Near-infrared photoimmunotherapy targeting PD-L1: Improved efficacy by preconditioning the tumor microenvironment.

Near-infrared photoimmunotherapy (NIR-PIT) is a new type of cancer therapy that employs antibody-IRDye700DX conjugates (AbPCs) and near-infrared (NIR) light at a wavelength of 689 nm, the excitation wavelength of IR700. Administered intravenously, injected AbPCs bind specifically to cells expressing the target antigen, whereupon NIR light exposure causes rapid, selective killing. This process induces an anticancer T cell response, leading to sustained anticancer host immune response. Programmed cell death ligand-1 (PD-L1) is a major inhibitory immune checkpoint molecule expressed in various cancers. In this study, we first assessed the efficacy of PD-L1-targeted NIR-PIT (αPD-L1-PIT) in immune-competent tumor mouse models. αPD-L1-PIT showed a significant therapeutic effect on the tumor models with high PD-L1 expression. Furthermore, αPD-L1-PIT induced an abscopal effect on distant tumors and long-term immunological memory. In contrast, αPD-L1-PIT was not as effective for tumor models with low PD-L1 expression. To improve the efficacy of PD-L1-targeted NIR-PIT, PEGylated interferon-gamma (IFNγ) was administered with αPD-L1-PIT. The combination therapy improved the treatment efficacy by increasing PD-L1 expression leading to more efficient cell killing by αPD-L1-PIT. Furthermore, the PEGylated IFNγ led to a CD8+ T cell-dominant tumor microenvironment (TME) with an enhanced anticancer T cell response after αPD-L1-PIT. As a result, even so-called cold tumors exhibited complete responses after αPD-L1-PIT. Thus, combination therapy of PEGylated IFNγ and PD-L1-targeted NIR-PIT has the potential to be an important future strategy for cancer immunotherapy.

Near-infrared photoimmunotherapy in the models of hepatocellular carcinomas using cetuximab-IR700.

Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in many cancers, and overexpression of EGFR is frequently observed in hepatocellular carcinomas (HCCs). Near-infrared photoimmunotherapy (NIR-PIT) is a new anticancer treatment that selectively damages the cell membrane of cancer cells after NIR light-induced photochemical reaction of IR700, which is bound to a targeting antibody on the cell membrane. NIR-PIT using cetuximab-IR700 has already been approved in Japan, is under review by the US Food and Drug Administration (FDA) for advanced head and neck cancers, and its safety has been established. However, EGFR has not been investigated as a target in NIR-PIT in HCCs. Here, we investigate the application of NIR-PIT using cetuximab-IR700 to HCCs using xenograft mouse models of EGFR-expressing HCC cell lines, Hep3B, HuH-7, and SNU-449. In vitro NIR-PIT using EGFR-targeted cetuximab-IR700 killed cells in a NIR light dose-dependent manner. In vivo NIR-PIT resulted in a delayed growth compared with untreated controls. In addition, in vivo NIR-PIT in both models showed histological signs of cancer cell damage, such as cytoplasmic vacuolation and nuclear dysmorphism. A significant decrease in Ki-67 positivity was also observed after NIR-PIT, indicating decreased cancer cell proliferation. This study suggests that NIR-PIT using cetuximab-IR700 has potential for the treatment of EGFR-expressing HCCs.

