Role of Circulating Tumor Cells in Determining Prognosis in Metastatic Breast Cancer.

Dinesh Chandra DovalBackground Circulating tumor cells (CTCs) in the peripheral blood may play a major role in the metastatic spread of breast cancer. This study was conducted to assess the role of CTCs to determine the prognosis in terms of survival in metastatic breast cancer patients. Methods This prospective study of 36 patients was conducted at the Hospital from April 2016 to May 2018. Details of each patient related to the demographic profile, tumor type, treatment, and follow-up information were recorded. The number of CTCs in the peripheral blood was measured by Celsee PREP 400 sample processing system and Celsee Analyzer imaging station. Results There was a positive correlation between the number of site of metastasis with number of CTCs ( p -value < 0.001). In the patients with clinical/partial response, a significant reduction in the number of CTCs after 1 month of therapy was observed ( p -value = 0.003). When the number of CTCs at baseline and 6 months were compared with the positron emission tomography response at 6 months, a statistically significant difference in CTCs in patients having partial response after 6 months was observed ( p -value = 0.001). On comparison with the responder groups, a statistically significant reduction in CTCs at baseline and 6 months was observed ( p -value = 0.001). Patients with CTCs less than 5 and more than or equal to 5 after 1 month of treatment had a mean progression-free survival of 11.1 months and 7.5 months ( p -value = 0.04) and a mean overall survival of 11.6 and 9.6 months ( p -value = 0.08), respectively. Conclusion Assessment of CTCs provides a more quantifiable response than radiographic evaluation and at a much earlier time point and is also a better predictor of survival.

Palbociclib plus letrozole as treatment for postmenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer for whom letrozole therapy is deemed appropriate: An expanded access study in Australia and India.

AIM: Palbociclib was approved in the United States in 2015 to treat estrogen receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This study evaluated outcomes and safety in patients treated with palbociclib in Australia and India with hormone receptor-positive (HR+)/HER2- ABC before palbociclib became commercially available. METHODS: Postmenopausal women (≥18 years) with HR+/HER2- ABC who were appropriate candidates for letrozole therapy received palbociclib 125 mg once daily for 21 days followed by 7 days off, and letrozole 2.5 mg once daily (continuous). Safety, tumor response, and patient-reported outcomes (Australian cohort) were evaluated. RESULTS: In total, 252 patients received palbociclib plus letrozole (Australia, n = 152; India, n = 100). More patients in the Australian versus Indian cohort had received prior chemotherapy (advanced/metastatic setting: 45.9% vs. 32.0%), endocrine therapy (advanced/metastatic setting: 63.2% vs. 54.3%), and advanced/metastatic therapies (61.8% vs. 31.0%). The most frequently reported all-grade palbociclib-related treatment-emergent adverse events were neutropenia (66.7%), fatigue (35.3%), and stomatitis (26.6%); grade 3/4 neutropenia was reported as palbociclib-related in 62.7% of patients. Febrile neutropenia was reported in six patients (2.4%). Eight patients (3.2%) discontinued because of an adverse event. The objective response rate was 19.4% (95% CI, 14.7%-24.9%) overall and 2.3% in Australian patients with ≥2 lines of prior therapy for metastatic disease. Patient-reported quality of life scores were maintained throughout the study. CONCLUSIONS: In an expanded access setting in Australia and India, palbociclib plus letrozole was well tolerated in patients with HR+/HER2- ABC, with a safety profile consistent with previous reports.

Colonic polyp-rare site of metastasis from primary lung carcinoma: Clinical presentations and outcome.

Although majority of lung cancers have distant metastasis at the time of initial diagnosis, colonic metastases are extremely rare. This report presents a rare clinical case which presented with lower limb deep vein thrombosis and found to have colon polyp incidentally detected while evaluating for occult blood positive in stool. Histopathology of the polyp was suggestive of lung primary and on further evaluation PET scan was suggestive of left lung mass with widespread distant metastasis.

Detection of human papillomavirus infection in oral cancers reported at dental facility: assessing the utility of FFPE tissues.

