Gemcitabine plus platinum-based chemotherapy in combination with bevacizumab for kidney metastatic collecting duct and medullary carcinomas: Results of a prospective phase II trial (BEVABEL-GETUG/AFU24).

BACKGROUND: Renal medullary carcinoma (RMC) and collecting duct carcinoma (CDC) are rare entities with a poor outcome. First-line metastatic treatment is based on gemcitabine + platinum chemotherapy (GC) regimen but retrospective data suggest enhanced anti-tumour activity with the addition of bevacizumab. Therefore, we performed a prospective assessment of the safety and efficacy of GC + bevacizumab in metastatic RMC/CDC. METHODS: We conducted a phase 2 open-label trial in 18 centres in France in patients with metastatic RMC/CDC and no prior systemic treatment. Patients received bevacizumab plus GC up to 6 cycles followed, for non-progressive disease, by maintenance therapy with bevacizumab until progression or unacceptable toxicity. The co-primary end-points were objective response rates (ORRs) and progression-free survival (PFS) at 6 months (ORR-6; PFS-6). PFS, overall survival (OS) and safety were secondary end-points. At interim analysis, the trial was closed due to toxicity and lack of efficacy. RESULTS: From 2015 to 2019, 34 of the 41 planned patients have been enroled. After a median follow-up of 25 months, ORR-6 and PFS-6 were 29.4% and 47.1%, respectively. Median OS was 11.1 months (95% confidence interval [CI]: 7.6-24.2). Seven patients (20.6%) discontinued bevacizumab because of toxicities (hypertension, proteinuria, colonic perforation). Grade 3-4 toxicities were reported in 82% patients, the most common being haematologic toxicities and hypertension. Two patients experienced grade 5 toxicity (subdural haematoma related to bevacizumab and encephalopathy of unknown origin). CONCLUSION: Our study showed no benefit for bevacizumab added to chemotherapy in metastatic RMC and CDC with higher than expected toxicity. Consequently, GC regimen remains a therapeutic option for RMC/CDC patients.

[Collecting duct carcinoma and renal medullary carcinoma in the age of new therapies]. / Tumeurs de Bellini et carcinomes médullaires rénaux à l'ère des nouvelles thérapies.

Collecting duct carcinoma (also known as Bellini tumour) and renal medullary carcinoma are two extremely rare and aggressive renal cancers. They are both less responsive to conventional treatments used in clear cell renal carcinoma. There are very few studies evaluating their optimal management and currently, at the metastatic stage, polychemotherapy based on platinum salts remains the most widely used. The emergence of new treatments such as anti-angiogenic TKIs, immunotherapy or treatments targeting specific genetic abnormalities, opens up a new field of possibilities in the management of these cancers. The evaluation of the response to these treatments is therefore essential. In this article, we will review the status of their management and the various studies that have evaluated recent treatments in these two cancers.

How does nintedanib overcome cancer drug-resistant mutation of RET protein-tyrosine kinase: insights from molecular dynamics simulations.

Targeted drug therapies represent a therapeutic breakthrough in the treatment of human cancer. However, the emergence of acquired resistance inevitably compromises therapeutic drugs. Rearranged during transfection (RET) proto-oncogene, which encodes a receptor tyrosine kinase, is a target for several kinds of human cancer such as thyroid, breast, and colorectal carcinoma. A single mutation L881V at the RET kinase domain was found in familial medullary thyroid carcinoma. Nintedanib can effectively inhibit the RET L881V mutant, whereas its analog compound 1 is unable to combat this mutant. However, the underlying mechanism was still unexplored. Here, molecular dynamics (MD) simulations, binding free energy calculations, and structural analysis were performed to uncover the mechanism of overcoming the resistance of RET L881V mutant to nintedanib. Energetic analysis revealed that the L881V mutant remained sensitive to the treatment of nintedanib, whereas it was insensitive to the compound 1. Structural analysis further showed that the distribution of K758, D892, and N879 network had a detrimental effect on the binding of compound 1 to the L881V mutant. The obtained results may provide insight into the mechanism of overcoming resistance in the RET kinase.

