Renal cell carcinoma with multiple bone metastases effectively treated by a combination of tyrosine kinase inhibitor, robot-assisted partial nephrectomy, and metastasectomy.

Key Clinical Message: Maintaining a disease-free status for a long time in cases of renal cell carcinoma with multiple bone metastases and repeated recurrences is challenging. What matters most in the multidisciplinary approach is the treatment strategy. Although this is a case where multidisciplinary treatment resulted in long-term CR during the TKI era, the treatment strategy is still relevant now that treatment options have increased. Abstract: Recent advances in medications, such as immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), have improved metastatic renal cell carcinoma (mRCC) outcomes. We report a case of mRCC with bone metastasis that was successfully treated using a multidisciplinary approach. Here, we present a case of a 56-year-old man with left renal cancer and large and painful bone metastases at the 11th thoracic vertebrae (Th11). Therefore, a metastasectomy of Th11 was performed. Systemic treatment with TKI, robot-assisted partial nephrectomy, and metastasectomy were then administered. No recurrence was observed in >2 years. Long-term disease-free survival with the TKI-era multidisciplinary approach in a patient with mRCC remains significant when considering treatment sequences, especially now that drug treatment options-including ICIs-have increased. Treatment strategy and indication and timing of resection of the primary lesion and metastasectomy should be carefully considered in each case.

Discovery of lipid profiles in plasma-derived extracellular vesicles as biomarkers for breast cancer diagnosis.

Lipids are a major component of extracellular vesicles; however, their significance in tumorigenesis and progression has not been well elucidated. As we previously found that lipid profiles drastically changed in breast tumors upon progression, we hypothesized that lipid profiles of plasma-derived extracellular vesicles could be utilized as breast cancer biomarkers. Here, we adopted modified sucrose cushion ultracentrifugation to isolate plasma-derived extracellular vesicles from breast cancer (n = 105), benign (n = 11), and healthy individuals (n = 43) in two independent cohorts (n = 126 and n = 33) and conducted targeted lipidomic analysis. We established a breast cancer diagnostic model comprising three lipids that showed favorable performance with the area under the receiver operating characteristic curve of 0.759, 0.743, and 0.804 in the training, internal validation, and external test sets, respectively. Moreover, we identified several lipids that could effectively discriminate breast cancer progression and subtypes: phosphatidylethanolamines and phosphatidylserines were relatively higher in Stage III, whereas phosphatidylcholines and sphingomyelins were higher in Stage IV; phosphatidylcholines and ceramides were correspondingly concentrated in HER2-positive patients, while lysophosphatidylcholines and polyunsaturated triglycerides were concentrated in the triple-negative breast cancer subtype. Lipid profiling of plasma-derived extracellular vesicles is a non-invasive and promising approach for diagnosing, staging, and subtyping breast cancer.

The Roles of Extracellular Vesicles in the Progression of Renal Cell Carcinoma and Their Potential for Future Clinical Application.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is thought to originate from renal tubular epithelial cells. Extracellular vesicles (EVs) are nanosized lipid bilayer vesicles that are secreted into extracellular spaces by nearly all cell types, including cancer cells and non-cancerous cells. EVs are involved in multiple steps of RCC progression, such as local invasion, host immune modulation, drug resistance, and metastasis. Therefore, EVs secreted from RCC are attracting rapidly increasing attention from researchers. In this review, we highlight the mechanism by which RCC-derived EVs lead to disease progression as well as the potential and challenges related to the clinical implications of EV-based diagnostics and therapeutics.

Extracellular vesicles secreted from bone metastatic renal cell carcinoma promote angiogenesis and endothelial gap formation in bone marrow in a time-dependent manner in a preclinical mouse model.