Incidence of human papillomavirus (HPV)-associated oral cancers is on the rise. However, epidemiological data of this subset of cancers are limited. Dental hospital poses a unique advantage in detection of HPV-positive oral malignancies. We assessed the utility of formalin-fixed paraffin-embedded (FFPE) tissues, which are readily available, for evaluation of high-risk HPV infection in oral cancer. For protocol standardization, we used 20 prospectively collected paired FFPE and fresh tissues of histopathologically confirmed oral cancer cases reported in Oral Medicine department of a dental hospital for comparative study. Only short PCRs (~ 200 bp) of DNA isolated using a modified xylene-free method displayed a concordant HPV result. For HPV analysis, we used additional 30 retrospectively collected FFPE tissues. DNA isolated from these specimens showed an overall 23.4% (11/47) HPV positivity with detection of HPV18. Comparison of HPV positivity from dental hospital FFPE specimens with overall HPV positivity of freshly collected oral cancer specimens (n = 55) from three cancer care hospitals of the same region showed notable difference (12.7%; 7/55). Further, cancer hospital specimens showed HPV16 positivity and displayed a characteristic difference in reported sub-sites and patient spectrum. Overall, using a xylene-free FFPE DNA isolation method clubbed with short amplicon PCR, we showed detection of HPV-positive oral cancer in dental hospitals.

Multicentric real world evidence with palbociclib in hormone positive HER2 negative metastatic breast cancer in Indian population.

The combination of cyclin dependent kinase 4/6 inhibitors with endocrine therapy is the standard therapy in hormone receptor positive HER-2 negative metastatic breast cancer (HR+/HER2- MBC). Several randomized trials have shown the benefits of this combination, however, real world evidence in the Indian patients is warranted. The present study reports the largest real world multicentric data from Indian population on the use of Palbociclib in HR+/HER2- MBC. A multicentric study on the HR+/HER2- MBC patients who received palbociclib with hormonal agent (Aromatase inhibitors/Fulvestrant) between February 2017 and May 2020 was conducted. Clinical and demographic information and survival data was retrieved from the Hospital medical records. Among a total of 188 patients, 57% patients were premenopausal and 17% patients had bone only disease. Altogether, 115 (61%) patients received palbociclib with Aromatase inhibitors in the first line whereas 73 (39%) patients received it in the second line with Fulvestrant. The median follow up period with advanced disease was 13 months. The median progression free survival in the first line and second line was 20.2 months and 12 months, respectively (p-value < 0.0001). The objective response rate was 80% and 47.9% in first and second lines, respectively. Dose interruptions/ discontinuation were done in 14.9% and 2.7% patients in the first and second lines, respectively. In terms of toxicity, 10% patients had grade 3-4 adverse events. The present real world data of the use of palbociclib in Indian population suggests similar effectiveness to previously published real world evidences and has been adapted as the standard of care in the first and second line treatment of HR+/HER2- MBC.

IAP Chemotherapy Regimen Is a Viable and Cost-effective Option in Children and Adolescents With Osteosarcoma: A Comparative Analysis With MAP Regimen on Toxicity and Survival.

BACKGROUND: Cisplatin and doxorubicin are integral components of chemotherapy regimens in the treatment of osteosarcoma. Choice of third agent high-dose methotrexate (HDMTX) or an alkylating agent such as ifosfamide is debatable. The present study compared the impact of MAP (HDMTX-doxorubicin-cisplatin) and IAP (ifosfamide-doxorubicin-cisplatin) chemotherapy regimens on toxicity and survival in children and adolescents with osteosarcoma. MATERIALS AND METHODS: This was a retrospective study including patients 18 years and younger with osteosarcoma during the study period. Clinical, demographic, chemotherapy regimen, and surgical details and treatment-related toxicity were retrieved from hospital medical records. Prognostic factors affecting overall survival (OS) and event-free survival (EFS) were analyzed. RESULTS: Among 102 patients included in the study, 59 (57.8%) and 43 (42.2%) patients were treated with MAP and IAP regimens, respectively. Two groups were comparable in terms of pretreatment characteristics and surgical treatment. Overall, 95.9% patients underwent limb salvage surgery. There was a statistically increased incidence in supportive care admissions and delay in starting the next cycle of chemotherapy in the MAP group. Among the MAP cohort, the 5-year OS and EFS were 62% and 55% compared with 47% and 44%, respectively, in the IAP cohort (P=0.143 and 0.316, respectively). On univariate and multivariate analyses, statistically significant factors affecting EFS of the whole group included tumor size, stage, site of metastasis, histologic necrosis, and type of surgery. CONCLUSIONS: OS and EFS with both regimens were similar. However, the MAP regimen was associated with a statistically significant increase in incidence of supportive care admissions, delay in next cycle of chemotherapy, and predicted higher cost of treatment.

