Clinical impact of proteinuria on renal function and treatment outcomes in patients with radioiodine-refractory thyroid cancer treated with lenvatinib.

Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age [>65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74-39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31-46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22-13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0-2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.

Comparison of Paclitaxel plus Carboplatin versus Observation in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma of the Head and Neck.

INTRODUCTION: Although systemic therapy, including multi-kinase inhibitors and cytotoxic chemotherapy, is an option for recurrent or metastatic adenoid cystic carcinoma of the head and neck (HNACC), it is not proven whether these therapies can prolong overall survival (OS). The present study investigated the impact of cytotoxic chemotherapy on survival outcomes compared with observation without chemotherapy. METHODS: We retrospectively reviewed the medical records of the patients diagnosed with recurrent or metastatic HNACC. We compared the survival outcomes, including survival time from recurrence/metastasis (OS) patients who received systemic chemotherapy with paclitaxel (200 mg/m2) and carboplatin (area under the curve 6) (TC) on day 1 of a 3-week cycle and observation alone. Subgroup analysis was conducted to identify patients who can get benefit from TC. RESULTS: Seventy-five patients (32 in TC and 43 in observation) were analyzed. There was no difference in median OS between TC and observation (52.2 months vs. 44.0 months, hazard ratio 0.76, 95% confidence interval 0.32-1.30, p = 0.21). Landmark analysis to reduce immortal bias also showed no difference between TC and observation in terms of OS. Subgroup analysis showed nonsignificant trends toward longer OS in asymptomatic patients with pulmonary metastasis and without bone metastasis. CONCLUSIONS: In our non-randomized comparison, patients who underwent TC did not show prolonged survival time from recurrence and/or metastasis diagnosis compared with observation alone in patients with recurrent or metastatic HNACC. Although systemic chemotherapy is a possible option for metastatic/recurrent HNACC, initial observation might be a valid strategy for asymptomatic patients without extrapulmonary diseases. Further research is warranted to identify the optimal patients and therapeutic regimens to prolong OS in HNACC.

Is CT or FDG-PET more useful for evaluation of the treatment response in metastatic HER2-positive breast cancer? a case report and literature review.

Response evaluation criteria in solid tumors version 1.1 (RECIST ver1.1) has been widely adopted to evaluate treatment efficacy in solid tumors, including breast cancer (BC), in clinical trials and clinical practice. RECIST is based mainly on computed tomography (CT) images, and the role of fluorodeoxyglucose-positron emission tomography (FDG-PET) is limited. However, because the rate of tumor shrinkage on CT does not necessarily reflect the potential remaining tumor cells, there may be a discrepancy between the treatment response and prognosis in some cases. Here we report a case of metastatic human epidermal growth factor receptor 2 (HER2)-positive BC where FDG-PET was preferable to CT for evaluation of the treatment response. A 40-year-old woman became aware of a lump in her right breast in September 201X. She was pregnant and underwent further examinations, including a biopsy, in November. The diagnosis was HER2-positive BC (cT2N2bM1, stage IV). Trastuzumab plus pertuzumab plus docetaxel (TPD) therapy was initiated in December 201X. CT performed in February 201X+1 showed cystic changes in the metastatic lesions in the liver, and the treatment response was stable disease (SD) according to RECIST. However, FDG-PET in March 201X+1 did not detect abnormal uptake of FDG in the hepatic lesions. The disease remained stable thereafter. Thus, tumor shrinkage may not be apparent in situations where the response to treatment results in rapid changes in blood flow within the tumor, which is associated with cystic changes. When patients with hypervascular liver metastases receive treatment with highly effective regimens, the target lesion may show cystic changes rather than shrinkage, as observed in the present case. Therefore, FDG-PET is sometimes superior to CT in judging a tumor response.

Late-onset doxorubicin-induced congestive heart failure in an elderly cancer survivor: A case report.