Combination Therapy With Bortezomib in Renal Medullary Carcinoma: A Case Series.

BACKGROUND: Renal medullary carcinoma (RMC) is a very rare, aggressive neoplasm occurring almost exclusively in adolescents and young adults with sickle cell trait. Given the rare nature of this tumor, accounting for less than 0.5% of all renal carcinomas, most of the published data on therapies is from case reports and small case series, and current treatments are insufficient, with most patients succumbing to their disease in months. We report our experience with a cytotoxic chemotherapy regimen consisting of platinum-based therapy, doxorubicin, and bortezomib. METHODS: Three patients with metastatic RMC at a single institution were treated off-label with a perioperative chemotherapy regimen for 4 cycles of 2 alternating regimens: regimen A consisting of cisplatin, doxorubicin, and bortezomib; regimen B consisting of carboplatin, paclitaxel, and gemcitabine. A radical nephrectomy was performed on all patients. Surveillance imaging was performed on all patients to assess response and disease burden. Patients received up to 12 months of maintenance therapy with everolimus. RESULTS: Three African American patients - 2 males and 1 female aged 14, 28, and 31 - with sickle cell trait and metastatic disease were treated with this regimen. The median follow-up was 18 months. All had resection of the primary tumor - 2 patients after receiving neoadjuvant therapy, and one patient underwent resection prior to referral. All 3 patients achieved complete responses based on imaging, 2 of which lasted for 12 months, and another is still in remission over 7 years after diagnosis. CONCLUSIONS: This regimen of alternating cycles of platinum-based chemotherapy with bortezomib appeared to be active against RMC and was generally well-tolerated. Given the extremely rare nature of this disease and dismal prognosis, new treatment modalities should be pursued, and whenever possible, patients should be enrolled in a clinical trial. We propose that a multiinstitution clinical trial of this regiment may be warranted.

Chemotherapy Negates the Effect of SDF1 mRNA to Distant Metastasis and Poor Overall Survival in Breast Cancer Patients.

OBJECTIVE: Investigate the effect of SDF1a, nuclear, and cytoplasmic CXCR4 breast cancer tissue on metastasis and overall survival in patients with complete-chemotherapy and no-chemotherapy. METHODS: Cohort ambidirectional design was employed with survival analysis that followed the patient's diagnosis until obtaining the outcome, distant metastasis, or death. We analyzed samples in three groups (all-patient, no-chemotherapy, and complete-chemotherapy groups).  Breast cancer cell nuclear and cytoplasm expressions of CXCR4 protein were examined using immunohistochemistry. Amplification of mRNA SDF1a of breast cancer tissue was examined using rtPCR on 131 samples from the same initial paraffin block. RESULTS: In the distant metastasis and Overall Survival (OS) analysis, there was no correlation between cytoplasmic and nuclear CXCR4 in all-patient, no-chemotherapy, and complete-chemotherapy groups. SDF1a was significantly correlated to shorter distant metastasis and poor OS in the all-patient (p=0.004 and p=0.04, respectively) and no-chemotherapy group (p=0.008 and p=0.026, respectively). However, in the complete-chemotherapy group, SDF1a was not correlated to either metastasis (p=0.527) or OS (p=0.993), advanced stage demonstrated a strong association on shorter distant metastatic in no-chemotherapy (p=0.021) and complete-chemotherapy group (p=0.004) and also poor OS in both groups (p=0.006 and p=0.002, respectively). The hormone receptor showed a protective effect on the no-chemotherapy group's OS (p= 0.019). Meanwhile, not undergoing chemotherapy was associated with poor OS in the all-patient group (p= 0.011). CONCLUSION: SDF1a mRNA amplification has a significant correlation with the occurrence of metastasis and OS in all-patient and no-chemotherapy group. Undergoing chemotherapy negates the effect of SDF1a for distant metastasis and OS.