Introduction: Bone is a major metastatic site of renal cell carcinoma (RCC). Recently, it is well recognized that bone metastatic tumor cells remodel bone marrow vasculature. However, the precise mechanism underlying cell-cell communication between bone metastatic RCC and the cells in bone marrow remains unknown. Extracellular vesicles (EVs) reportedly play crucial roles in intercellular communication between metastatic tumor cells and bone marrow. Therefore, we conducted the current study to clarify the histological alteration in vascular endothelium in bone marrow induced by EVs secreted from bone metastatic RCC cells as well as association between angiogenesis in bone marrow and bone metastasis formation. Materials and methods: We established a bone metastatic RCC cell line (786-O BM) by in vivo selection and observed phenotypic changes in tissues when EVs were intravenously injected into immunodeficient mice. Proteomic analysis was performed to identify the protein cargo of EVs that could contribute to histological changes in bone. Tissue exudative EVs (Te-EVs) from cancer tissues of patients with bone metastatic RCC (BM-EV) and those with locally advanced disease (LA-EV) were compared for in vitro function and protein cargo. Results: Treatment of mice with EVs from 786-O BM promoted angiogenesis in the bone marrow in a time-dependent manner and increased the gaps of capillary endothelium. 786-O BM EVs also promoted tube formation in vitro. Proteomic analysis of EVs identified aminopeptidase N (APN) as a candidate protein that enhances angiogenesis. APN knockdown in 786-O BM resulted in reduced angiogenesis in vitro and in vivo. When parental 786-O cells were intracardially injected 12 weeks after treatment with786-O BM EVs, more bone metastasis developed compared to those treated with EVs from parental 786-O cells. In patient samples, BM-EVs contained higher APN compared to LA-EV. In addition, BM-EVs promoted tube formation in vitro compared to LA-EVs. Conclusion: EVs from bone metastatic RCC promote angiogenesis and gap formation in capillary endothelium in bone marrow in a time-dependent manner.

Efficacy and Tolerability of Second-line Pembrolizumab With Radiation Therapy in Advanced Urothelial Carcinoma.

BACKGROUND/AIM: Considering the limited data available on immune checkpoint inhibitors and radiation combination therapy in advanced urothelial carcinoma, this study evaluated the survival benefit and associated toxicity of adding radiation therapy to second-line pembrolizumab. PATIENTS AND METHODS: We retrospectively examined 24 consecutive patients with advanced bladder or upper urinary tract urothelial carcinoma and for whom second-line pembrolizumab was initiated between August 2018 and October 2021 in combination with radiation therapy (with curative intent in 12 patients, and palliative intent in 12 patients). Their survival outcomes and toxicities were compared with those of propensity-score-matched cohorts from a Japanese multicenter study with similar characteristics who received pembrolizumab monotherapy. RESULTS: The median follow-up periods after pembrolizumab initiation were 15 months for the curative cohort and 4 months for the palliative cohort. The median overall survival was 27.7 months for the curative cohort and 4.8 months for the palliative cohort. Compared with the matched pembrolizumab monotherapy cohort, overall survival was better among the curative cohort although not statistically significant (p=0.13), but similar between the palliative and matched pembrolizumab monotherapy cohorts (p=0.44). There was no difference in the incidence of grade ≥2 adverse events between the combination and monotherapy cohorts, irrespective of the intent of radiation therapy. CONCLUSION: The combination of radiation therapy and pembrolizumab can be performed with a clinically acceptable safety profile, and the addition of radiation therapy to immune checkpoint inhibitors may improve survival outcome after pembrolizumab treatment in cases where the intent of radiation therapy is curative.

HDR-brachytherapy for accelerated partial breast irradiation: Long-term experience from a Japanese institution.

Purpose: We investigated the long-term oncological outcome of high-dose-rate (HDR) multicatheter interstitial brachytherapy (MIB) for adjuvant accelerated partial breast irradiation (APBI) after breast conserving surgery in Japanese patients. Material and methods: Between June 2002 and October 2011, 86 breast cancer patients were treated at National Hospital Organization Osaka National Hospital (trial number of the local institutional review board, 0329). Median age was 48 years (range, 26-73 years). Eighty patients had invasive and 6 patients non-invasive ductal carcinoma. Tumor stage distribution was pT0 in 2, pTis in 6, pT1 in 55, pT2 in 22, and pT3 in one patient, respectively. Twenty-seven patients had close/positive resection margins. Total physical HDR dose was 36-42 Gy in 6-7 fractions. Results: At a median follow-up of 119 months (range, 13-189 months), the 10-year local control (LC) and overall survival rate was 93% and 88%, respectively. Concerning the 2009 Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology risk stratification scheme, the 10-year LC rate was 100%, 100%, and 91% for patients considered as low-risk, intermediate-risk, and high-risk, respectively. According to the 2018 American Brachytherapy Society risk stratification scheme, the 10-year LC rate was 100% and 90% for patients 'acceptable' and 'unacceptable' for APBI, respectively. Wound complications were observed in 7 patients (8%). Risk factors for wound complications were the omission of prophylactic antibiotics during MIB, open cavity implantation, and V100 ≥ 190 cc. No grade ≥ 3 late complications (CTCVE version 4.0) were observed. Conclusions: Adjuvant APBI using MIB is associated with favorable long-term oncological outcomes in Japanese patients for low-risk, intermediate-risk, and acceptable groups of patients.