Application of the Kaiser score to increase diagnostic accuracy in equivocal lesions on diagnostic mammograms referred for MR mammography.

INTRODUCTION: We aimed to interpret MR mammography (MRM) using the Kaiser scores for equivocal or inconclusive lesions on mammography (MG). METHODS: Retrospective IRB-approved evaluation of 3623 MG for which MRM was deployed as a problem-solving tool, after inclusion-exclusion criteria were met. Three readers with different levels of experience assigned a final score from 1 to 11 based on the previously established tree classification system. Area under the curve (AUC) derived from receiver operating characteristic (ROC) analysis was used to determine the overall diagnostic performance for all lesions and separately for mass and non-mass enhancement. Sensitivity, specificity, and likelihood ratio values were obtained at different cut-off values of >4, > 5, and > 8 to rule in and rule out malignancy. RESULT: Histopathology of 183 mass and 133 non-mass enhancement (NME) lesions show benign etiology in 95 and malignant in 221. The AUC was 0.796 [0.851 for mass and 0.715 for NME]. Applying the Kaiser score upgraded 202 lesions with correct prediction in 77 %, and downgraded 28 lesions with correct prediction in 60.8 %. Using a score <5 instead of <4 to rule out malignancy improved our diagnostic ability to correctly identify 100 % benign lesions. Applying Kaiser score correctly downgraded 60.8 % (17/28) lesions; thus avoiding biopsies in these. Using a high cut-off value>8 to rule-in malignancy, we correctly identified 59.7 % of lesions with 80 % specificity and positive likelihood ratio of 3. CONCLUSION: The Kaiser score has clinical translation benefits when used as a problem-solving tool for inconclusive MG findings.

Prognostic role of microRNA 182 and microRNA 18a in locally advanced triple negative breast cancer.

BACKGROUND: The study assessed the epigenetic regulation and the role of microRNA (miR) expression in locally advanced triple negative breast cancers (TNBC) and comparison with the clinico-pathological variables and survival. METHODS: Fifty patients of locally advanced TNBC during the period 2011-2013 were included. Expression level of test microRNA (miR-182 and miR-18a) was determined using Taqman quantitative Real time polymerase chain reaction (qRT-PCR) from formalin fixed paraffin embedded biopsy blocks. Clinical and demographic information and survival data was retrieved from the Hospital medical records. RESULTS: An improved clinical complete response (cCR) was observed in patients with age ≥ 45 years (80%), premenopausal status (70%), tumor size < 6 cms (80%), nodal status N0-N1 (95%) and grade II-III tumor (80%). A statistically significant correlation was observed on comparison of cCR with menopausal status (p-value 0.020), T category (p-value 0.018) and the clinical nodal status (p-value 0.003). pCR also correlated with clinical nodal status (p-value 0.008). Epigenetically, miR-18a under expression (< 8.84) was most commonly associated with tumor size < 6 cms (76.7%), clinical nodal status N0-N1 (90%), cCR (60%) and pCR (53.3%). A similar trend was observed with miR-182. Statistical significance was observed with T category (p-values 0.003 and 0.004), clinical nodal status (p-values 0.001 and 0.001), clinical response (p-values 0.002 and 0.002) and pathological response (p-values 0.007 and 0.006) with respect to miR-18a and miR-182, respectively. Also, the menopausal status significantly correlated with the miR-182 expression (p-value 0.009). miR-182 overexpression (≥ 6.32) was not observed in any of the postmenopausal patients. A univariate cox proportional hazard regression model also showed statistical interactions (p-values <0.004). CONCLUSION: miR-182 and miR-18a overexpression correlates with worse clinical and pathological tumor characteristics in locally advanced TNBC and hence could be used to predict the outcomes and prognosis in these patients.

Role of 18F-Flurodeoxyglucose Positron-Emission Tomography/Computed Tomography in the Evaluation of Early Response to Neoadjuvant Chemotherapy in Patients with Locally Advanced Triple-Negative Breast Cancer.

