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Background Human epidermal growth factor receptor 2 (HER2) is tyrosine kinase receptor that belongs to the ErbB family and is overexpressed on the membrane surface of various cancer cells, including small cell lung cancer (SCLC); however, no HER2 targeted therapy for SCLC have yet been established. Near‐infrared photoimmunotherapy (NIR‐PIT) is a novel cancer therapy based on photo‐absorber, IRDye‐700DX (IR700), ‐antibody conjugates, and near‐infrared (NIR) light. Methods We used HER2‐positive SCLC parental cell lines (SBC‐3) and its chemoresistant cell lines, and examined therapeutic efficacy of HER2 targeting NIR‐PIT using anti HER2 antibody trastuzumab. Results We found that HER2 expression was upregulated on chemoresistant cell lines, especially cisplatin‐resistance (SBC‐3/CDDP). In vitro, the rate of cell death increased with the amount of NIR‐light irradiation, and it was significantly higher in SBC‐3/CDDP than in SBC‐3. In vivo, tumor growth was more suppressed in SBC‐3/CDDP group than in SBC‐3 group, and survival period tended to be prolonged. Conclusion In this study, we demonstrated that HER2 targeting NIR‐PIT using trastuzumab is promising therapy for HER2‐positive SCLC, and is more effective when HER2 expression is upregulated due to CDDP resistance, suggesting that the HER2 expression level positively corelated with the efficacy of NIR‐PIT., We found that human epidermal growth factor receptor 2 (HER2) was expressed in small‐cell lung cancer (SCLC) parental cell lines (SBC‐3) and its chemoresistant cell lines, and HER2 was upregulated in chemoresistant SCLC cells, especially CDDP‐resistant cells (SBC‐3/CDDP). The HER2‐targeting near‐infrared photoimmunotherapy (NIR‐PIT) using an anti‐HER2 antibody, trastuzumab, induced HER2‐expressing SCLC cells death, and efficacy of this therapy was significantly higher in SBC‐3/CDDP than in SBC‐3 in vitro and in vivo. These findings suggest a positive correlation between the cancer antigen expression level and the NIR‐PIT effect. Implications of all the available evidence. Our finding suggests that NIR‐PIT targeting HER2 using trastuzumab is a novel therapeutic approach for HER2‐positive SCLC when SCLC acquired CDDP‐based chemotherapy resistance and HER2 expression was upregulated.

Ideal cancer treatments specifically target and eradicate tumor cells without affecting healthy cells. Therefore, antibody-based therapies that specifically target cancer antigens can be considered ideal cancer therapies. Antibodies linked with small-molecule drugs (i.e., antibody-drug conjugates [ADCs]) are widely used in clinics as antibody-based therapeutics. However, because tumors express antigens heterogeneously, greater target specificity and stable binding of noncleavable linkers in ADCs limit their antitumor effects. To overcome this problem, strategies, including decreasing the binding strength, conjugating more drugs, and targeting tumor stroma, have been applied, albeit with limited success. Thus, further technological advancements are required to remotely control the ADCs. Here, we described a drug that is photo-releasable from an ADC created via simple double conjugation and its antitumor effects both on target and nontarget tumor cells. Specifically, noncleavable T-DM1 was conjugated with IR700DX to produce T-DM1-IR700. Although T-DM1-IR700 itself is noncleavable, with NIR-light irradiation, it can release DM1-derivatives which elicited antitumor effect in vitro mixed culture and in vivo mixed tumor model which are mimicking heterogeneous tumor-antigen expression same as real clinical tumors. This cytotoxic photo-bystander effect occurred in various types mixed cultures in vitro, and changing antibodies also exerted photo-bystander effects, suggesting that this technology can be used for targeting various specific cancer antigens. These findings can potentially aid the development of strategies to address challenges associated with tumor expression of heterogeneous antigen.

