Papillary Cancer Research Articles

PSAT279 Thyroid Oncocytic tissue: Presenting as metastatic thyroid carcinoma

Abstract Case A 76-year-old male with status post thyroidectomy in 2017 for compressive multi-nodular goiter. Pathology reported as benign thyroid tissue with follicular hyperplasia. In 2020, he presented with incidental finding of left neck mass on MRI. Ultrasound neck confirmed two extra-thyroidal masses left neck largest dimension of 2.9 cm. FNA reported as benign follicular cells favoring benign thyroid tissue. Surgical resection of the neck masses revealed benign thyroid tissue with focal oncocytic features and two benign lymph nodes. In 2021, he presented with left chest mass. Biopsy reported benign thyroid tissue, no evidence of papillary cancer. PET CT confirmed hypermetabolic chest mass, multiple lytic bone lesions and pulmonary nodules. Referred to Endocrinology for further evaluation, Thyroglobulin level elevated at >4500 ng/mL (Tg Ab <1.0 IU/mL). Molecular testing of chest wall mass was positive for TERT and HRAS mutations, loss of 22q and gain of 17q on microarray consistent with changes found in thyroid cancer. Surgical resection of the chest wall mass not feasible due to size and location. External beam radiation for cytoreduction of the sternal mass planned and radioactive iodine therapy if tumor RAI (radioactive iodine) avid. He is currently not a candidate for tyrosine kinase inhibitor (TKI) as he recently had acute coronary event. Zoledronic acid infusions initiated for bone involvement. Discussion Thyroid carcinomas that exhibit vascular invasion, or anaplastic dedifferentiation are readily and consistently diagnosed. However, the morphology of primary oncocytic thyroid tumors is similar to their non-oncocytic counterparts posing a huge challenge for the pathologist. This controversial and often confusing area of thyroid pathology requires careful evaluation for accurate diagnosis and management for patients with oncocytic thyroid lesions. Molecular and microarray testing should be considered when in doubt. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Abnormal tongue discoloration following radioactive iodine-131 ablation therapy for papillary cancer thyroid

Category: Head and neck

RF17 | PSUN202 DICER1 Gene Mutation: Association With Thyroid Cancer and Other Endocrine Tumors

Abstract Introduction DICER1 syndrome is a rare autosomal dominant hereditary tumor predisposition syndrome and is known to have many endocrine manifestations. Case Description A 21-year-old female with DICER1 syndrome presented to the clinic to establish care. She had a significant family history of DICER1 mutation in her father and two siblings. She was diagnosed with malignant neuroepithelioma of the uterus at the age of 12 and was treated with cisplatin/cyclophosphamide. Hepatic embryonal rhabdomyosarcoma and pleuropulmonary blastoma type 1 were diagnosed at the age of 16 and she underwent hepatic lobectomy, left lower lung lobectomy, and received additional chemotherapy. She was first diagnosed with multiple thyroid nodules at the age of 14. Surveillance thyroid ultrasounds were performed biannually over the next 6 years. She also had multiple thyroid nodule FNAs, all showing benign results. Subsequently, CT chest revealed enlarging thyroid nodules with a chest wall lesion which prompted total thyroidectomy. Surgical pathology confirmed a 0.5 cm papillary thyroid carcinoma involving the left superior thyroid lobe; there was no lymph node involvement or extrathyroidal invasion and the surgical margins were intact. Surveillance ultrasounds have not shown any residual or recurrent disease. Excision of chest wall lesion showed nodular epithelia proliferation with rare eccrine duct present in the margin. She also suffered from secondary amenorrhea from chemotherapy induced ovarian failure. She was started on estrogen patch and cyclical progesterone therapy, following which menstrual cycles resumed. Discussion DICER1 encodes an Rnase III endonuclease that processes miRNA precursor hairpins into mature miRNAs. miRNA-mediated effects that lead to this syndrome is due to loss-of-function in tumor suppressor genes or gain of function in oncogenes. This predisposes patients to a variety of different tumors, including many endocrine tumors. Multiple thyroid nodules, as was seen in our patient, is a common finding in individuals with DICER1 syndrome. Rates of thyroid cancer are 10–20% higher in these patients. Follicular variant of papillary cancer and follicular thyroid cancer are the most common histologies seen. Thyroid cancer in these patients usually follows an indolent course with thyroidectomy typically curative. For screening of thyroid cancer, recommendations include annual thyroid examination, with some authors advocating for thyroid ultrasounds starting at the age 8, with repeated scans every 3 years if normal. Other endocrine tumors that are associated with DICER1 mutations include pituitary blastomas and pineoblastoma. Patients with pituitary blastomas may present with features of Cushing disease with elevated ACTH. Pineoblastoma can be detected with surveillance brain MRI, but routine screening for these tumors is not currently recommended as these tumors are rare, even within this syndrome. References Endocr Relat Cancer. 2018 Mar;25(3): R197-R208. Presentation: Sunday, June 12, 2022 12:48 p.m. - 12:53 p.m.