Male mammary gland development after apatinib therapy in advanced gastric cancer: A case report.

RATIONALE: Most gastric cancer patients are diagnosed at mid- to late-stage and lose the chance of radical surgery, medical treatment is especially important to prolong the survival of patients. Apatinib mesylate, which is a small molecule vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, could be used as antiangiogenesis therapy for gastric cancer. PATIENT CONCERNS: A 67-year-old man sought medical care for upper abdominal discomfort. DIAGNOSIS: The patient was diagnosed as mixed medullary differentiated gastric adenocarcinoma, and immunohistochemistry suggested HER-2 (2+). INTERVENTIONS: The patient received chemotherapy consisting of oxaliplatin combined with S-1 as first-line treatment, and targeted therapy with apatinib mesylate as second-line treatment. OUTCOMES: After 4 months of first-line chemotherapy, the patient received apatinib treatment immediately at a dose of 500 mg/d orally and died of cardiac arrest with 8.5 months of overall survival. During this period of targeted therapy with apatinib mesylate, this male patient suffered mammary gland development besides other common adverse reactions. LESSONS: This case report is the first to report the case of male mammary gland development after oral apatinib.

Novel renal medullary carcinoma cell lines, UOK353 and UOK360, provide preclinical tools to identify new therapeutic treatments.

Renal medullary carcinoma (RMC) is a rare, aggressive disease that predominantly afflicts individuals of African or Mediterranean descent with sickle cell trait. RMC comprises 1% of all renal cell carcinoma diagnoses with a median overall survival of 13 months. Patients are typically young (median age-22) and male (male:female ratio of 2:1) and tumors are characterized by complete loss of expression of the SMARCB1 tumor suppressor protein. Due to the low incidence of RMC and the disease's aggressiveness, treatment decisions are often based on case reports. Thus, it is critical to develop preclinical models of RMC to better understand the pathogenesis of this disease and to identify effective forms of therapy. Two novel cell line models, UOK353 and UOK360, were derived from primary RMCs that both demonstrated the characteristic SMARCB1 loss. Both cell lines overexpressed EZH2 and other members of the polycomb repressive complex and EZH2 inhibition in RMC tumor spheroids resulted in decreased viability. High throughput drug screening of both cell lines revealed several additional candidate compounds, including bortezomib that had both in vitro and in vivo antitumor activity. The activity of bortezomib was shown to be partially dependent on increased oxidative stress as addition of the N-acetyl cysteine antioxidant reduced the effect on cell proliferation. Combining bortezomib and cisplatin further decreased cell viability both in vitro and in vivo that single agent bortezomib treatment. The UOK353 and UOK360 cell lines represent novel preclinical models for the development of effective forms of therapy for RMC patients.

[Efficacy and safety of vandetanib on advanced medullary thyroid carcinoma: single center result from a phase â ¢ study].

Objective: There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib,a novel multitargeted receptor tyrosine kinase inhibitor, has previously shown antitumor activity in phase Ⅱ studies of patients with advanced MTC. This study was to evaluate the efficacy and the safety of vandetanib on advanced MTC. Methods: This study was an open, international multi-center phase Ⅲ clinical trial and the study number was NCT01298323. The single-center study was a sub-group analysis of the international study, which was conducted on 9 pathologically confirmed advanced MTC patients by Cancer Hospital Chinese Academy of Medical Sciences between March 2012 and October 2017. Vandetanib (300 mg) was orally administered daily till death or withdrawal. The efficacy was evaluated according to RECIST criteria and the adverse events were evaluated according to NCI criteria. Results: The objective response rate was 3/9,and the disease control rate was 4/9. The median progression-free survival was 44 months. All patients who had the elevated levels of calcitonin (CTN) and carcino-embryonic antigen (CEA) before treatment began to show the decreases in the level of CTN and CEA after 3 months and later showed again the increases in the levels of both tumor markers with tumor progression. By ROC curve analysis, CTN was of statistically significance(P<0.05, 95%CI 0.558-0.834), but CEA was not(P>0.05). Adverse events were generally mild (grade 1 or 2),including hypertension (9 cases),skin rash (9 cases), and diarrhea (6 cases). Two patients developed grade 3 elevation of serum glutamate pyruvate transaminase and one patient developed grade 3 elevation of drug-related bowel disease. No grade 4 drug-related adverse event occurred. Conclusions: Vandetanib is effective and well tolerated for patients with locally advanced or metastatic MTC who have no chance for surgery. This indicates the increase of CTN is clinically relevant to disease progression, but the number of patients are extremely low, and, therefore further research is needed. Long-term use of vandetanib may cause resistance.