Background: Recently, the survival rate of patients with cancer has improved annually due to advancements in cancer diagnosis and treatment technologies. Meanwhile, late-onset complications associated with cancer treatment significantly affect survival and quality of life. However, different from pediatric cancer survivors, there is no unified view on the follow-up of late complications in elderly cancer survivors. We reported a case of congestive heart failure as a late-onset complication of doxorubicin (DXR) in an elderly cancer survivor. Case report: The patient is an 80-year-old woman with hypertension and chronic renal failure. She received six cycles of chemotherapy for Hodgkin's lymphoma that started in January 201X-2. The total dose of DXR was 300 mg/m2, and a transthoracic echocardiogram (TTE) performed in October 201X-2, showed good left ventricular wall motion (LVWM). In April 201X, she suddenly developed dyspnea. Upon arrival at the hospital, a physical examination revealed orthopnea, tachycardia, and leg edema. A chest radiograph showed cardiac enlargement and pleural effusion. A TTE showed diffusely reduced LVWM and a left ventricular ejection fraction in the 20% range. After close examination, the patient was diagnosed with congestive heart failure due to late-onset DXR-induced cardiomyopathy. Conclusion: Late-onset DXR-induced cardiotoxicity is considered high-risk from 250 mg/m2 or higher. Elderly cancer survivors are at higher risk of cardiotoxicity than non-elderly cancer survivors and may require closer follow-up.

Slowly Progressive Bone Marrow Metastasis of Gastric Cancer Followed-up Without Treatment.

BACKGROUND/AIM: Bone marrow metastasis (BMM) of gastric cancer (GC) is complicated by disseminated intravascular coagulation syndrome (DIC), which is more prominent in poorly differentiated carcinoma. This is one of the first case reports of a slowly progressing BMM of GC after approximately 1 year of follow-up without treatment. CASE REPORT: A 72-year-old woman underwent total gastrectomy and splenectomy for GC in February 2012. The pathological diagnosis was that of a moderately differentiated adenocarcinoma. Five years later in December 2017, she developed anemia; however, its cause remained unknown. Due to worsening of the anemia, the patient visited the Kakogawa Central City Hospital in October 2018. Bone marrow biopsy revealed an infiltration of caudal type homeobox 2-positive cancer cells, and our diagnosis was BMM of GC. There was no DIC. The incidence of BMM is high in well- or moderately differentiated breast cancer but rarely causes DIC. CONCLUSION: As with breast cancer, in moderately differentiated cancer cells, BMM of GC may progress slowly after the appearance of symptoms without causing DIC.

Clinical characteristics of sarcoma cases in which long-term disease control was achieved with trabectedin treatment: A retrospective study.

Trabectedin is a therapeutic option for patients with advanced sarcoma. While a randomized trial demonstrated its prolonged progression-free survival (PFS), the reported PFS was <6 months. Some patients can achieve long-term disease control with this treatment. However, the reference information is insufficient. Herein, we retrospectively reviewed 51 sarcoma patients who received trabectedin. We analyzed the clinicopathological features, trabectedin dose, administration schedule, and clinical outcomes, including the overall response rate (ORR) and PFS. Among them, we assessed the detailed data of patients who achieved long-term disease control (PFS >1 year). The ORR in the 49 evaluable patients was 8%, and the median PFS in 51 patients was 7.5 months. Six patients (12%) achieved PFS of >1 year. Five of the six patients had metastatic lesions at trabectedin initiation. The pathological subtypes were myxoid liposarcoma (n = 2), leiomyosarcoma (n = 2), synovial sarcoma (n = 1), and Ewing sarcoma (n = 1). The final administration dose was the minimum dose (0.8 mg/m2) in two patients who continued the treatment over 20 cycles. The best radiological response was partial response (PR) in two myxoid liposarcoma patients and stable disease in four. The durations from trabectedin initiation to the first response in the two PR cases were 163 and 176 days, respectively. Our results support the validity of continuing trabectedin at a sustainable dose and interval in patients who can tolerate it. These results may be useful when considering the clinical application of trabectedin.