The role of multimodal salvage therapy in the management of recurrent adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma is an aggressive tumor which often recurs despite apparent complete resection. This study assessed the long-term outcomes for patients with recurrent adrenocortical carcinoma after multimodal salvage therapy with chemotherapy, chemoradiotherapy and surgery. METHODS: We retrospectively reviewed medical records of patients who had a pathological diagnosis of adrenocortical carcinoma between 1996 and 2017. Kaplan-Meier curves were used to assess progression-free and cancer-specific survivals among all patients and cancer-specific survival among patients with tumor recurrence. Log-rank test was used to compare patient survivals by modality of salvage therapy (chemotherapy, chemoradiotherapy and chemotherapy/chemoradiotherapy plus surgery). RESULTS: Of 20 patients who underwent initial surgery, recurrence occurred in 14 (70%) with a median interval of 7.5 (range 1.0-12.6) months. Salvage therapy provided was chemotherapy only (n = 7), chemoradiotherapy (n = 2) and chemotherapy/chemoradiotherapy plus surgery (n = 5). Of the five patients who received salvage surgery, three underwent repeated resections. The potential benefit of multimodal salvage therapy was suggested in five patients (4 with chemotherapy/chemoradiotherapy plus surgery and 1 with chemoradiotherapy) who achieved durable disease control (cancer-specific survival from initial recurrence, 22-258 months). With a median follow-up of 25 months from recurrence, the 5-year cancer-specific survival rate was 58%. cancer-specific survival after recurrence was prolonged in patients with ≤ stage 3 disease, positive response to chemotherapy/chemoradiotherapy and salvage surgery. CONCLUSIONS: Long-term disease control and survival could be achieved in highly selected patients with recurrent adrenocortical carcinoma using a multidisciplinary approach. Patients who had relatively limited recurrent sites and responded well to chemotherapy/chemoradiotherapy may be considered for salvage surgery on a case-by-case basis.

Significance of dorsal bladder neck involvement in predicting the progression of non-muscle-invasive bladder cancer.

OBJECTIVES: Accurately predicting of progression is important for patients with non-muscle-invasive bladder cancer (NMIBC). We previously reported that bladder neck involvement (BNI) was significantly associated with progression of NMIBC. In this study, we evaluated the prognostic significance of the detailed BNI location in NMIBC patients. METHODS: We retrospectively reviewed 651 patients diagnosed with primary NMIBC at a single center between 2000 and 2018. Using the detailed BNI location, patients were divided into the following three groups: dorsal BNI (BNId; 4 to 8 o'clock position), ventral BNI (BNIv; 8 to 4 o'clock but not 4 to 8 o'clock position), and non-BNI group. Both time to progression to muscle-invasive disease and distant metastasis was compared among the three groups. A prognostic model was developed and its discriminative ability was evaluated. RESULTS: Dorsal bladder neck involvement and BNIv were observed in 43 (6.6%) and 36 (5.5%) patients, respectively. During a median follow-up of 61 months, 35 (5.4%) patients progressed. The cumulative incidence at 5 years was 12%, 0%, and 5.0% in BNId, BNIv, and non-BNI groups, respectively. On multivariate analysis, BNId was a significant and independent risk factor for progression, tumor stage pT1, and histologic grade G3. One point was assigned to each factor, and patients were classified into four well-stratified prognostic groups based on the total score. CONCLUSION: Dorsal bladder neck involvement was an independent and significant risk factor for progression in primary NMIBC. Our simple and practical prognostic model including BNId is easy to use and may help selecting the optimal treatment and its timing.

Prognostic impact of the radiological infiltrative feature of primary renal tumor in metastatic renal cell carcinoma.

OBJECTIVES: Recent studies suggest that the radiological infiltrative feature (r-IF) of renal tumors is strongly correlated with poor oncologic outcomes in locally advanced renal cell carcinoma (RCC). This study investigated the prognostic impact of r-IF of primary renal tumors in metastatic RCC (mRCC) in comparison with International Metastatic RCC Database Consortium (IMDC) risk model. METHODS: We retrospectively analyzed 91 patients with previously untreated mRCC. Dynamic computed tomography of the primary renal tumor was reviewed to assess r-IF, defined as a focally/extensively ill-defined tumor interface with normal renal parenchyma. RESULTS: The median age was 67 years, and 69 patients (76%) were men. Prior nephrectomy was performed in 47 patients (52%). The median size of the primary renal tumor was 6.7 cm, and 50 patients (55%) presented with cT3-4 stage. Overall, 25 (28%)/52 (57%)/14 (15%) patients were classified into IMDC favorable/intermediate/poor-risk groups, respectively. An image review identified r-IFs in the primary renal tumor in 40 patients (44%). The incidences of r-IFs were 28%/46%/64% in IMDC favorable/intermediate/poor-risk groups, respectively. During a median follow-up of 2.6 years, 31 patients (34%) died of RCC. On multivariable analysis, r-IF and IMDC intermediate-poor risks were independently associated with poor cancer-specific survival (CSS). Two-year CSS were 64%/87% in patients with/without r-IF, respectively. C-index was improved from 0.73 to 0.81 by adding r-IF to the IMDC risk factors. CONCLUSIONS: R-IF of the primary renal tumor was an independent risk factor for poor CSS in patients with mRCC, which may improve the prognostic accuracy when combined with the IMDC risk model.