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition.

Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one SMARCB1 allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of SMARCB1 for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC. Inhibition of the UPS caused a G2/M arrest due to constitutive accumulation of cyclin B1. These observations extend across cancers that harbor SMARCB1 loss, which also require expression of the E2 ubiquitin-conjugating enzyme, UBE2C. Our studies identify a synthetic lethal relationship between SMARCB1-deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.

Rare complications of multikinase inhibitor treatment

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Anlotinib for the Treatment of Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer.

BACKGROUND: The prognosis of advanced or metastatic medullary thyroid carcinoma (MTC) is poor, and there are few therapeutic options. Anlotinib has previously shown promising antitumor activity on MTC in preclinical models and a Phase I study. This Phase II clinical trial was devised to confirm the antitumor activity of anlotinib in patients with advanced or metastatic MTC. METHODS: Patients with unresectable locally advanced or metastatic MTC received once daily oral anlotinib 12 mg, two weeks on/one week off, until disease progression, death, unacceptable toxicity, or withdrawal of consent for any reason. The dose was adjusted on the basis of observed toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Fifty-eight patients received anlotinib treatment. The primary endpoint PFS has not yet been reached at the time of analysis. On the basis of investigator assessments, 56.9% of patients experienced a partial response. PFS rate at 48 weeks was 85.5%. Forty-five patients had a ≥50% decrease in serum calcitonin concentration from baseline. The most common adverse events were hand-foot syndrome, hypertriglyceridemia, cholesterol elevation, fatigue, and proteinuria. CONCLUSIONS: Anlotinib demonstrated a durable antitumor activity with a manageable adverse event profile in locally advanced or metastatic MTC.

The antiproliferative effect of pasireotide LAR alone and in combination with everolimus in patients with medullary thyroid cancer: a single-center, open-label, phase II, proof-of-concept study.

PURPOSE: Medullary thyroid cancer (MTC) is a neuroendocrine tumour of the thyroid C cells. Pasireotide, a multi-receptor targeted somatostatin analogue, and everolimus, an inhibitor of mTOR, showed antitumour properties in neuroendocrine tumours. Aim of this study was to evaluate pasireotide alone and in combination with everolimus in patients with MTC. METHODS: Patients with progressive metastatic or persistent postoperative MTC received pasireotide LAR 60 mg/m for at least 6 months. Patients exhibiting progressive disease received everolimus 10 mg/d as combination therapy. Primary endpoint was progression free survival (PFS). Secondary endpoints included, overall survival, objective response rates, change in circulating markers, safety. Study registration no. NCT01625520. RESULTS: Nineteen consecutive patients were enrolled. Median follow-up was 31 months. Median PFS with pasireotide was 36 months (95% CI: 19.5-52.5). Nine patients (47%) had tumour progression: seven of them started everolimus in combination with pasireotide, achieving a median PFS of 9.0 months (95% CI: 0-21.83). Five of them (71%) had further tumour progression, one objective response (14.3%), one stopped treatment because of pulmonary embolism. Pasireotide alone and with everolimus was safe and required withdrawal only in one case. Diarrhoea and hyperglycaemia were the most frequent adverse events with pasireotide (grade 3 in 5.3% each). Hyperglycaemia was the most frequent grade 3 toxicity with the combination therapy (28.6%). CONCLUSIONS: Pasireotide therapy shows antiproliferative effects in persistent postoperative MTC suggesting further investigation on larger series of patients. In progressive MTC lesions, the combination pasireotide plus everolimus may be of benefit. Both schemes were safe and well tolerated.

Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib.

Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression.Results: Seventeen patients [8 male, age 13 (9-17)* years] enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in 9 patients. Best response was partial response in 10, stable disease in 6, and progressive disease in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression-free survival (PFS) was 6.7 years [95% confidence interval (CI): 2.3 years-undefined] and 5-year overall survival (OS) was 88.2% (95% CI: 60.6%-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression-free survival was 6.7 years (95% CI: 3.1-undefined) and 5-year overall survival was 93.8% (95% CI: 63.2%-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)].Conclusions: This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib. Clin Cancer Res; 24(4); 753-65. ©2017 AACR.

Rare complications of multikinase inhibitor treatment.

OBJECTIVE: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. SUBJECTS AND METHODS: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. RESULTS: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. CONCLUSIONS: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma.

BACKGROUND: Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up. PATIENTS AND METHODS: EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported. RESULTS: Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis. CONCLUSION: The secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib. TRIAL REGISTRATION NUMBER: NCT00704730.

Predictive role of PD-L1 expression in the response of renal Medullary carcinoma to PD-1 inhibition.

BACKGROUND: Renal medullary carcinoma is one of the rarest malignancies arising from the kidney. Despite various aggressive therapeutic regimens, mortality remains significantly high (95%) with a median overall survival of 5 months. Furthermore, the scarcity of this malignancy renders randomized clinical trials impossible. We examined the expression of programmed death ligand 1 (PD-L1) in two new renal medullary carcinoma cases, investigated their responses to the PD-L1 inhibitor nivolumab and explored the predictive role of the rate of PD-L1 expression in such response. CASE PRESENTATION: Two African-American patients (male and female) with sickle cell trait who presented to our center with hematuria and flank pain were diagnosed with metastatic renal medullary carcinoma. PD-L1 was expressed at rate of 25% and 60% in patient 1 and 2 respectively. Following nephrectomy, they were started on nivolumab. Patient 1 initially responded to the treatment with regression of metastatic lesions. However, following this early response, patient 1 who has been receiving nivolumab for more than 15 months, was noted to have a disease progression. Patient 2 had disease progression after 3 months of nivolumab therapy. CONCLUSIONS: Although PD-L1 is expressed in these patients with renal medullary carcinoma, response to nivolumab was only observed in patient 1 whose tumor has the lowest rate of PD-L1 expression. This may suggest that in RMC, response to PD-L1 inhibition therapy may not correlate with the rate of PD-L1 expression.

Genomic Characterization of Renal Medullary Carcinoma and Treatment Outcomes.

BACKGROUND: Renal medullary carcinoma (RMC) is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait; outcomes are poor despite treatment. Identifying molecular features of this tumor could provide biologic rationale for novel targeted therapies. The objective was to report on clinical outcomes with systemic therapy and characterize molecular features. PATIENTS AND METHODS: This was a retrospective analysis on 36 patients given a pathologic diagnosis of RMC at one institution from 1995 to 2015. Tumors were analyzed for expression of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through immunohistochemistry and for genomic alterations with fluorescence in situ hybridization for SMARCB1, and targeted next-generation sequencing. Time from initiation of therapy to progression of disease and overall survival were calculated using the Kaplan-Meier method. RESULTS: The median age in the cohort was 28 (range, 12-72) years, and all patients tested had sickle cell trait. Overall survival was 5.8 months (95% confidence interval [CI], 4.1-10.9) and for 12 patients who received platinum-based therapy, median progression-free survival was 2.5 months (95% CI, 1.2-not reached). A total of 10 available tumors underwent analysis with fluorescence in situ hybridization for SMARCB1; this revealed loss of heterozygosity with concurrent translocation in 8, and biallelic loss in 2. Next-generation targeted sequencing showed no recurring mutations. CONCLUSIONS: Outcome was generally poor in this cohort of patients with RMC. Uniform loss of SMARCB1 is a key molecular feature in this tumor and mechanism of loss appears to be mostly through translocations and deletions.