Combined Hypophysitis and Type 1 Diabetes Mellitus Related to Immune Checkpoint Inhibitors.

Context: The occurrence of multiple endocrinopathies due to immune checkpoint inhibitors (ICIs) is a relatively common adverse event. However, the occurrence of a combination of hypophysitis and type 1 diabetes mellitus (T1DM) is extremely rare, and its clinical features are unclear. Objective: We comparatively analyzed the clinical features of this combination and each individual ICI-induced endocrinopathy. Methods: We reported 3 cases that we encountered and reviewed previously reported cases of patients with combined hypophysitis and T1DM due to ICIs. Results: Anti-programmed cell death-1 (anti-PD-1) antibodies were prescribed to all 3 cases. The duration from ICI initiation to the onset of endocrine disease was 12 to 48 weeks. Several human leukocyte antigen (HLA) haplotypes that have disease susceptibility to hypophysitis were detected in all 3 patients. With the 17 previously reported cases, combined endocrinopathies were more common in men (85%). The onset age was in the 60s for both combined and single endocrinopathies. Anti-PD-1 antibodies were used in most of the cases (90%). The time from ICI initiation to the onset of endocrinopathies was 24 (8-76) weeks for hypophysitis and 32 (8-76) weeks for T1DM in patients with combined endocrinopathies, which was not significantly different from that for each single endocrinopathy. Conclusion: We presented 3 cases of patients with combined endocrinopathies of hypophysitis and T1DM that may have been caused by anti-PD-1 antibodies. There was no difference in the time from ICI initiation to the onset of endocrinopathies between combined and single endocrinopathies. Further case accumulation and pathogenic investigations are required.

Delayed diagnosis of bladder cancer in a patient with autosomal dominant polycystic kidney disease.

ABSTRACT: Approximately 50% of autosomal dominant polycystic kidney disease (ADPKD) patients have gross hematuria, but few cases of bladder cancer complications are known. We report a case of a 49-year-old female ADPKD patient with bladder cancer, who was presented to our hospital 4 months after the onset of gross hematuria. A computed tomography (CT) scan showed a bladder mass, enlarged pelvic and left inguinal lymph nodes, multiple liver cysts, and a polycystic kidney. Based on family history, CT scan results, and lymph node biopsy, we diagnosed the patient with uroplakin III-negative bladder cancer with squamous metaplasia and ADPKD. The patient was treated with systemic chemotherapy but died 2 months after the definitive diagnosis. The delayed diagnosis was disastrous, and malignancy should be considered in the differential diagnosis when symptoms suggestive of malignancy such as hematuria appear. Particularly, uroplakin III-negative advanced bladder cancer has a poor prognosis and requires early diagnosis and treatment.

Case report: Paratesticular dedifferentiated liposarcoma with poor prognosis.

Background/Aim: Most paratesticular liposarcomas (PLPSs) are well-differentiated liposarcomas (WDLPSs) with favourable prognoses. As such, the rare occurrence of PLPS often leads to its misdiagnosis as a hernia or hydrocele on physical examination. Curative resection of the tumour may not be possible in cases where PLPSs have transformed into dedifferentiated liposarcomas (DDLPSs) owing to a delay in diagnosis. Herein, we describe a case of unresectable paratesticular dedifferentiated liposarcoma (PDDLPS) with poor prognosis due to delayed diagnosis. Case Report: A 57-year-old man visited our hospital with a chief complaint of a right scrotal mass, which was diagnosed as scrotal hydrocele but without treatment or follow-up. Eight years later, the patient complained of abdominal distension, and a computed tomography scan revealed the presence of retroperitoneal and right scrotal masses. The right scrotal mass was removed, and histopathology revealed DDLPS. The patient was diagnosed with unresectable PDDLPS metastasising to the retroperitoneum, and the left pleura was treated with doxorubicin. After an initial response, pleural effusion and ascites increased during the sixth cycle of chemotherapy. The patient subsequently received eribulin but died 5 months after the initial DDLPS diagnosis. Conclusion: It is difficult to distinguish PLPS from benign inguinal hernia and hydrocele testis on physical examination. PLPS generally has a considerably good prognosis. However, failure to diagnose WDLPS can be dangerous as it might lead to malignant transformation to DDLPS, which has a poor prognosis. Physicians should consider this malignancy when examining patients with hernias or hydroceles of the inguinal region and should perform ultrasonography or magnetic resonance imaging.