Thyroglobulin Levels as a Predictor of Papillary Cancer Recurrence After Thyroid Lobectomy.

The effectiveness of using serum thyroglobulin (TG) to predict thyroid cancer recurrence after a thyroid lobectomy is unknown. This study aimed to evaluate the predictive nature of serum TG and TG trends after thyroid lobectomies. We analyzed 514 papillary thyroid cancer (PTC) patients. The pre-, low-, high, and last-TG levels were reviewed and stratified into three groups. An ascending TG trend was defined if the last-TG level was more than 200% as high as the value of low-TG level. A descending trend was defined if the last-TG level decreased by more than 50% and a flat trend as between them. During a median follow-up period of 73.0 months, there were 21 (4.1%) recurrences. Most patients showed a descending (54.1%) or flat (35.6%) TG trend, but 10.3% of patients showed an ascending TG trend. Overall and lateral recurrences were significantly higher in the ascending TG group, indicating that an ascending TG trend was a good predictor for recurrence. Other factors such as positive node ratio (PNR), patient risk, age, and sex were not significant risk factors. In a Kaplan-Meier analysis, ascending TG trend was a good predictor of lateral recurrence. TG levels as a predictor of papillary cancer recurrence after thyroid lobectomy were found to be poor classifiers, and optimal cut-off values were not verified. An ascending TG trend was a good predictor of lateral recurrence. Further studies are warranted to investigate whether an ascending TG trend was due to an incomplete thyroid lobectomy or if the cancer had already metastasized to the lateral compartment.

ПОИСК МАРКЕРОВ МОЛЕКУЛЯРНОЙ ДИАГНОСТИКИ ДЛЯ ОПТИМИЗАЦИИ ХИРУРГИЧЕСКОЙ ТАКТИКИ ПРИ ЗАБОЛЕВАНИЯХ ЩИТОВИДНОЙ ЖЕЛЕЗЫ

The routine execution of a fine-needle aspiration puncture biopsy is the most informative method for the preoperative diagnosis of thyroid neoplasms, as well as a promising base for improving molecular diagnostics in an endocrine surgery clinic in conjunction with a pathological laboratory. The aim of our work was a comparative analysis of the expression of cell cycle signaling molecules in various thyroid diseases: toxic goiter, adenomatous goiter, autoimmune thyroiditis and papillary cancer. We investigated the quantitative ratio of expression of apoptosis markers CD-95 (Fas-R) and Ki-67 mitosis detected in thyrocytes by immunocytochemistry and immunohistochemistry using standard protocols. The index Z = Fas / (Ki67 + 1) is proposed.
 The performed cluster analysis of the Z-index calculated on the basis of punctate immunocytochemistry material allowed us to identify a group of patients relatively uniform in value (in this group, after the operation, the diagnosis of papillary cancer was histologically confirmed in all patients). Marker expression values were 2,3–9,0 for Ki67 and 0,9–4,1 for Fas, and the Z-index was in the range 0,6–3,9. It can be useful for the differential diagnosis of thyroid cancer based on punctate material, which is important when deciding on the amount of surgical intervention, as well as in the morphological substantiation of the prognosis of the disease.
 Mathematical analysis showed that if the percentage of fissile nuclei visualized immunohistochemically with the Ki-67 marker is unpromising as a singular diagnostic indicator, then in combination with the apoptosis marker it plays an important role in a comprehensive assessment. These data are also interesting in the context of the pathophysiological pattern of inhibition of the expression of CD95 by tumor cells. This is important to justify the approaches of chemotherapy or immunotherapy of cancer of different tissue belonging.