Up-regulation of secretory leukocyte protease inhibitor in human samples might have a potential role of predicting prostate cancer recurrence and progression after surgery and hormonal therapy.

Using new castration-resistant prostate cancer (CRPC) cell lines developed from LNCaP cells as a model for CRPC, we searched for novel biomarkers by analyzing the proteins secreted in culture supernatants. The results showed that the levels of secretory leukocyte protease inhibitor (SLPI) in these cell lines were 4.7-6.7 times higher than those secreted in parental LNCaP. Patients with localized prostate cancer (PC) and who expressed SLPI had a significantly lower prostate-specific antigen (PSA) progression-free survival rate than those who did not. Multivariate analysis revealed that SLPI expression was an independent risk factor for PSA recurrence. By contrast, when immunostaining of SLPI was performed on consecutive prostate tissue samples obtained from 11 patients, both in hormone naive (HN) and castration resistant (CR) conditions, only one patient expressed SLPI in the HNPC state; however, four of the 11 patients expressed SLPI in the CRPC state. In addition, two of these four patients were resistant to enzalutamide, and there was a discrepancy between their serum PSA levels and radiographic progression of the disease. These results suggest that SLPI can be a predictor of prognosis in patients with localized PC and disease progression in CRPC patients.

Long-term treatment with ALK inhibitors for postoperative recurrence of ALK-rearranged lung cancer.

We encountered a 40-year-old female patient who developed, in chronological order, carcinomatous pleuritis and lymphangitis, multiple lymph node metastases, brain metastases, and intramedullary spinal cord metastases after resection of lung adenocarcinoma followed by adjuvant chemotherapy. Echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) fusion gene, variant 2 was identified in her cancer cells. By changing the ALK inhibitors from the 1st to 3rd generation each time when metastases were identified and incorporating local treatments in a timely fashion, such as metastasectomy or radiation therapy, she has survived for more than 11 years since the start of treatment, while maintaining a good Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0. To our knowledge, this is the first reported case in which ALK fusion variant 2 was identified and prolonged disease control was achieved with the continuous prescription of ALK tyrosine kinase inhibitors (TKIs) and timely consolidative treatments.

Case Report: A Case of Renal Cell Carcinoma Unclassified With Medullary Phenotype Exhibiting a Favorable Response to Combined Immune Checkpoint Blockade.

Renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) is an extremely rare variant of kidney cancer with poor prognosis. Recently, immune checkpoint inhibitors (ICIs) have been the mainstay of treatment for advanced clear cell renal cell carcinoma (RCC). However, the efficacy of ICI in the treatment of RCCU-MP remains unclear. Here, we report about a 63-year-old Japanese man who was referred to our hospital with a diagnosis of RCC of the left kidney with multiple-lymph node involvement (cT3aN1M1). The patient underwent nephrectomy with lymph node biopsy, which was histopathologically diagnosed as RCCU-MP. Thereafter, he received combined immune checkpoint blockade with nivolumab and ipilimumab. After induction therapy, follow-up computed tomography revealed shrinkage of the metastatic lymph nodes. Moreover, the patient was relieved of his subjective symptoms and his performance status improved. However, after 15 months, maintenance ICI therapy was discontinued because of disease progression, and the patient died 28 months after diagnosis. Longitudinal analysis of peripheral blood mononuclear cells revealed increased stem cell memory and central memory CD8+ T-cell subsets during response to therapy and enhanced expression of exhaustion markers on CD8+ T cells upon treatment resistance. Combined immune checkpoint blockade could be effective in the treatment of metastatic RCCU-MP.

Mediastinal and Hilar Lymph Node Metastases from Renal Cell Carcinoma with Concomitant Lung Carcinoma: A Rare Case with Unique Diagnostic Challenges.