Validity of the Cancer and Aging Research Group Predictive Tool in Older Japanese Patients.

Background: This study aimed to evaluate the usefulness of the Cancer and Aging Research Group (CARG) predictive tool in older Japanese patients with cancer. Methods: Patients aged 65 years or older with solid tumors treated with new anticancer regimens in Kakogawa Central City Hospital between April 2016 and March 2019 were included. Grade 3 or higher risks of developing chemotherapy-related adverse events (CRAEs) were calculated using the tool (low-, intermediate-, or high-risk scores). The association between grade 3−5 CRAE incidence during the first course of each regimen and the calculated risk or the patient characteristics was evaluated. The difference in the incidences of CRAEs between the groups was evaluated by Fisher's exact test. Results: This study examined 76 patients (mean age: 71 (65−82) years). The incidence of grade 3−5 CRAE was 38%, 55%, and 76% in patients classified as low, medium, and high CARG risk scores (p = 0.035), and the incidence of severe non-hematological toxicities was 4%, 31%, and 52% (p < 0.01), respectively. Eastern Cooperative Oncology Group performance status and age were not associated with chemotherapy toxicity. Conclusions: The CARG predictive tool was valid, suggesting its usefulness in optimizing chemotherapy outcomes in older patients with cancer.

Transition of the PD-1 occupancy of nivolumab on T cells after discontinuation and response of nivolumab re-challenge.

Although nivolumab is administered every two or four weeks, high programmed cell death-1 (PD-1) binding of nivolumab on T cells lasting for several months has been reported. A relationship between the PD-1 occupancy rate on T-cells and the efficacy of nivolumab is not yet fully understood. The present study used flow cytometric analyses to determine the time-dependence of PD-1 occupancy in five patients who discontinued nivolumab. The relationship between PD-1 occupancy at relapse and the efficacy of re-challenge was also studied. Occupancies after discontinuation were measured at a total of 32 points. The data indicated that it took 32.4 and 48.9 weeks to decrease occupancy by 50 and 70%, respectively. Subsequently, two patients had recurrence and were re-challenged with nivolumab. At that time, one patient had 70.8% occupancy while the other had 6.6%. Treatment was effective only for the patient with lower occupancy. Overall, the present study suggests that re-challenge with nivolumab may be efficacious in patients with low occupancy at recurrence.

Difficulty in Distinguishing Pulmonary Arterial Intimal Sarcoma from Pulmonary Thromboembolism Using FDG PET/CT.

BACKGROUND/AIM: Pulmonary arterial intimal sarcoma (PAIS) is a rare malignant soft tissue tumor that is difficult to differentiate from pulmonary thromboembolism (PTE). Therefore, pre-operative diagnosis is often difficult. However, recent advances in fluorodeoxyglucose positron emission tomography (FDG-PET) have enabled the use of standardized uptake values (SUVs) for the differential diagnosis of PAIS from PTE, and the frequency of diagnosis of PAIS has increased. Here, we report a case of PAIS that was difficult to differentiate from PTE despite using FDG-PET. CASE REPORT: A 40-year-old woman presented with gradually worsening exertional dyspnea. Contrast-enhanced computed tomography (CT) revealed lesions with poor enhancement in the right lateral basal pulmonary artery. FDG-PET/CT did not reveal any tumor or thrombosis in other areas. Cytological evaluation using a right ventricular catheter did not lead to a definitive diagnosis. Because the patient did not respond to anticoagulation, we performed pulmonary artery endarterectomy. Pathological examination of the pulmonary artery tumor revealed a mucinous tumor with an edematous stroma and spindle-shaped tumor-cell proliferation, which confirmed the diagnosis of PAIS. However, FDG/PET demonstrated a low SUV of 3.4. CONCLUSION: Some PAISs with low cellular densities and high mucous tissue proportions have SUVs similar to those in PTE. In patients with low FDG uptake, if PAIS is suspected based on other objective findings, additional exploration using highly invasive tests or surgical procedures specific to PAIS is warranted.