Cyanine Phototruncation Enables Spatiotemporal Cell Labeling.

Photoconvertible tracking strategies assess the dynamic migration of cell populations. Here we develop phototruncation-assisted cell tracking (PACT) and apply it to evaluate the migration of immune cells into tumor-draining lymphatics. This method is enabled by a recently discovered cyanine photoconversion reaction that leads to the two-carbon truncation and consequent blue-shift of these commonly used probes. By examining substituent effects on the heptamethine cyanine chromophore, we find that introduction of a single methoxy group increases the yield of the phototruncation reaction in neutral buffer by almost 8-fold. When converted to a membrane-bound cell-tracking variant, this probe can be applied in a series of in vitro and in vivo experiments. These include quantitative, time-dependent measurements of the migration of immune cells from tumors to tumor-draining lymph nodes. Unlike previously reported cellular photoconversion approaches, this method does not require genetic engineering and uses near-infrared (NIR) wavelengths. Overall, PACT provides a straightforward approach to label cell populations with spatiotemporal control.

Intercellular adhesion molecule-1-targeted near-infrared photoimmunotherapy of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and conventional chemotherapy and molecular-targeted therapies show limited efficacy. Near-infrared photoimmunotherapy (NIR-PIT) is a new anticancer treatment that selectively damages the cell membrane of cancer cells based on NIR light-induced photochemical reactions of the antibody (Ab)-photoabsorber (IRDye700Dx) conjugate and the cell membrane. TNBC is known to express several adhesion molecules on the cell surface providing a potential new target for therapy. Here, we investigated the therapeutic efficacy of intercellular adhesion molecule-1 (ICAM-1)-targeted NIR-PIT using xenograft mouse models subcutaneously inoculated with two human ICAM-1-expressing TNBC cell lines, MDAMB468-luc and MDAMB231 cells. In vitro ICAM-1-targeted NIR-PIT damaged both cell types in a NIR light dose-dependent manner. In vivo ICAM-1-targeted NIR-PIT in both models showed early histological signs of cancer cell damage, such as cytoplasmic vacuolation. Even among the cancer cells that appeared to be morphologically intact within 2 h post treatment, abnormal distribution of the actin cytoskeleton and a significant decrease in Ki-67 positivity were observed, indicating widespread cellular injury reflected in cytoplasmic degeneration. Such damage to cancer cells by NIR-PIT significantly inhibited subsequent tumor growth and improved survival. This study suggests that ICAM-1-targeted NIR-PIT could have potential clinical application in the treatment of TNBC.

Selection of antibody and light exposure regimens alters therapeutic effects of EGFR-targeted near-infrared photoimmunotherapy.

Near-infrared photoimmunotherapy (NIR-PIT) is a cell-specific cancer therapy that uses an antibody-photoabsorber (IRDye700DX, IR700) conjugate (APC) and NIR light. Intravenously injected APC binds the target cells, and subsequent NIR light exposure induces immunogenic cell death only in targeted cells. Panitumumab and cetuximab are antibodies that target human epidermal growth factor receptor (hEGFR) and are suitable for NIR-PIT. In athymic nude mouse models, panitumumab-based NIR-PIT showed superior therapeutic efficacy compared to cetuximab-based NIR-PIT because of the longer half-life of panitumumab-IR700 (pan-IR700) compared with cetuximab-IR700 (cet-IR700). Two light exposures on two consecutive days have also been shown to induce superior effects compared to a single light exposure in the athymic nude mouse model. However, the optimal regimen has not been assessed in immunocompetent mice. In this study, we compared panitumumab and cetuximab in APCs for NIR-PIT, and single and double light exposures using a newly established hEGFR-expressing cancer cell line derived from immunocompetent C57BL/6 mice (mEERL-hEGFR cell line). Fluorescence imaging showed that the decline of pan-IR700 was slower than cet-IR700 confirming a longer clearance time. Among all the combinations tested, mice receiving pan-IR700 and double light exposure showed the greatest tumor growth inhibition. This group was also shown to activate CD8+ T lymphocytes in lymph nodes and accumulate CD8+ T lymphocytes to a greater extent within the tumor compared with the control group. These results showed that APCs with longer half-life and double light exposure lead to superior outcomes in cancer cell-targeted NIR-PIT in an immunocompetent mouse model.