Chronic Arsenic Exposure Upregulates the Expression of Basal Transcriptional Factors and Increases Invasiveness of the Non-Muscle Invasive Papillary Bladder Cancer Line RT4.

The bladder is a target organ for inorganic arsenic, a carcinogen and common environmental contaminant found in soil and water. Urothelial carcinoma (UC) is the most common type of bladder cancer (BC) that develops into papillary or non-papillary tumors. Papillary tumors are mostly non-muscle invasive (NMIUC), easier treated, and have a better prognosis. Urothelial carcinoma can be molecularly sub-typed as luminal or basal, with papillary tumors generally falling into the luminal category and basal tumors exclusively forming muscle invasive urothelial carcinomas (MIUC). It is unclear why some UCs develop more aggressive basal phenotypes. We hypothesized that chronic arsenic exposure of a papillary luminal bladder cancer would lead to the development of basal characteristics and increase in invasiveness. We treated the human papillary bladder cancer cell line RT4 with 1 µM arsenite (As3+) for twenty passages. Throughout the study, key luminal and basal gene/protein markers in the exposed cells were evaluated and at passage twenty, the cells were injected into athymic mice to evaluate tumor histology and measure protein markers using immunohistochemistry. Our data indicates that chronic As3+- treatment altered cellular morphology and decreased several luminal markers in cell culture. The histology of the tumors generated from the As3+-exposed cells was similar to the parent (non-treated) however, they appeared to be more invasive in the liver and displayed elevated levels of some basal markers. Our study demonstrates that chronic As3+ exposure is able to convert a non-invasive papillary bladder cancer to an invasive form that acquires some basal characteristics.

Palliative care usage in metastatic thyroid cancer: An analysis of the National Cancer Database.

196 Background: Metastatic thyroid cancer portends a poor prognosis, especially in patients over the age of 55 or in more aggressive histologies, such as anaplastic. Palliative care (PC), which focuses on improving the quality of life in patients with severe disease, may be beneficial to these patients. To our knowledge, there has yet to be a study describing the demographic and usage factors associated with PC in metastatic thyroid cancer. Methods: We conducted a retrospective analysis of the National Cancer Database (NCDB) from 2004-2017 for subjects with metastatic thyroid cancer (n = 5,229) of all histologies. Analysis was completed between patients who utilized PC (n = 826) and patients who did not use PC (n = 4,403). The NCDB defines palliative care as care provided to alleviate or palliate symptoms, including radiation therapy, surgery, pain management, and/or systemic therapy. PC usage and survival were compared between cancer subtypes. Demographic factors were analyzed using Pearson chi-squared tests and t-tests, while survival was estimated using Kaplan-Meier curves. Results: Of the subjects with metastatic thyroid cancer, 50.6% had papillary, 25.2% had anaplastic, 15.9% had follicular, and 8.3% had medullary thyroid cancer. Anaplastic, medullary, follicular, and papillary metastatic cancers had median survivals of 2.4, 19.9, 49.5, and 55.3 months, respectively (p < 0.001). PC usage increased between 2004 (3.4%) and 2017 (11.4%) across all subtypes. The mean age at diagnosis of PC patients was 69.2 years old compared to 66.9 years old for non-PC patients (p < 0.001). Anaplastic thyroid cancer made up the greatest proportion of PC usage (42.5%) compared to other histologies (p < 0.001). Subjects of Spanish/Hispanic origin received PC at lower proportions (p < 0.001). In addition, Asian patients made up a smaller fraction of the PC cohort (4.2%) compared to the non-PC cohort (6.7%) (p = 0.028). Patients with private insurance made up a smaller proportion of PC users (26.5%) compared to non-PC users (35.6%), while subjects with government insurance or no insurance made up a greater proportion of PC usage (p < 0.001). Less PC usage was seen by patients who lived in an area where greater than 17.6% of individuals did not attain a high school degree; these patients made up 25.3% and 19.9% of the non-PC and PC cohorts, respectively (p = 0.006). Patients who received PC tended to live closer to the reporting hospital (p = 0.007). No statistically significant difference was seen between PC and non-PC cohorts for income and facility type. Conclusions: In this study, we highlighted several disparities in PC usage across common types of thyroid cancer. We also compared usage between categories and noted a greater proportion of PC usage in recent years. Our study is a valuable baseline as PC continues to be integrated in cancer care.