Predicting Chemotherapy-Related Adverse Events in Elderly Cancer Patients with Prior Anticancer Therapy.

To test the usefulness of the Cancer and Aging Research Group (CARG) predictive tool, it was used to assess elderly cancer patients with prior anticancer therapy. Among patients with solid malignancies aged ≥ 65 years receiving second-line chemotherapy who were admitted to the Department of Medical Oncology/Hematology at Kakogawa Central City Hospital between April 2016 and September 2019, the risk ≥ grade 3 of developing chemotherapy-related adverse events (CRAEs) (low, intermediate, or high) was calculated using the tool. Correlations between grades 3 and 5 CRAE incidence rates in the first course of each regimen and CARG risk score, age, and Eastern Cooperative Oncology Group performance status (ECOG PS) were assessed. Included patients (n = 62) had a mean age of 71 years (range, 65−82 years). Severe CRAE incidence in patients with low, medium, or high CARG risk was 27%, 54%, and 71%, respectively (p = 0.026). The incidence of severe non-hematological toxicities was 5%, 35%, and 64%, respectively (p < 0.01). There was no association between age or ECOG PS and chemotherapy toxicity. The results suggest the validity of the CARG predictive tool in elderly cancer patients with prior anticancer therapy. Particularly, the tool showed potential for predicting non-hematological toxicity.

Identification of Breast Cancer Stem Cells Using a Newly Developed Long-acting Fluorescence Probe, C5S-A, Targeting ALDH1A1.

BACKGROUND/AIM: Aldehyde dehydrogenase (ALDH) 1A1 is a well-known marker for cancer stem cells (CSCs), characterized by self-renewal capacity and multidrug resistance in breast cancer. We developed a near-infrared turn-on fluorescence probe for ALDH1A1, C5S-A, which is suitable for observing and analyzing viable cells. Here, we demonstrated the utility of C5S-A in CSC research using breast cancer cell lines. MATERIALS AND METHODS: To evaluate concordance between C5S-A and conventional stem cell markers, breast cancer cells sorted for ALDEFLUOR-positive cells and for CD44+/CD24- cell populations were stained with C5S-A. Tumorigenicity of C5S-A-positive cells was examined by mammosphere formation assay and subcutaneous transplantation to immunodeficient mice. Additionally, to determine how long fluorescence from a single staining remained observable, we cultured breast cancer cells for 5 days after C5S-A staining. We then evaluated whether C5S-A-positive cells possessed resistance to cytotoxic drugs by chronological imaging. RESULTS: C5S-A staining showed good concordance with conventional breast CSC markers, and good utility for research into CSC characteristics in breast cancer cell lines, including tumorigenesis. Additionally, C5S-A was observable for more than 3 days with a single staining. Using this property, we then confirmed that C5S-A-positive cells possessed resistance to cytotoxic drugs, which is one of the characteristics of CSCs. CONCLUSION: We showed that C5S-A is suitable for CSC research using breast cancer cell lines, and confirmed its utility in observing cells over time.

Post-Systemic Chemotherapy Prognoses of Recurrent/Metastatic Soft Tissue Sarcoma Patients with Retroperitoneal/Intra-Abdominal Origin versus Those with Extremities/Trunk Origin.