Opening up new VISTAs: V-domain immunoglobulin suppressor of T cell activation (VISTA) targeted near-infrared photoimmunotherapy (NIR-PIT) for enhancing host immunity against cancers.

V-domain immunoglobulin suppressor of T cell activation (VISTA) is an inhibitory immune checkpoint molecule that is broadly expressed on lymphoid and myeloid cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Near-infrared photoimmunotherapy (NIR-PIT) is a cancer treatment that utilizes an antibody-photoabsorber (IRDye 700DX NHS ester) conjugate to selectively kill target cells after the local application of NIR light. Depletion of VISTA-expressing cells in the tumor microenvironment (TME) using NIR-PIT could enhance anti-tumor immune responses by removing immune suppressive cells. The purpose of this study was to evaluate the anti-tumor efficacy of VISTA-targeted NIR-PIT using two murine tumor models, MC38-luc and LL2-luc. VISTA was expressed on T cells including Tregs and MDSCs in the TME of these tumors. In contrast, CD45 - cells, including cancer cells, did not express VISTA. VISTA-targeted NIR-PIT depleted VISTA-expressing cells ex vivo. In vivo VISTA-targeted NIR-PIT inhibited tumor progression and prolonged survival in both models. After VISTA-targeted NIR-PIT, augmented CD8 + T cell and dendritic cell activation were observed in regional lymph nodes. In conclusion, VISTA-targeted NIR-PIT can effectively treat tumors by decreasing VISTA-expressing immune suppressor cells in the TME. Local depletion of VISTA-expressing cells in the tumor bed using NIR-PIT is a promising new cancer immunotherapy for treating various types of tumors.

Comparison of the Effectiveness of IgG Antibody versus F(ab')2 Antibody Fragment in CTLA4-Targeted Near-Infrared Photoimmunotherapy.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment modality that utilizes antibody-photoabsorber conjugates (APCs) and selectively kills target cells after irradiation with NIR light. Originally, NIR-PIT was targeted against cancer cell surface antigens, but as it became clear that NIR-PIT induced a strong immune response, an effort was made to target selected immune cell populations in the tumor microenvironment to encourage an even stronger immune response. Thus, CD25-targeted NIR-PIT and cytotoxic T-lymphocyte associated protein 4 (CTLA4)-targeted NIR-PIT were developed to kill regulatory T cells (Tregs) in conjunction with cancer-cell-targeted NIR-PIT, in order to amplify the host immune response. It was found that CD25-targeted NIR-PIT, using an antibody with the Fc portion removed, led to better results than the unmodified anti-CD25 antibody-directed NIR-PIT presumably because of a negative effect on activated T cells. The aim of this study was to compare the efficacy of an antibody fragment [anti-CTLA4-F(ab')2] and a whole antibody (anti-CTLA4-IgG) for NIR-PIT. There was no significant difference in NIR-PIT-induced Treg killing between the anti-CTLA4-F(ab')2 and anti-CTLA4-IgG antibodies. Although both the antibody and the antibody fragment resulted in significant tumor growth inhibition, the antibody induced more robust CD8+ T cell activation in ipsilateral lymph nodes and was more effective compared to the antibody fragment. The slower clearance of the anti-CTLA4-IgG APC enhanced antitumor immunity by promoting T cell priming in lymph nodes. In conclusion, unlike the results with CD25 where modified antibodies produced superior results to unmodified antibodies, anti-CTLA4-IgG antibody-based NIR-PIT proved more effective in reducing tumor growth than anti-CTLA4-F(ab')2 antibody-based NIR-PIT.