Five-year relative survival and determinants of excess mortality in patients with head and neck and thyroid cancers: A population-based study from Golestan province, Northern Iran

BackgroundWe aimed to assess relative survival (RS) and determinants of excess mortality rate in patients with head and neck squamous cell carcinomas (HNSCC) and thyroid cancer in Golestan province, Northern Iran. MethodsWe recruited new primary HNSCC and thyroid cancer cases from Golestan, 2006–2016. Five-year age-standardized RS with their 95% confidence intervals (CIs) were calculated. The relationships between different variables with excess mortality rates were assessed by estimating adjusted excess hazard ratios (aEHRs) with their 95% CIs. ResultsOverall, 718 cases of HNSCC and 386 thyroid cancer cases were enrolled. Five-year age-standardized RS (95% CI) were 36% (31−41) and 61% (52−69) in HNSCC and thyroid cancer patients, respectively. There were significant relationship between excess mortality rates in HNSCC patients with metastasis (aEHR= 3.31; 95%CI: 2.26–4.84), treatment type (4.19; 2.54–6.91, for no treatment as compared to receiving both surgery and chemoradiotherapy), age (2.16; 1.57–2.96, for older age group) and smoking (2.00; 1.45–2.75, for smokers as compared to non-smokers). Determinant of the excess mortality in thyroid cancer patients included metastasis (19.65; 8.08–47.79), tumor morphology (12.27; 4.62–32.58, for anaplastic cancer as compared to papillary cancer), treatment type (8.95, 4.13–19.4, for no treatment as compared to receiving both surgery and iodine therapy) and age (2.31; 1.17–4.54, for older age group). ConclusionOur findings suggested low RS for thyroid cancer in our population, while the estimates for HNSCC were comparable with other population. Metastasis, treatment type and age were determinants of mortality both in thyroid and HNSCC patients.

The relationship between papillary thyroid cancer and triglyceride/glucose index, which is an indicator of insulin resistance.

The incidence of thyroid cancer and metabolic syndrome has been increasing at the same rate over the past few decades. We hypothesized that there would be a direct relationship between thyroid papillary cancer and triglyceride/glucose index (TyG). A total of 382 operated patients were divided into two groups: patients operated on for papillary thyroid cancer and for non-malignant reasons. Each patient's age, gender, operation times, presence of neck dissection, serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4), fasting blood glucose and triglyceride levels were scanned retrospectively from the archive system. TyG index was statistically higher in the malignant group. Receiver operating characteristic (ROC) curves obtained for TyG levels at the time of diagnosis of thyroid papillary cancer were AUC: 0.608. The threshold value for TyG was 6,252. The sensitivity of this value was 62.8% and the specificity was 49.2%. In this study, we investigated the predictive effect of the TyG index in differentiating thyroid papillary carcinoma from non-malignant thyroid lesions. We concluded that the TgY index can be used to identify people at high risk of thyroid papillary cancer and to plan treatment.