BACKGROUND: The clinical benefit of systemic chemotherapy for recurrent/metastatic retroperitoneal/intra-abdominal soft tissue sarcoma (STS) compared to its benefits for other primary lesions has not been known or sufficiently evaluated. METHODS AND PATIENTS: We retrospectively reviewed the cases of the STS patients who consulted a department of medical oncology in Tokyo between June 2011 and March 2018, and we extracted the cases of patients with primary sites at the retroperitoneum/intra-abdomen (cohort R) or extremities/trunk (cohort E) who received systemic chemotherapy in a recurrent/metastatic setting, comparing the cohorts' characteristics, chemotherapy details, and prognoses. RESULTS: Of all 337 STS patients, we enrolled 49 patients in cohort R and 75 patients in cohort E. Liposarcoma was more frequently observed in cohort R (51.0%) than cohort E (22.7%). The median chemotherapy treatment line was two lines (range: 1-6) in cohort R and three lines (range: 1-9) in cohort E. The doxorubicin usage rates differed in recurrent/metastatic settings (90.0% in cohort R and 55.0% in cohort E), due mainly to the higher rate of a perioperative chemotherapy treatment history in cohort E (52.0% vs. 6.1% in cohort R). The median overall survival from the start of salvage chemotherapy was 31.9 months (cohort R; 95% CI: 20.9-42.8) and 27.1 months (cohort E; 95% CI: 21.6-32.5) (p = 0.549). CONCLUSION: There were differences in the distributions of pathology and antitumor drugs used in a salvage setting between retroperitoneal/intra-abdominal and extremities/trunk STS patients in recurrent/metastatic settings, but the prognoses with salvage chemotherapy were similar in the two cohorts.

A proposed clinical scoring system for initiation of lenvatinib treatment in radioiodine-refractory thyroid cancer patients.

PURPOSE: The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients. METHODS: We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups. RESULTS: A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p < 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p < 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p < 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib. CONCLUSION: Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

Microsatellite instability-high colorectal cancer patient-derived xenograft models for cancer immunity research.

CONTEXT: There is an increasing demand for appropriate preclinical mice models for evaluating the efficacy of cancer immunotherapies. AIMS: Therefore, we established a humanized patient-derived xenograft (PDX) model using microsatellite instability-high (MSI-H) colorectal cancer (CRC) tissues and patient-derived peripheral blood mononuclear cells (PBMCs). SUBJECTS AND METHODS: The CRC tissues of patients scheduled for surgery were tested for MSI status, and CRC tumors were transplanted into NOD/LtSz-scid/IL-2Rg-/-(NSG) mice to establish MSI-H PDX models. PDX tumors were compared to the original patient tumors in terms of histological and genetic characteristics. To humanize the immune system of MSI-H PDX models, patient PBMCs were injected through the tail vein. RESULTS: PDX models were established from two patients with MSI-H CRC; one patient had a germline mutation in MLH1 (c.1990-2A > G), and the other patient had MLH1 promoter hypermethylation. PDX with the germline mutation was histologically similar to the patient tumor, and retained the genetic characteristics, including MSI-H, deficient mismatch repair (dMMR), and MLH1 mutation. In contrast, the histological features of the other PDX from a tumor with MLH1 promoter hypermethylation were clearly different from those of the original tumor, and MLH1 promoter hypermethylation and MSI-H/dMMR were lost in the PDX. When T cells from the same patient with MLH1 mutation were injected into the PDX through the tail vein, they were detected in the PDX tumor. CONCLUSIONS: The MSI-H tumor with an MMR mutation is suitable for MSI-H PDX model generation. The PBMC humanized MSI-H PDX has the potential to be used as an efficient model for cancer immunotherapy research.

Immunosuppressive effects and mechanisms of three myeloid-derived suppressor cells subsets including monocytic-myeloid-derived suppressor cells, granulocytic-myeloid-derived suppressor cells, and immature-myeloid-derived suppressor cells.