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

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.

Metastatic Diffusion Volume Based on Apparent Diffusion Coefficient as a Prognostic Factor in Castration-Resistant Prostate Cancer.

BACKGROUND: Whole-body diffusion-weighted MRI (WB-DWI) is useful for assessing disease activity in castration-resistant prostate cancer (CRPC). MET-RADS-P is a subjective assessment-based reporting system proposed to standardize the interpretation of WB-DWI. However, a quantitative evaluation of WB-DWI has not been fully investigated. PURPOSE: To investigate the validity, and analyze the prognostic value, of quantitative evaluation of WB-DWI based on apparent diffusion coefficient (ADC) values for CRPC. STUDY TYPE: Retrospective. POPULATION: Sixty-six patients with CRPC. The median age was 75 years. During the median follow-up period of 25.2 months, 23 of 66 patients (34.8%) died of prostate cancer. FIELD STRENGTH/SEQUENCE: A 1.5 T WB-DWI was used with two b-values (0 s/mm2 -1000 s/mm2 ). A single-shot echo-planar imaging sequence was used. ASSESSMENT: WB-DWI were evaluated by three readers according to MET-RADS-P scoring system. Using imaging software, Attractive BDScore, tumor diffusion volume (mDV) and ADC value of metastatic lesion (mADC) was calculated by two readers. The mDV was calculated with ADC values (×10-3  mm2 /sec) of 0.4-0.9 (mDV0.4-0.9 ), 0.9-1.4 (mDV0.9-1.4 ), and 1.4-1.8 (mDV1.4-1.8 ), respectively. STATISTICAL TESTS: Spearman's rank correlation coefficient was used to assess the correlation. The relationships between the variables with cancer-specific survival (CSS) were evaluated. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS: mDVs showed a strong positive correlation with MET-RADS-P scores (r = 0.90/0.87, P < 0.05 for both). mDV showed a statistically significant association with CSS (hazard ratio [HR]: 1.01, P < 0.05). When the mDVs calculated based on the ADC values were included, mDV0.4-0.9 (HR: 1.02, P < 0.05) and the number of therapeutic lines (HR: 1.35, P < 0.05) were significant independent indicators of CSS shortening. CONCLUSION: Assessment of metastatic tumor volume based on ADC values can be used in the prognostic evaluation of patients with CRPC. WB-DWI might be a potential prognostic imaging biomarker for CRPC. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Trends and safety of robot-assisted partial nephrectomy during the initial 2-year period after government approval in Japan: A nationwide database study from 2016 to 2018.

OBJECTIVES: To evaluate the trends and safety of robot-assisted partial nephrectomy during the initial 2-year period after government approval for this type of procedure in April 2016. METHODS: This nationwide retrospective study included 3722 received robot-assisted partial nephrectomy cases carried out from April 2016 to March 2018 in 124 participating institutions. The institutions were divided into lower- and higher-volume institutions according to the median of 19 robot-assisted partial nephrectomy cases during the study period. Surgical outcomes between 616 cases from lower-volume institutions and 3106 cases from higher-volume institutions were compared using propensity score matching. RESULTS: During the study period, both the number of robot-assisted partial nephrectomy surgeries and the number of institutions in which the surgery was carried out steadily increased. Overall, the median anesthesia time was 217 min, the median postoperative length of stay was 9 days, and the proportion of blood transfusions, complications and readmissions were 0.8%, 5.1% and 1.0%, respectively. There were no significant differences in anesthesia time, incidence of blood transfusions, and complication rates between the lower-volume and higher-volume institutions. However, a slightly, but significantly, longer postoperative length of stay and a lower incidence of readmission were observed in lower-volume institutions both before and after propensity score matching. CONCLUSIONS: Robot-assisted partial nephrectomy has become widespread during the initial 2-year period after government approval with an acceptable safety profile, regardless of the institutional caseloads. This technique has become a standard of care for stage 1 renal cancer patients in Japan.