Techniques for Treating a Single Cold Thyroid Nodule

Background: The goal of this article is to raise awareness of malignancy and surgical options for the solitary inflection point of the cold nodule thyroid. Methods: People mentioned after the community or hospitalized straight via Observational Patient Treatment Tartary care hospital kpk with a diagnosis of a single cold nodule thyroid gland were accounted for in the study. Results: The patients' ages varied from 15 to 65, with a mean of 35 10 years, and 90% were female. Sixty-four percent of patients had problems in the right lobe of the thyroid gland, whereas only two percent had problems in the isthmus. Each patient had had surgery and was deemed euthyroid. In 50% of patients, FNAC revealed adenomatous colloid goiter, while in 5%, FNAC revealed papillary cancer of the thyroid gland. Mainly, lobectomy with isthmusectomy was done (95%), whereas complete thyroidectomy was done (5%). Adenomatous colloid goiter was found in 45% of patients, whereas 9% had thyroid cancer that forms in follicles, and 3% had cancer of the follicle based on the histopathology report. In 7% of those who needed it, complete thyroid removal was accomplished. Postoperatively, 5% of patients had an infection at the surgical site, and 3% experienced temporary hypocalcemia. People didn't die outright or anything like that. Conclusion: Women are more likely to have a single cold nodule in their thyroid gland. The most effective surgical procedure is a combination of lobectomy and isthmusectomy. When a single cold nodule develops in the thyroid, papillary carcinoma is the most prevalent kind of cancer that may develop there. Keywords: Techniques, Treating, Cold Thyroid, Nodule

Radiofrequency Ablation of Recurrent Metastatic Papillary Thyroid Cancer to a Lymph Node

Radiofrequency Ablation of Recurrent Metastatic Papillary Thyroid Cancer to a Lymph Node

Papillary carcinoma of breast: An institutional overview of a rare histopathologic type.

Papillary carcinoma of the breast is a rare malignant tumor, constituting 1%-2% of all breast carcinomas in women. We studied a total of 6 cases of papillary cancer breast of which five were in female patients, and one was a male patient. Three were invasive papillary carcinoma while one was encapsulated papillary carcinoma without invasion, one was encapsulated papillary carcinoma with invasion and one was a solid type of papillary carcinoma. The median age of the patients was 45.5 years. All the tumors except one were seen in the left breast. Grossly, the size of the tumors ranged from 2 cm × 2 cm × 1.5 cm to as large as 6 cm × 10 cm × 4 cm. Three of the cases had positive axillary nodes. To conclude, papillary carcinoma is a rare tumor with a better prognosis as compared to Infiltrating duct carcinoma breast, and hence, it is important to be aware of the different subtypes and diagnostic pitfalls of this tumor to correctly diagnose it.

Hereditary leiomyomatosis and renal cell cancer: a case report

This article presents a case report of hereditary leiomyomatosis and renal cell cancer (HLRCC) with new mutation in a 25-year-old female patient admitted to the clinic for diagnosis and treatment due to multiple skin and uterus leiomyomas. The patient has a history of surgery to remove adrenal pheochromocytoma and papillary kidney cancer. Clinical and laboratory examination as well as medical genetic counseling of the patient were performed. We have detected the heterozygous c.395_399del (p.L132*) germline nonsense mutation in exon 4 of the FH gene using polymerase chain reaction/Sanger sequencing of exons 1–10 of this gene and confirmed the diagnosis of HLRCC. The mutation c.395_399del in a patient with HLRCC was described for the first time. The identical mutation was also found in the mother and sister of the patient. Based on the obtained results, medical genetic counseling was carried out in this family, recommendations were given for further oncological monitoring. The case report could be useful for geneticists, oncologists and other specialists to interpretate the clinical heterogeneity of HLRCC and improve the genetic diagnosis of this rare hereditary oncological syndrome.

