fluorescence Imaging.

Mol Pharm 2017 12 22;14(12):4628-4635. Epub 2017 Nov 22.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, NIH , Bethesda, Maryland 20892, United States.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that induces highly selective immunogenic cell death. It is based on an antibody-photoabsorber conjugate (APC) that is activated by NIR light. The purpose of this study was to investigate the effects of NIR-PIT as measured by luciferase-luciferin photon-counting and fluorescence imaging. Six days after subcutaneous injection of A431-luc-GFP cells tumors formed in a xenograft mouse model. The EGFR-targeting antibody, panitumumab, was conjugated to the photoabsorber, IRDye-700DX (pan-IR700), and was intravenously administered to tumor-bearing mice. Serial luciferase-luciferin photon-counting images and both green fluorescent protein (GFP) and IR700 fluorescence images were obtained from the same mice before and after NIR-PIT treatment (0, 10, 20, 30 min (early phase), and 24, 48 h (late phase) after NIR light exposure). Optical signal intensities were compared for each modality. IR700 fluorescence and luciferase-luciferin photon-counting images showed decreased intensities in both the early and late phases after NIR-PIT (p < 0.01). On the other hand, GFP fluorescence images showed decreased intensities only in the late phase (p < 0.01). In the early phase, GFP fluorescence images showed smaller intensity reductions compared to IR700 fluorescence and luciferase-luciferin photon-counting (p < 0.01), while in the late phase, IR700 fluorescence showed smaller intensity reductions than luciferase-luciferin photon-counting and GFP fluorescence (p < 0.05), due to redistribution of pan-IR700 within the tumor bed. In conclusion, luciferase-luciferin photon-counting imaging is suitable to evaluate early phase NIR-PIT effects, while both luciferase-luciferin photon-counting and GFP reflected later phase effects.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333314PMC
December 2017

Characteristics of ovarian cancer detection by a near-infrared fluorescent probe activated by human NAD(P)H: quinone oxidoreductase isozyme 1 (hNQO1).

Oncotarget 2017 Sep 20;8(37):61181-61192. Epub 2017 May 20.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, United States National Institutes of Health, Bethesda, Maryland 20892-1088, USA.

Near-infrared (NIR) fluorescent probes are ideal for imaging, because they offer deeper tissue penetration by the light and lower background autofluorescence than fluorophores that emit in the visible range. QSTCy is a newly synthesized, NIR light-emitting probe that is activated by an enzyme commonly overexpressed in tumor cells, human nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase isozyme 1, known as hNQO1 or DT-diaphorase. The purpose of this study is to compare the sensitivity of detecting peritoneal ovarian cancer metastasis (POCM) with QSTCy and gGlu-HMRG, a green fluorescent probe, upon their surface application. uptake of QSTCy was significantly higher than that of gGlu-HMRG. Using a red fluorescence protein (RFP)-labeled tumor model of POCM, the QSTCy probe provided high sensitivity (96.9%) but modest specificity (61.0%), most likely the result of albumin-probe interactions and non-specific activation in nearby altered but healthy cells. Three types of kinetic maps based on maximum fluorescence signal (MF), wash-in rate (WIR), and area under the curve (AUC) allowed for differentiation of the activated fluorescence signal associated with POCM from the background signal of the small intestine, thereby significantly improving the specificity of QSTCy to 80%, 100%, and 100% for MF, WIR, and AUC, as well yielding a moderate improvement in sensitivity (100% for all approaches) that is comparable to that with gGlu-HMRG, but with the added advantages of NIR fluorescence as the transduction modality. Such a new methodology has the potential to afford identification of cancerous lesions deeper within tissue.
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http://dx.doi.org/10.18632/oncotarget.18044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617415PMC
September 2017

Syngeneic Mouse Models of Oral Cancer Are Effectively Targeted by Anti-CD44-Based NIR-PIT.

Mol Cancer Res 2017 12 18;15(12):1667-1677. Epub 2017 Sep 18.

Molecular Imaging Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Oral cavity squamous cell carcinoma (OSCC) is considered one of the most aggressive subtypes of cancer. Anti-CD44 monoclonal antibodies (mAb) are a potential therapy against CD44 expressing OSCC; however, to date the therapeutic effects have been disappointing. Here, a new cancer treatment is described, near-infrared photoimmunotherapy (NIR-PIT), that uses anti-CD44 mAbs conjugated to the photoabsorber IR700DX. This conjugate is injected into mice harboring one of three CD44 expressing syngeneic murine oral cancer cell (MOC) lines, MOC1 (immunogenic), MOC2 mKate2 (moderately immunogenic), and MOC2-luc (poorly immunogenic). Binding of the anti-CD44-IR700 conjugate was shown to be specific and cell-specific cytotoxicity was observed after exposure of the cells to NIR light The anti-CD44-IR700 conjugate, when assessed , demonstrated deposition within the tumor with a high tumor-to-background ratio. Tumor-bearing mice were separated into four cohorts: no treatment; 100 μg of anti-CD44-IR700 i.v. only; NIR light exposure only; and 100 μg of anti-CD44-IR700 i.v. with NIR light exposure. NIR-PIT therapy, compared with the other groups, significantly inhibited tumor growth and prolonged survival in all three cell model systems. In conclusion, these data reveal that anti-CD44 antibodies are suitable as mAb-photoabsorber conjugates for NIR-PIT in MOC cells. This study using syngeneic mouse models, which better model the disease in humans than conventional xenografts, suggests that NIR-PIT with anti-CD44-IR700 is a potential candidate for the treatment of OSCC. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712275PMC
December 2017

Pseudo-grey platelet syndrome in a pregnant patient.