Nonuse of antimicrobial prophylaxis in clean surgeries for adrenal and renal tumors: Results of the risk-based strategy in 1362 consecutive patients.

OBJECTIVES: To evaluate the incidence of perioperative infections without antimicrobial prophylaxis in patients undergoing clean surgeries for adrenal and renal tumors. METHODS: We prospectively enrolled 1362 consecutive patients who underwent minimally invasive adrenalectomy (n = 303), radical nephrectomy (n = 499), and partial nephrectomy (n = 560) using the gasless laparoendoscopic single-port surgery technique between 2005 and 2019. In 1059 patients, antimicrobial prophylaxis was not administered. The remaining 303 patients were considered at high risk for infection and received single-dose antimicrobial prophylaxis. The endpoint was the incidence of perioperative infections within 1 month from the surgery date. Perioperative infections were classified into surgical site infections, urinary tract infections, and remote infections. RESULTS: Seventy-four patients whose collecting systems were opened during partial nephrectomy were excluded, and the remaining 1013 patients with nonuse of antimicrobial prophylaxis and 275 patients with single-dose antimicrobial prophylaxis were retrospectively analyzed. The incidence of superficial surgical site infections, deep/organ-space surgical site infections, urinary tract infections, and remote infections was 1.6%, 0.7%, 2.8%, and 1.3%, respectively, in patients with nonuse of antimicrobial prophylaxis and 0.4%, 1.8%, 1.5%, and 1.5%, respectively, in patients with single-dose antimicrobial prophylaxis. All patients who developed perioperative infections were successfully treated. No clinical or surgical variables were significantly associated with the incidence of surgical site infections. One limitation of the present study was its nonrandomized and noncontrolled design. CONCLUSIONS: In minimally invasive clean surgeries for adrenal and renal tumors, antimicrobial prophylaxis is not necessary when individual risk of infection is considered low.

Infiltrative tumor interface with normal renal parenchyma in locally advanced renal cell carcinoma: Clinical relevance and pathological implications.

OBJECTIVES: Locally advanced renal cell carcinoma is considered clinically aggressive, despite heterogeneity in survival outcomes. We investigated the clinical relevance and pathological implications of infiltrative tumor interface with normal renal parenchyma on preoperative imaging in locally advanced renal cell carcinoma. METHODS: A total of 77 patients with locally advanced renal cell carcinoma (≥pT3a Nany M0) who underwent radical or partial nephrectomy (2008-2018) were analyzed. Preoperative dynamic computed tomography images were reviewed to assess radiological infiltrative features. A radiological infiltrative feature was defined as an ill-defined tumor interface with normal renal parenchyma. The tumor interfaces were analyzed histologically and compared with radiological findings. RESULTS: The median tumor size was 6.4 cm. Lymphadenopathy was observed in four patients (5.2%). Clear cell renal cell carcinoma was diagnosed in 66 patients (86%) and Fuhrman grade was 3-4 in 38 patients (49%). A total of 30 patients (39%) showed radiological infiltrative features, which were significantly associated with larger tumor size and higher clinical T stage. The specificity and sensitivity of radiological infiltrative features in predicting pathological renal parenchymal infiltration were 90 and 64%, respectively. During a median follow-up period of 3.8 years, 27 patients (35%) developed cancer recurrences, and six patients (7.8%) died of renal cell carcinoma. Multivariable analysis showed that the presence of radiological infiltrative features was an independent risk factor for cancer recurrence. Cancer recurrence and cancer-specific mortality were significantly stratified by the presence or absence of radiological infiltrative features (P < 0.001 and P = 0.02, respectively). CONCLUSIONS: Locally advanced renal cell carcinoma can show radiological infiltrative features preoperatively, which are significantly associated with unfavorable prognosis. Radiological infiltrative features on preoperative imaging correspond with a high specificity to pathological renal parenchymal infiltration.

Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti-PD-1 Treatment Efficacy in Urothelial Carcinoma.