Bone Marrow Mesenchymal Stem Cells (BMSCs) Promote the Metastasis of Thyroid Papillary Cancer by Inhibiting Poly-Pyrimidine Tract Binding Protein 1 (PTBP1)

We aimed to explore the mechanism underlying the role of bone marrow mesenchymal stem cells (BMSCs) in the invasion of papillary thyroid cancer (PTC) cells. BMSCs were co-cultured with PTC cells WRO or normal thyroid follicular epithelial cells T3TD followed by analysis of cell migration and proliferation by Transwell assay and MTT assay. Cells were transfected with shRNA or overexpression of PTBP1, followed by measuring cell proliferation and invasion and PTBP1 expression by RT-qPCR and Western blot. Co-cultivation with MSC promoted the malignant transformation of WRO, inhibited the RNA-binding protein PTBP1 and activation of GS3Kβ/Akt. In addition, silencing of PTBP1 accelerated cell invason and induced overexpression of EMT proteins, while overexpression of PTBP1 inhibited cell proliferation and migration. In conclusion, BMSCs might promote PTC invasion and metastasis by inhibiting PTBP1 expression, providing a novel insight into the treatment of PTC.

Clinical and morphological features of thyroid tumors with mutations in the <i>NTRK</i>, <i>RAS</i>, <i>BRAF</i>, <i>RET</i> genes

Despite the rather favorable clinical course of thyroid tumors, the issue of timely and high-quality diagnosis is still relevant. Due to the development of personalized treatment in medicine and the emergence of drugs that target specific mutations, timely detection of these mutations is very important. The pathologist should be focused on the search for certain morphological markers that suggest the presence of certain mutations in tumor cells. To narrow the differential diagnostic search, it is important to know the mechanisms of development of key mutations, mutually exclusive mutations, to have information about the clinical course of the disease. Based on these data, the next step will be more specific diagnostics (IHC, molecular genetic methods). Based on the analysis of literature data, it was possible to identify some distinctive morphological signs that can help the pathologist to suspect the presence of a particular mutation in the tumor. For mutations in the NTRK genes, such signs are the follicular variant of papillary cancer, nuclear pseudo-inclusions, presence of an oncocytic component, metastases, and the absence of a solid component. For the assumption of RAS mutations, attention paid to tumors of the follicular structure with an aggressive clinical course. The young age of the patient, metastases to the lymph nodes, and cancer of the thyroid gland of the classic papillary structure will allow one to assume the presence of a mutation in the RET gene. The BRAF mutation is characterized by specific cellular changes (pseudo-inclusions in the nuclei, the presence of plump cells or cells with sickle-shaped nuclei) in a thyroid cancer with a classic papillary structure.

Outcomes of Patients With Metastatic Differentiated Thyroid Cancer After Excellent Response to Treatment.

BackgroundTo evaluate the outcomes in differentiated thyroid cancer (DTC) patients who achieved excellent response to initial treatment and developed distant metastasis during follow-up.MethodsThyroid cancer patients registered in Chang Gung Memorial Hospital thyroid cancer database between January 1979 and December 2019 were assessed.ResultsAmong 1053 DTC patients with excellent response to initial therapy, 14 (1.3%) patients developed metastatic disease during follow-up, including 6 males and 8 females with median age of 50.2 years [interquartile range (IQR), 39.9-53.7]. Nine (64.3%) patients had papillary cancer, four (28.6%) had follicular cancer, and one (7.1%) had Hürthle cell cancer. Most patients (92.9%) had stage I disease at diagnosis. The sites of metastasis were lung (71.4%), bone (7.1%), mediastinum (7.1%) and multiple sites (14.3%). With a median follow-up of 18.3 years (IQR, 14.8-23.8), 2 patients had disease-specific mortality. The 5- and 10-year disease-specific survival after the diagnosis of distant metastasis was 92% and 74%, respectively. Multiple sites of metastasis was associated with increased risk of mortality (P = 0.022).ConclusionsA small proportion of DTC patients with an excellence response to initial therapy developed distant metastasis during follow-up. Multiple organ distant metastases conferred a worse disease-specific survival.

Selective delipidation of Mycobacterium bovis BCG retains antitumor efficacy against non-muscle invasive bladder cancer.