Br J Haematol 2017 09 23;178(6):836. Epub 2017 Jun 23.

Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan.

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http://dx.doi.org/10.1111/bjh.14808DOI Listing
September 2017

Near-Infrared Photoimmunotherapy Targeting Prostate Cancer with Prostate-Specific Membrane Antigen (PSMA) Antibody.

Mol Cancer Res 2017 09 6;15(9):1153-1162. Epub 2017 Jun 6.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.

Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for molecular therapy. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photoabsorber conjugate (APC). Here, we describe the efficacy of NIR-PIT, using a fully human IgG anti-PSMA monoclonal antibody (mAb), conjugated to the photoabsorber, IR700DX, in a PSMA-expressing PC3 prostate cancer cell line. Anti-PSMA-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR light In the study, anti-PSMA-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (i) no treatment; (ii) 100 μg of anti-PSMA-IR700 i.v.; (iii) NIR light exposure; (iv) 100 μg of anti-PSMA-IR700 i.v., NIR light exposure was administered. These were performed every week for up to 3 weeks. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other control groups ( < 0.001), and significantly prolonged survival was achieved ( < 0.0001 vs. other control groups). More than two thirds of tumors were cured with NIR-PIT. In conclusion, the anti-PSMA antibody is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with the anti-PSMA-IR700 antibody is a promising candidate of the treatment of PSMA-expressing tumors and could be readily translated to humans. NIR-infrared photoimmunotherapy (NIR-PIT) using a fully human anti-PSMA-IR700 conjugate showed potential therapeutic effects against a PSMA-expressing prostate cancer that is readily translated to humans. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581714PMC
September 2017

A topically-sprayable, activatable fluorescent and retaining probe, SPiDER-βGal for detecting cancer: Advantages of anchoring to cellular proteins after activation.

Oncotarget 2017 Jun;8(24):39512-39521

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, United States National Institutes of Health, Bethesda, Maryland 20892, USA.

SPiDER-βGal is a newly-developed probe that is activated by β-galactosidase and is then retained within cells by anchoring to intracellular proteins. Previous work has focused on gGlu-HMRG, a probe activated by γ-glutamyltranspeptidase, which demonstrated high sensitivity for the detection of peritoneal ovarian cancer metastases in an animal model. However, its fluorescence, after activation by γ-glutamyltranspeptidase, rapidly declines over time, limiting the actual imaging window and the ability to define the border of lesions. The purpose of this study is to compare the fluorescence signal kinetics of SPiDER-βGal with that of gGlu-HMRG using ovarian cancer cell lines in vitro and ex vivo tissue imaging. In vitro removal of gGlu-HMRG resulted in a rapid decrease of fluorescence intensity followed by a more gradual decrease up to 60 min while there was a gradual increase in fluorescence up to 60 min after removal of SPiDER-βGal. This is most likely due to internalization and retention of the dye within cells. This was also confirmed ex vivo tissue imaging using a red fluorescence protein (RFP)-labeled tumor model in which the intensity of fluorescence increased gradually after activation of SPiDER-βGal. Additionally, SPiDER-βGal resulted in intense enhancement within the tumor due to the high target-to-background ratio, which extended up to 60 min after activation. In contrast, gGlu-HMRG fluorescence resulted in decreasing fluorescence over time in extracted tumors. Thus, SPiDER-βGal has the advantages of higher signal with more signal retention, resulting in improved contrast of the tumor margin and suggesting it may be an alternative to existing activatable probes.
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http://dx.doi.org/10.18632/oncotarget.17080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503628PMC
June 2017

Near-infrared photoimmunotherapy: a comparison of light dosing schedules.

Oncotarget 2017 May;8(21):35069-35075

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, United States of America.

Near infrared photoimmunotherapy (NIR-PIT) is a newly-developed cancer therapy in which a monoclonal antibody is conjugated to a near-infrared photoabsorber, IR700 to form an antibody photoabsorber conjugate (APC). After the APC binds to cancer cells expressing the cognate antigen, exposure to NIR light results in rapid, highly selective necrotic cell death of the cancer cells with minimal off-target effects. Several hours after NIR-PIT, the tumor vessels become supraphysiologically permeable and circulating APC can therefore readily leak into the already-treated tumor space where it can bind with viable cancer cells that is called super-enhanced permeability and retention effect. The presence of the SUPR effect after NIR-PIT has prompted regimens in which there is a repeat exposure of NIR light 24 hours after the initial NIR-PIT to take advantage of the leakage of additional APC deeper into the tumor. However, this post-treatment APC penetration was fully induced within 3 hours, therefore, it is possible that repeated exposures of NIR light could be administered much earlier than 24 hours and still produce the same effects. To test this idea, we compared several modes of delivering additional doses of light after initial NIR-PIT. We found that repeated exposures of NIR light starting 3 hours after initial NIR-PIT produced equal or superior results to more delayed exposures of NIR light. This finding has practical implications of an easy-to-perform regimen as repeated light exposures could be performed during a single day rather than extending the procedure over two days which is the current recommendation.
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http://dx.doi.org/10.18632/oncotarget.17047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471035PMC
May 2017