The therapeutic benefit of immune checkpoint inhibitor monotherapy is limited to a subset of patients in urothelial carcinoma (UC). Previous studies showed the immunogenicity of cisplatin and irradiation. Here, we investigated whether chemoradiotherapy (CRT), a combination of cisplatin and irradiation, could improve the efficacy of postirradiation anti-programmed cell death 1 (PD-1) treatment in UC. In our advanced UC patient cohort, patients with CRT showed a significantly better objective response rate (75%/22%) and overall survival (88%/30% at 12 months) following later pembrolizumab therapy compared to those without. Then, we created syngeneic UC mouse models by inoculating MB49 cells s.c. in C57BL/6J mice to examine the potential of CRT to enhance antitumor immunity in conjunction with postirradiation anti-PD-1 treatment. Nonirradiated tumors of the mice treated with CRT/postirradiation anti-PD-1 treatment had a significantly slower growth rate and a significantly higher expression of cytotoxic T cells compared to those of the mice treated with anti-PD-1 treatment alone. The mice treated with CRT/postirradiation anti-PD-1 treatment showed the best survival. Mechanistically, CRT provoked strong direct cytotoxicity and increased expressions of immunogenic cell death markers in MB49 cells. Therefore, the combination of cisplatin and irradiation induces immunogenic cell death and potentiates postirradiation anti-PD-1 treatment efficacy in UC.

Impact of sarcopenia on the efficacy of pembrolizumab in patients with advanced urothelial carcinoma: a preliminary report.

Sarcopenia, the degenerative and systemic loss of skeletal muscle mass, is a multifactorial syndrome reflecting frailty, poor general health status, and the possible presence of cancer cachexia. Here, we aimed to investigate the effect of sarcopenia on the efficacy of pembrolizumab in patients with advanced urothelial carcinoma (aUC). This retrospective study included 28 patients with aUC treated with pembrolizumab as a second or later-line therapy. Sarcopenia was determined based on computed tomography images. Associations of sarcopenia with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. In total, 19 (68%) patients had sarcopenia. ORR was 21% in the patients with sarcopenia, while those without sarcopenia showed significantly higher ORR (67%, P = 0.019). PFS was significantly shorter in patients with sarcopenia than in those without (median, 3 vs. 15 months, P = 0.038). Although the statistical significance was not reached, OS was shorter in patients with sarcopenia than in those without (median, 7 months vs. not reached; P = 0.086). Our preliminary results demonstrated that more than half of patients with aUC who received pembrolizumab had sarcopenia, which was significantly associated with poor therapeutic efficacy. This indicates the clinical relevance of sarcopenia in pembrolizumab therapy for patients with aUC.

Contact with renal sinus is associated with poor prognosis in surgically treated pT1 clear cell renal cell carcinoma.

OBJECTIVE: To investigate the prognostic significance of contact with the renal sinus in patients with clear cell renal cell carcinoma. METHODS: A total of 787 pT1N0M0 clear cell renal cell carcinoma patients who had undergone radical or partial nephrectomy were reviewed retrospectively. A tumor in contact with the renal sinus was defined as a tumor radiologically attached to the renal sinus. Metastatic-free survival rates were analyzed in the total and propensity score-matched cohorts. A risk score model for metastasis after surgery was developed. RESULTS: Of the 787 patients, 411 (52.2%) had tumors in contact with renal sinus. The contact with renal sinus group showed poorer metastatic-free survival in both total and matched cohorts. In multivariate analysis, contact with renal sinus was an independent prognostic factor of metastasis, as well as Fuhrman grade, microvascular invasion and age. The scoring model likewise consisted of Fuhrman grade, microvascular invasion, age and contact with renal sinus. Metastasis-free survival curves were clearly stratified according to risk, with 5-year metastasis-free survival rates of 95.7% and 65.2% in the low- and high-risk groups, respectively (P < 0.001). CONCLUSIONS: Contact with the renal sinus is a significant risk factor for metastasis in T1 clear cell renal cell carcinoma after surgery. More intensive follow up should be recommended for patients with renal cell carcinoma that is in contact with the renal sinus.