Repeated instillations of bacillus Calmette et Guérin (BCG) are the gold standard immunotherapeutic treatment for reducing recurrence for patients with high-grade papillary non-muscle invasive bladder cancer (NMIBC) and for eradicating bladder carcinoma-in situ. Unfortunately, some patients are unable to tolerate BCG due to treatment-associated toxicity and bladder removal is sometimes performed for BCG-intolerance. Prior studies suggest that selectively delipidated BCG (dBCG) improves tolerability of intrapulmonary delivery reducing tissue damage and increasing efficacy in preventing Mycobacterium tuberculosis infection in mice. To address the lack of treatment options for NMIBC with BCG-intolerance, we examined if selective delipidation would compromise BCG's antitumor efficacy and at the same time increase tolerability to the treatment. Murine syngeneic MB49 bladder cancer models and in vitro human innate effector cell cytotoxicity assays were used to evaluate efficacy and immune impact of selective delipidation in Tokyo and TICE BCG strains. Both dBCG-Tokyo and dBCG-TICE effectively treated subcutaneous MB49 tumors in mice and enhanced tumor-infiltrating CD8+ T and natural killer cells, similar to conventional BCG. However, when compared to conventional BCG, only dBCG-Tokyo retained a significant effect on intratumoral tumor-specific CD8+ and γδ T cells by increasing their frequencies in tumor tissue and their production of antitumoral function-related cytokines, i.e., IFN-γ and granzyme B. Further, dBCG-Tokyo but not dBCG-TICE enhanced the function and cytotoxicity of innate effector cells against human bladder cancer T24 in vitro. These data support clinical investigation of dBCG-Tokyo as a treatment for patients with BCG-intolerant NMIBC.

A phase 2 study of bevacizumab, erlotinib, and atezolizumab in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) associated or sporadic papillary renal cell cancer (pRCC).

TPS4604 Background: Papillary RCC accounts for 10-15% of kidney cancers and is the second most common subtype of RCC after clear cell RCC. HLRCC is a familial cancer syndrome characterized by a propensity for developing papillary kidney cancer. HLRCC-associated renal tumors are known to be clinically aggressive, with a paucity of treatment options. The combination of bevacizumab and erlotinib has shown promising activity in patients with HLRCC-associated RCC and sporadic pRCC (Srinivasan et al, ASCO 2020). We hypothesize that the addition of a PDL-1 inhibitor might provide synergistic clinical activity against these tumors. Methods: This is an ETCTN-sponsored, open-label, multicenter, phase 2 study evaluating bevacizumab, erlotinib and atezolizumab in adult and pediatric patients with advanced 1) HLRCC-associated RCC or 2) sporadic pRCC. Eligible patients will have cytologically or histologically confirmed advanced HLRCC- associated or sporadic pRCC, age ≥12 years, ECOG PS ≤2, no more than two prior regimens targeting the VEGF pathway, no prior treatment with PD-1 or PD-L1 inhibitors and adequate organ and marrow function. Patients with HLRCC-associated RCC or sporadic pRCC will be enrolled into parallel, independent cohorts. Initially, 12 adult patients with advanced HLRCC-associated RCC or sporadic pRCC will be enrolled into the safety run-in portion of the trial. If ≤ 3 dose-limiting toxicities are observed, enrollment will proceed into both cohorts and pediatric patients will be allowed to enroll. A Simon two-stage phase 2 minimax design will be used to determine accrual to each cohort. In the first stage, 12 evaluable patients will be enrolled into cohort 1) HLRCC-associated RCC or cohort 2) sporadic pRCC. If 0 of 12 patients have a CR, then no further patients will be enrolled in that cohort. If 1 or more of the first 12 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 21 evaluable patients (adult or pediatric) have been enrolled into each cohort for a total of 42 patients. Adult patients will receive a fixed dose of bevacizumab (15 mg/kg IV every 21 days) plus atezolizumab (1,200 mg IV every 21 days) and erlotinib (150 mg PO daily). Pediatric patients will receive bevacizumab (15 mg/kg IV every 21 days) plus atezolizumab 15 mg/kg (max 1,200 mg IV every 21 days) and erlotinib 85 mg/m2 (max 150 mg PO daily). The primary endpoint is to assess the complete response rate according to RECIST 1.1 in patients with advanced 1) HLRCC-associated RCC and 2) sporadic pRCC. Secondary endpoints include safety and tolerability, objective response rate, disease control rate, progression-free survival and overall survival. Key exploratory endpoints include evaluation of immunologic modulation associated with this regimen. The study has just opened to accrual. Clinical trial information: NCT04981509.