Background: GPR87 is a G protein receptor that is specifically expressed in tumor cells, such as lung cancer, and rarely expressed in normal cells. GPR87 is a promising target for cancer therapy, but its ligand is controversial. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy in which a photosensitizer, IRDye700DX (IR700), binds to antibodies and specifically destroys target cells by irradiating them with near-infrared light. Here, we aimed to develop a NIR-PIT targeting GPR87. Methods: We evaluated the expression of GPR87 in resected specimens of lung cancer and malignant pleural mesothelioma (MPM) resected at Nagoya University Hospital using immunostaining. Humanized anti GPR87 antibody (huGPR87) was generated by introducing VH and VL genes into mouse anti GPR87 antibody which generated by standard hybridoma method. HuGPR87 was conjugated with IR700 and the therapeutic effect of NIR-PIT was evaluated in vitro and in vivo using lung cancer or MPM cell lines. Findings: Among the surgical specimens, 54% of lung cancer and 100% of MPM showed high expression of GPR87. It showed therapeutic effects on lung cancer and MPM cell lines in vitro, and showed therapeutic effects in multiple models in vivo. Interpretation: These results suggest that NIR-PIT targeting GPR87 is a promising therapeutic approach for the treatment of thoracic cancer. Funding: Funding: This research was supported by the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, JSPS), Souhatsu (JST). Declaration of Interest: None to declare Ethical Approval: All in vivo procedures were performed in accordance with the Nagoya University Animal Care and Use Committee's "Guide for the Management and Use of Laboratory Animal Resources" (approval numbers 2017-29438, #2018-30096, # 2019-31234, #2020-20104). The use of specimens from patients was approved by the Ethics Committee of the Nagoya University Clinical Research Committee (Approval No. 2018-0046).

BackgroundNear-infrared photoimmunotherapy (NIR-PIT) is a new modality for treating cancer, which uses antibody-photoabsorber (IRDye700DX) conjugates that specifically bind to target tumor cells. This conjugate is then photoactivated by NIR light, inducing rapid necrotic cell death. NIR-PIT needs a highly expressed targeting antigen on the cells because of its reliance on antibodies. However, using antibodies limits this useful technology to only those patients whose tumors express high levels of a specific antigen. Thus, to propose an alternative strategy, we modified this phototechnology to augment the anticancer immune system by targeting the almost low-expressed immune checkpoint molecules on tumor cells.MethodsWe used programmed death-ligand 1 (PD-L1), an immune checkpoint molecule, as the target for NIR-PIT. Although the expression of PD-L1 on tumor cells is usually low, PD-L1 is almost expressed on tumor cells. Intratumoral depletion with PD-L1-targeted NIR-PIT was tested in mouse syngeneic tumor models.ResultsAlthough PD-L1-targeted NIR-PIT showed limited effect on tumor cells in vitro, the therapy induced sufficient antitumor effects in vivo, which were thought to be mediated by the ‘photoimmuno’ effect and antitumor immunity augmentation. Moreover, PD-L1-targeted NIR-PIT induced antitumor effect on non-NIR light-irradiated tumors.ConclusionsLocal PD-L1-targeted NIR-PIT enhanced the antitumor immune reaction through a direct photonecrotic effect, thereby providing an alternative approach to targeted cancer immunotherapy and expanding the scope of cancer therapeutics.

Adrenocortical carcinomas are relatively rare, but they are considered to be highly aggressive malignant tumors. Sarcomatoid carcinomas represent an even more aggressive type. Bilateral malignant adrenal tumors are extraordinary rare, except for those that represent metastatic spread from a primary neoplasm. Here we report a case of a 69-year-old woman who presented symptoms that raised strong suspicions of adrenal insufficiency. Bilateral adrenal masses, identified in the imaging study, were responsible for the clinical manifestation and surgically resected. Surgical specimens of the bilateral adrenal tumors shared histological features compatible with sarcomatoid carcinoma. It was very difficult to confirm that the sarcomatoid carcinomas were derived from the cortex of the adrenal glands, but careful morphological observation and the panel of antibodies used for immunohistochemistry made the diagnosis possible. This is the first report of sarcomatoid carcinomas involving both adrenal glands. It should be emphasized that sarcomatoid carcinoma can arise bilaterally from even functionally impaired adrenal glands.