Lenvatinib induces early tumor shrinkage in patients with advanced thyroid carcinoma.

Although advanced thyroid carcinoma patients who cannot be cured by conventional therapy have lacked effective treatment, multitargeted tyrosine kinase inhibitors have recently become available. Phase 3 trials of lenvatinib showed a median time to objective response of 2 (95 % confidence interval (CI) 1.9-3.5) months, demonstrating that shrinks tumors rapidly. The phenomenon of immediate tumor shrink is known as early tumor shrinkage (ETS) which is related to clinical outcome in other malignancies. However, precisely when within 8 weeks lenvatinib starts to affect tumors remains unclear. In tumors near the carotid arteries, trachea, or esophagus, a rapid therapeutic effect can induce fistula formation or arterial bleeding. To prevent such treatment-emergent serious adverse events (SAE), early imaging evaluation seems to be very important. In this study, the point in time when lenvatinib started to shrink tumors was retrospectively investigated. The subjects were 16 patients who started lenvatinib administration between May and August 2015. Tumor size was evaluated by computed tomography (CT) scans frequently within the first 8 weeks according to the Response Evaluation Criteria In Solid Tumors (RECIST) guideline. Initial tumor response was defined as ≥ 10% tumor reduction. Serum thyroglobulin (Tg) level was monitored in 8 differentiated thyroid carcinoma (DTC) without TgAb patients. At the first evaluation, 13 patients (83.3 %) showed tumor reduction and that decreased with time. Thirteen patients (83.3 %) showed >10 % tumor reduction within 8 weeks. In all DTC patients, serum Tg level was markedly decreased. In conclusion, lenvatinib immediately shrinks tumors, the so-called ETS phenomenon. Therefore, careful attention should be paid to fistula formation from the early phase.

Genetics of medullary thyroid cancer: An overview.

Medullary thyroid carcinoma (MTC) represents 3-5% of thyroid cancers. 75% is sporadic and 25% is the dominant component of the hereditary multiple endocrine neoplasia (MEN) type 2 syndromes. Three different subtypes of MEN2, such as MEN2A, MEN2B, and Familial MTC (FMTC) have been defined, based on presence or absence of hyperparathyroidism, pheocromocytoma and characteristic clinical features. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC, but there are many other mutational patterns involved. In MEN2A, Codon 634 in exon 11 (Cys634Arg), corresponding to a cysteine in the extracellular cysteine-rich domain, is the most commonly altered codon. Many other mutations include codons 611, 618, 620. In the genetical testing of RET mutations in MTCs, Next-Generation Sequencing (NGS) is taking an increasingly important role. One of the most important benefit is the comprehensive analysis of molecular alterations in MTC, which allows rapidly to select patients with different risk levels. There is a difference in miRNA expression pathway between sporadic and hereditary MTCs. Among sporadic cases, expression of miR-127 was significantly lower in those who harbor somatic RET mutations than those with wild-type RET. CDKN1B mutations are associated with many clinical pictures of cancers, such as MEN4. V109G polymorphism is associated with sporadic MTCs negative for RET mutations, and might influence the clinical course of the patients affected by MTC. Although surgery (i.e. total thyroidectomy with neck lymph node dissection) is the elective treatment for MTCs, about 80% of patients have distant metastases at diagnosis and in this cases surgery is not enough and an additional treatment is needed. Interesting results come from two large phase III clinical trials with two targeted tyrosine kinase inhibitors (TKIs), vandetanib and cabozantinib. CONCLUSIONS: New genetical testings and therapeutical approaches open new perspectives in MTC management.