A 75-year-old man presented to our hospital 1 year after partial renal resection for clear cell carcinoma. A right lower lobe lung nodule noted at the time of surgery had increased to 3.0 cm in diameter and was confirmed as squamous cell lung carcinoma by bronchoscopic cytology. Computed tomography had also revealed paratracheal lymph node swelling. He underwent right lower lobectomy with lymph node dissection by video-assisted thoracic surgery. Pathological examination confirmed squamous cell carcinoma of the lung but diagnosed the right hilar and mediastinal lymph node metastases as clear cell carcinoma.

[A Case of Sigmoid Colon Cancer with Bladder Fistula Treated by Laparoscopic Radical Resection].

The patient was a woman in her 70 s. Computed tomography(CT)showed a sigmoid colon tumor invading the uterus and ovaries, and a fistula to the bladder. The patient was scheduled to receive neoadjuvant chemotherapy(NAC), but while waiting for treatment, generalized peritonitis due to perforation of the tumor was observed, and a laparoscopic transverse colostomy was performed. After NAC with CAPOX and FOLFIRI plus panitumumab, the tumor was found to have shrunk, and a laparoscopic posterior pelvic exenteration was performed. The bladder including the fistula was partially resected, and the tumor, uterus, and right ovary were resected in combination as R0, besides the ureter and remaining bladder could be preserved. The postoperative course was uneventful, and the patient is alive without recurrence to date. In this article, we report a case of a patient with sigmoid colon cancer with a bladder fistula who underwent laparoscopic surgery after NAC, and bladder function could be preserved, with some discussion of the literature.

Use of uniportal video-assisted thoracic surgery combined with a posterior approach to resect a dumbbell-shaped mediastinal granular cell tumor: A case report.

INTRODUCTION: A dumbbell-shaped mediastinal granular cell tumor has never been reported, and there have been no reports of dumbbell-shaped tumors resected with a combination of uniportal video-assisted thoracic surgery and the posterior approach. PRESENTATION OF CASE: An 18-year-old woman was diagnosed with a mediastinal dumbbell-shaped granular cell tumor by computed tomography. Complete resection was achieved via a posterior approach combined with the uniportal video-assisted thoracic surgery. First, a T3 left hemilaminectomy was performed in the prone position and the tumor located inside the intervertebral foramen was removed as far as possible. Next, the patient was repositioned to the right lateral decubitus position, a 2.5-cm skin incision was made on the 4th intercostal posterior axillary line, and resection of the residual tumor was performed. Pathological diagnosis of the resected tumor revealed a benign granular cell tumor. The patient recovered post-surgery and no tumor was reported in the 4-month follow-up magnetic resonance imaging. DISCUSSION: This is the first reported case of a mediastinal dumbbell-shaped granular cell tumor and its successful resection using a combined posterior and uniportal video-assisted thoracic surgery approach. CONCLUSION: This is a potentially safe and effective procedure for mediastinal granular cell tumors, with outstanding cosmetic advantages.

Detection of von Hippel-Lindau gene mutation in circulating cell-free DNA for clear cell renal cell carcinoma.

The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel-Lindau gene (VHL) using a combination of digital PCR and multiplex PCR-based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell-free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%-4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%-2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.

[Postoperative Gastric Metastasis from Needle Tract Seeding after Using of EUS-FNA for Pancreatic Body Cancer-A Case Report].

A 67-year-old woman with a pancreatic cancer diagnosed by endoscopic ultrasound with fine needle aspiration(EUS- FNA)was underwent distal pancreatectomy. Two years and 10 months after the operation, a computed tomography scan revealed a tumor in the posterior wall of the lower body of the stomach. Upper gastrointestinal endoscopy showed a 15 mm-sized submucosal tumor on the posterior wall of the angular region, and its biopsy showed tubular adenocarcinoma that it was resembling the resected pancreatic cancer. Needle tract seeding(NTS)of the pancreatic cancer to the gastric wall was suspected. After 5 courses of chemotherapy with gemcitabine and nab-paclitaxel, the tumor shrank and there were no other signs of metastasis, we performed distal gastrectomy. The pathological findings of the resected specimen showed a tubular adenocarcinoma, consistent with the primary pancreatic tumor. We finally diagnosed as the NTS of the pancreatic cancer to the gastric wall. In the case of EUS-FNA for the body or tail tumor of pancreas, it should be paid attention to the recurrence due to NTS because the surgical resection does not include the needle tract site.