Final clinical results of pivotal trial of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive CIS and papillary nonmuscle-invasive bladder cancer (NMIBC).

4508 Background: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL15RaFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase 1b data in BCG-naïve patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. Pembrolizumab was approved in 2020 with a 41% complete response (CR) rate in a single arm phase 2 trial of 96 patients. We report data on 160 subjects from an open-label, 3 cohort multicenter study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825). Methods: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A (CIS) is incidence of CR of CIS at any time. The primary endpoint for Cohort B (Papillary) is disease-free rate (DFS) at 12 months. Results: To date, we enrolled 160 patients (83 CIS, 77 Papillary). In the overall population, median age is 72.3 years, 81% male, with mean number of prior TURBT = 4. Median number of prior BCG doses = 12. CIS patients have a CR rate of 71% (59/83), with a mediation duration of CR of 24.1 months in responders; 91% avoided cystectomy and 96% 24 month bladder cancer specific progression free survival (defined as progression to MIBC). Papillary patients have a 57% 12 month DFS rate, 48% 24 month DFS rate, and 95% avoided cystectomy. Median time to cystectomy in responders (N = 4) is 12.9 months versus 7.8 in non-responders (N = 8) for a 5.1 month delay in cystectomy. PK data shows no systemic levels of N-803; activity is confined to the bladder. Low grade treatment related AEs (grade 1-2) include dysuria (22%), pollakiurua (19%), hematuria (18%), fatigue (16%), and urgency (12%), all other AEs were seen at 7% or less. No treatment related grade 4 or 5 AE were seen. No SAE's were considered treatment related. No immune related SAE's have been seen. Conclusions: In 160 patients with BCG-unresponsive NMIBC, there is a 99% bladder cancer specific overall survival at 2 years. In CIS patients 71% CR rate with 24.1 months median duration of response, and 53% DFS rate at 18 months in Papillary disease. Cystectomy was avoided in over 90% of patients with 2 years of follow-up. The efficacy and safety profile of N-803+BCG exceeds that of other available intravesical and systemic options for BCG-unresponsive NMIBC. Clinical trial information: NCT03022825.

Excessive iodine in iodized household salt in Nepal.

Iodine is an essential trace element required for the regulation of physiological processes involving the thyroid gland. However, inadequate and excessive intake of iodine are responsible for health problems, such as iodine deficiency disorders, hypothyroidism, hyperthyroidism, thyroiditis, thyroid papillary cancer, and thyrotoxicosis. The Universal Salt Iodization (USI) program has become successful in providing supplemental iodine at the population level globally. Packaging quality, fortification level, and transportation and storage conditions of iodized salt determine the availability of iodine. Previous studies have reported severe health issues caused by excessive iodine intake after the implementation of the USI program. To understand the levels of iodine, we collected 2117 household salt samples from seven districts of Nepal and tested them for iodine content; among them, 98.1% were iodized. Overall median concentration of iodine was 53.9ppm (range: 43.5-61.4ppm). The majority (67.2%) of samples had iodine in the range of 45-75ppm. Approximately 0.9% of samples had inadequate, 13.3% contained adequate, and 83.9% had excessive iodine than the World Health Organization-recommended value. Iodine content varied among the sampling districts and seasons, to some extent. Our study confirmed that iodized salt is widely used in Nepal and is excessively iodized. Excessive intake of iodine through iodized salt requires further attention by policy makers. The iodine level may need adjustment to address the health impact.