INTRODUCTION AND OBJECTIVES: Efficacy in the prostate cancer detection of real-time tissue elastogarpahy (RTE) has been reported. But RTE has a major problem that RTE is highly operator dependent procedure. We hypothesized that the pressure device might decrease the operator dependency and increase the prostate cancer detection rate of RTE. The pressure device run with water pressure was developed for this study, called this procedure real-time balloon inflation elastography (RBIE). The results of targeted prostate biopsy with RBIE was studied for detection of prostate cancer. METHODS: 233 patients and 1978 were enrolled in this study with abnormal findings of digital rectal examination (DRE), PSA and/ or TRUS. Median age was 73 year-old (range 54e89), median PSA was 7.6 ng/mL (range 0.8-2606.0), and median number of biopsy cores taken on each patient was 8 (range 8e10). All of 233 patients were examined with MRI prior to prostate needle biopsy. A total of 1978 specimens obtained by systemic biopsy were studied. The findings of RBIE, RTE, TRUS, PDUS and MRI (T2WI, dynamic contrast enhanced images (DCEI) and diffusion weighted image (DWI)) were compared to the histopathological findings of biopsy specimens. RESULTS: The prostate cancer was detected in 113 of 233 patients (48.5%), and 412 of 1978 specimens (20.8%). Gleason score of 5 to 6, 7 and 8 to 10 tumors was 110, 166 and 138 specimens respectively. Clinical stages of T1c, T2a-c, T3a-b, and T4 were 20, 60, 22 and 11 cases. The sensitivity of RBIE, RTE, TRUS, PDUS, T2WI, DCEI and DWI were 72.1%, 72.1%, 74.5%, 72.8%, 78.2%, 77.2% and 77.2%, the specificity were 94.3%, 93.6%, 85.4% 90.5%, 92.0%, 93.7% and 92.6%, respectively. Both of the sensitivity and the specificity of RBIE were not significantly inferior to those of MRI. The results of targeted biopsy (PPV) of RBIE, RTE, TRUS, PDUS, T2WI, DCEI and DWI were 76.7%, 74.8%, 57.4%, 67.0%, 72.0%, 76.4% and 73.3%. PPV of RBIE was also comparable to those of MRI. CONCLUSIONS: RBIE was low cost and low invasive procedure. The prostate cancer detection capability of RBIE might be not inferior to that of MRI, expensive and time consuming procedure. Furthermore, RBIE reveals prostate in real-time, so RBIE could enhance the prostate cancer detection as a biopsy guidance image.

protein (BMP)-2, a member of the transforming growth factor b superfamily, has been shown to act as a tumor suppressor in several cancers by activating signaling cascades that cause cell cycle arrest. In addition, the expression level of BMP-2 is downregulated because of promoter CpG hypermethylation. We hypothesized that impaired regulation of BMP-2 through epigenetic pathways is associated with the pathogenesis of renal cell carcinoma. METHODS: To test this hypothesis, CpG methylation of the BMP-2 gene was analyzed in 3 renal tumor cell lines and 96 renal tumor and matched normal renal tissue. Promoter CpG methylation was analyzed by methylation specific PCR using bisulfite-modified DNA as template. BMP-2 expression was measured by quantitative RT-PCR. RESULTS: BMP-2 mRNA expression was significantly enhanced after 5-aza-2€ treatment in renal tumor cell lines. The prevalence of BMP-2 promoter methylation was significantly higher and BMP-2 mRNA expression was significantly lower in renal tumor samples than in normal kidney samples (p

To evaluate dynamic postural control, the Body Tracking Test (BTT) was developed. This paper investigated the optical target speed. The subject standing on the stabilometer was asked to track a moving optical target displayed on the screen by his/her bodily movement. Stabilometric data were recorded and computer-analyzed. The horizontal or vertical span of the target was 15 cm. The optical target moved in a horizontal or vertical manner. The movement of the optical target was programmed by controlled triangular waves. The sampling time was 50 mseconds for a total of 60 seconds. The subject stood erect on the stabilometer with feet together and the display screen was placed at eye level.In the horizontal BTT, the gain for target and tracking was 1.8. In the vertical BTT, the gain for target and tracking was 1.6.Fifty healthy young adult volunteers (male 24, female 26) were tested. The mean age was 23.6 (19-34). They were examined in groups of five by target movement speed.We established the optical target speed at 0.025-0.4 Hz. Total distance of bodily movements was adjusted by body weight.To compare the results of each scale, the total distance of bodily movements was divided by total target movement.This ratio was named "Index of BTT movement". At 0.025 Hz, the index of BTT movement was at a maximum, while at 0.4 Hz, the index of BTT movement was almost 1.0.However at 0.4 Hz, the bodily movement became a fixed rhythmical movement. With a slow amplification such as 0.025 Hz, a larger adjustment was made accordingly amplification. Therefore, it was considered appropriate to use 0.125 Hz to obtain stable stabilometric data.

Nyquist sampling theorem in an image calculation with angular spectrum method restricts a propagation distance and a focal length of a lens. In order to avoid these restrictions, we studied suitable expressions for the image computations depending on their conditions. Additionally, a lateral scale in an observation plane can be magnified freely by using a scaled convolution in each expression.

We propose a design method of phase-analysis algorithms based on two-dimensional grating phase shifting for Talbot interferometry, Talbot-Lau imaging, or the Ronchi test. These algorithms are designed to separate the two orthogonal shearing wavefronts and eliminate error effects of unwanted diffraction orders, simultaneously. Taking the effect of multidiffraction into account, moving the two-dimensional grating along a certain pass leads to a series of phase-shifted interfrograms, from which two orthogonal shearing wavefronts are derived, for the tested wavefront to be retrieved. The designing process is demonstrated, and the residual errors are analyzed via simulation works and experimental comparison.