CONTEXT: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immune cells of myeloid lineage. Recent reports have suggested that human MDSC are divided into three subsets: monocytic MDSC (M-MDSC), granulocytic MDSC (G-MDSC), and immature MDSC (I-MDSC). However, the characteristics of each human MDSC subset still remain unclear. MATERIALS AND METHODS: To evaluate the immunosuppressive effects and mechanisms, we first performed a T-cell suppression assay using cells obtained from healthy donor peripheral blood samples. The levels of immune inhibitory molecules in the culture supernatant of each MDSC subset were measured to reveal the T-cell suppressive mechanisms. Then, we compared these results with the results from cells obtained from cancer patient blood samples. Finally, we investigated the difference in the frequency of each MDSC subset between the healthy donors and the cancer patients. RESULTS: Although M-MDSC and G-MDSC suppressed T-cell activation, I-MDSC had no T-cell suppressive effect. We found that the culture supernatant of M-MDSC and G-MDSC contained high levels of interleukin-1 receptor antagonist (IL-1RA) and arginase, respectively, in both healthy donors and cancer patients. No inhibitory molecules were detected in the culture supernatant of I-MDSC. The population of functional MDSC (M-MDSC and G-MDSC) in the total MDSC was significantly increased in cancer patients compared with that in healthy donors. CONCLUSIONS: Although M-MDSC and G-MDSC, which released IL-1RA and arginase, respectively, suppressed T-cell activation, I-MDSC did not have an immunosuppressive effect. The population of functional MDSC was increased in cancer patients compared with that in healthy donors.

Exploratory Analysis to Predict Optimal Tumor Burden for Starting Lenvatinib in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer.

BACKGROUND: We previously reported that a high tumor burden is a prognostic factor based on an analysis of 26 patients with radioactive iodine-refractory differentiated thyroid cancer (RR-DTC) who were treated with lenvatinib. However, the optimal tumor burden for starting lenvatinib still remains to be defined. The aim of this retrospective study was to further explore in the same patient cohort the optimal timing for the start of lenvatinib by focusing on the pre- and post-treatment tumor burden. METHODS: The 26 patients were treated with lenvatinib from 2012 to 2017. We explored the optimal timing for the start of lenvatinib by comparing the characteristics of long-term responders who were defined as patients with progression-free survival ≥ 30 months and non-long-term responders. RESULTS: Long-term responders had a smaller post-treatment tumor burden at maximum shrinkage than non-long-term responders. Further, post-treatment tumor burden had a strong linear correlation with baseline tumor burden. We created an estimation formula for baseline tumor burden related to prognosis, using these regression lines. Patients with a sum of diameters of target lesions < 60 mm or maximum tumor diameter < 34 mm at baseline were estimated to have significantly better survival outcomes. CONCLUSIONS: We found a strong linear correlation between pre- and post-treatment tumor burden. Our results suggested a cut-off value for baseline tumor burden for long-term prognosis among patients treated with lenvatinib.

Serum Soluble Interleukin-2 Receptor as a Potential Biomarker for Immune-related Adverse Events.

BACKGROUND/AIM: Biomarkers for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) are required. We encountered a patient whose skin irAE fluctuated in parallel with serum soluble interleukin-2 receptor (sIL-2R). PATIENTS AND METHODS: We examined 15 patients with cancer who received ICIs. Serum sIL-2R levels before and during ICI treatment were measured. The sIL-2R levels of preserved serum samples from another five patients who developed grade 3 irAEs were measured. RESULTS: Twelve patients showed no significant changes in sIL-2R levels during ICI treatment. Baseline serum sIL-2R levels in three patients increased beyond the normal range before the second cycle. These three patients had grade ≥2 irAEs at the second cycle treatment visit, supporting our hypothesis. Furthermore, at diagnosis of irAEs, the sIL-2R levels of all preserved samples from patients with grade 3 irAEs were significantly elevated. CONCLUSION: Serum sIL-2R is a promising biomarker for the diagnosis of irAEs.