Functional and genomic characterization of patient-derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma.

Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus-resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.

Simultaneous triple cancer of the esophagus, pancreas and rectum treated with multimodal strategies: a case report.

BACKGROUND: Due to the development of diagnostic imaging technology, we have increased chance of detecting multiple primary cancers. However, simultaneous triple cancer is still a very rare finding whose frequency is not yet known. Treatment of simultaneous triple cancer is a clinical challenge because it requires multimodal strategies including surgery, chemotherapy and radiotherapy. CASE PRESENTATION: Here, we present the case of a 74-year-old male with triple cancer involving esophageal and pancreatic cancer, and rectal carcinoma. Each cancer was surgically resectable, but simultaneous resection of all cancers seemed to cause too much surgical stress for the patient. First, we performed a laparoscopic Hartmann's operation for rectal cancer to minimize the risk of postoperative complications. Then treatment for pancreatic cancer was initiated by administering neoadjuvant chemotherapy with gemcitabine plus nab-paclitaxel. The pancreatic tumor shrank in size, so pancreatoduodenectomy was performed. We chose S-1 as adjuvant chemotherapy. The esophageal cancer showed regression during the treatment of the other two cancers, likely because the chemotherapeutic agents administered for pancreatic cancer had some effect on the esophageal cancer. Definitive chemoradiotherapy was selected instead of esophagectomy because the patient had already undergone two major surgeries. The patient is still alive nine months after the whole course of treatment with no sign of recurrence. CONCLUSIONS: The treatment of triple cancer requires an elaborate strategy to determine which cancer has to be dealt with first and which can be treated later. An aggressive multimodal treatment strategy may be an important option for a patient with triple cancer.

[A Case of Giant Gastrointestinal Stromal Tumor of the Jejunum in the Kingdom of Cambodia].

A 60-year-old Khmer woman visited a hospital established by a Japanese non-profit organization in the Kingdom of Cambodia with complaints of swelling in the left abdomen and appetite loss for 2 months. Abdominal computed tomography scan showed a mass measuring 14.6×13.4×19.3 cm with internal necrosis in the left abdomen. On laparotomy, a large tumor involving the jejunum had adhered to the transverse and descending colons. The tumor, measuring 25×20×10 cm and weighing 2,994 g, was excised along with 65 cm of the jejunum. Histopathological examination revealed a gastrointestinal stromal tumor(GIST). Postoperative course was uneventful. Thanks to the cooperation with the Japanese and the Cambodian people, the surgery was successful in spite of a shortage of medical personnel and medical resources in Cambodia.

[Advanced Colon Cancer Resected after a Neoadjuvant Chemotherapy of CAPOXIRI-A Case Report].

We report a case ofadvanced colon cancer, stage cT4bN0M0 in the descending colon with formation ofabscesses in the retroperitoneal space ofa 66-year-old woman. After constructing a transverse colostomy and percutaneous abscess drainage, chemotherapy was initiated with CAPOX. After 4 courses of CAPOX, the tumor had significantly regressed; therefore, the regimen was switched to a triplet combination called CAPOXIRI. After 3 courses of CAPOXIRI, the tumor had become smaller and had separated from the iliopsoas muscle, which led us to perform surgical resection. Left hemicolectomy was performed with R0 resection, and the tumor was pathologically diagnosed as ypT3N0M0. The patient is alive 12 months after the surgery, with no signs of recurrence.

[A Case of Late-Onset Recurrent Rectal Cancer Associated with Anal Fistulas].

A 71-year-old man underwent laparoscopic lower anterior resection(D3 dissection)for rectal cancer and bilateral lung metastases. Histopathological findings indicated Ra, type 2, tub2, ly0, v2, pN0, pM1(PUL1), pStage Ⅳ. The lung metastases had disappeared after postoperative chemotherapy and the patient entered cCR. Two years after the surgery, the patient's anal fistulas appeared sclerotic. Biopsy revealed recurrent rectal cancer. We performed an abdominoperineal resection and rectus abdominis muscle flap. Currently, the patient is alive at 9 months after surgery with no re-recurrence.