Feasibility and outcomes of selective tetramodal bladder-preservation therapy in elderly patients with muscle-invasive bladder cancer.

OBJECTIVE: To assess the feasibility and functional/oncological outcomes of selective tetramodal bladder-preservation therapy in elderly patients with muscle-invasive bladder cancer. METHODS: This study analyzed 154 patients with non-metastatic muscle-invasive bladder cancer who were enrolled into the protocol. After maximal transurethral resection and induction chemoradiotherapy, patients with clinical complete response were offered consolidative partial cystectomy to achieve bladder preservation; otherwise, radical cystectomy was recommended. Postoperative complications, preserved bladder function, and oncological outcomes were compared between elderly (aged ≥75 years) and younger patients (aged <75 years). Frailty and sarcopenia were further assessed as potential factors that could affect the feasibility and outcomes of the protocol. RESULTS: A total of 44 patients (29%) were elderly, and 31 (20%) were frail (modified frailty index 2-3). Sarcopenia was observed in 68 (54%) of 126 eligible patients. Clinical complete response to induction chemoradiotherapy was achieved in 125 (81%) patients, and the bladder-preservation protocol was completed in 107 (69%) patients with consolidative partial cystectomy. Over a median follow-up period of 48 months, 5-year cancer-specific and muscle-invasive bladder cancer recurrence-free survival rates after protocol completion were 98% and 95%, respectively. There were no significant differences in complication rates related to partial cystectomy, preserved bladder function, and oncological outcomes between the elderly and younger groups. Neither frailty nor sarcopenia negatively affected these outcomes. CONCLUSIONS: Tetramodal bladder-sparing therapy incorporating consolidative partial cystectomy is feasible and yielded favorable functional/oncological outcomes in patients with muscle-invasive bladder cancer, regardless of advanced age, frailty or sarcopenia. This protocol could be a viable treatment option for such high-risk patient populations.

Impact of fluorodeoxyglucose uptake on positron emission tomography/computed tomography on chemosensitivity and survival in patients with metastatic urothelial carcinoma.

OBJECTIVES: To evaluate the impact of fluorodeoxyglucose uptake on positron emission tomography/computed tomography on chemosensitivity and survival in patients with metastatic urothelial carcinoma. METHODS: The present study assessed 51 metastatic urothelial carcinoma patients undergoing fluorodeoxyglucose positron emission tomography/computed tomography before first-line systemic chemotherapy. Fluorodeoxyglucose uptake in metastases was evaluated using the maximum standardized uptake value, which was measured for all eligible lesions, and the highest value among the maximum standardized uptake value measurements in each case was defined as the highest maximum standardized uptake value. The associations between the highest maximum standardized uptake value and objective response rate to chemotherapy, progression-free survival or cancer-specific survival were analyzed. For cancer-specific survival, the C-index was compared between multivariate models that incorporated predictors in the Bajorin model including the Karnofsky performance status and the presence of visceral metastasis, and the Apolo model additionally including hemoglobin and albumin levels, with/without the highest maximum standardized uptake value. RESULTS: The median age was 69 years. The Karnofsky performance status was ≥80% for all patients. Visceral metastasis was observed in 12 patients (24%). The objective response rate, median progression-free survival and median cancer-specific survival were 61%, 9 and 26 months in the entire cohort, respectively. The higher highest maximum standardized uptake value was significantly associated with a lower objective response rate, shorter progression-free survival and shorter cancer-specific survival (P = 0.01, <0.001 and 0.004, respectively). On multivariate analyses, the highest maximum standardized uptake value was an independent predictor for all end-points. In the multivariate models for cancer-specific survival, the C-index improved from 0.559 to 0.601 and from 0.604 to 0.652 by adding the highest maximum standardized uptake value to the parameter set of the Bajorin model and Apolo model, respectively. CONCLUSIONS: Higher fluorodeoxyglucose uptake in metastases was significantly and independently associated with poor chemosensitivity and worse survival outcomes. Fluorodeoxyglucose positron emission tomography/computed tomography might aid in patient counseling and treatment decisions for metastatic urothelial carcinoma patients.