BACKGROUND: Response evaluation in locally advanced breast cancer is done through different methods ranging from clinical examination to magnetic resonance imaging, however evaluation with positron-emission tomography/computed tomography (PET/CT) in now being incorporated for the response evaluation. The aim of the present study is to correlate response to neoadjuvant chemotherapy (NACT) with PET/CT scan. MATERIALS AND METHODS: The present study is a retrospective analysis of 30 locally advanced, triple-negative breast cancer patients. PET/CT scan was done pretreatment and post three and six cycles of NACT and was correlated with pathologic complete response (pCR). Responding disease was considered when there was at least a 50% reduction in the longest diameter. RESULTS: The median pretreatment size of the breast lesion in CT scan was 3.9 ± 2.3 cm (2-12 cm) and maximum standardized uptake value (SUVmax) on PET/CT was 8.5 ± 5.5 (2.9-24). Among the responders, the median decrease in size of lesion was 3.2 ± 1.3 cm and median reduction in SUV of the tumor among was -8.1 ± 5.4 and was statistically significant when compared with nonresponders (P < 0.001). CT scan has 66% accuracy and PET has 82% accuracy at post three cycles NACT in predicting the pathological response. PET/CT had higher sensitivity and specificity when compared with CT findings alone in response evaluation. CONCLUSION: PET/CT scan can be considered as a sensitive tool for predicting pCRs and further larger trials are required to establish these findings.

A multi-institutional real world data study from India of 3453 non-metastatic breast cancer patients undergoing upfront surgery.

The present analysis reports the clinical, pathological, treatment profile and overall survival (OS) and disease-free survival (DFS) outcomes of consecutive breast cancer patients from three Indian centres, who underwent curative surgery as their first treatment. Among the 3453 patients, stage I, II, and III cases were 11.75%, 66.79%, and 21.64%, respectively while hormone receptor positive/HER2 negative, triple negative (TNBC) and hormone receptor any/HER2 positive cases were 55.2%, 24.2% and 20.6%, respectively. The five-year OS in the entire cohort, node-negative and node-positive patients were 94.1% (93.25-94.98), 96.17% (95.2-97.15) and 91.83% (90.36-93.31), respectively, and the corresponding DFS were 88.1% (86.96-89.31), 92.0% (90.64-93.39) and 83.93% (82.03-85.89), respectively. The five-year OS in hormone receptor positive/HER2 negative, TNBC and HER2 subgroups were 96.11% (95.12-97.1), 92.74% (90.73-94.8) and 90.62% (88.17-93.15), respectively, and the corresponding DFS were 91.59% (90.19-93.02), 85.46% (82.79-88.22) and 81.29% (78.11-84.61), respectively. This is the largest dataset of early breast cancer patients from India with survival outcome analysis and can therefore serve as a benchmark for future studies.

Are Basal-Like and Non-Basal-Like Triple-Negative Breast Cancers Really Different?

OBJECTIVE: Triple-negative breast cancer (TNBC) accounts for 15-25% of breast cancers. It is increasingly recognized that TNBC is a motley disease. TNBC and basal-like (BL) subtype are different molecular classes of breast cancer with a high degree of overlap. However, a smaller fraction lacks the expression of basal markers in spite of being TNBC and is called non-basal-like (NBL). The aim of this study is to assess the clinicopathological features in TNBC and compare its BL and NBL subtypes. Material and Methods. A total of 200 subjects fulfilling the inclusion criteria of study were identified from the electronic medical records of institution. The tumor sections of subjects were immunohistochemically stained for basal markers, namely, 34ßE12, c-Kit, and EGFR, in order to differentiate between BL and NBL subtypes. Comprehensive data were assembled from subjects' clinical records. The features of TNBC and their associations with the two subtypes were assessed using statistical analyses. RESULTS: TNBC constituted 22% of all breast cancers. The family history of cancer was observed to be significantly associated with stage (p=0.013). The proportions of BL and NBL subtypes were equal. Of all parameters compared between two subtypes, only lymphovascular invasion was found to have statistically significant difference (p=0.019). Though no statistical significant difference between overall survival (OS) and disease-free survival (DFS) of two subgroups was found, BL subtype has slightly shorter DFS and OS compared to NBL. CONCLUSION: Both BL and NBL subtypes occur in equal proportions; hence, basalness and triple negativity are not synonyms. Though BL and NBL are prognostically similar, BL subtype shows a trend towards slightly shorter DFS and OS compared to NBL.

Role of Maintenance Gemcitabine in Advanced Carcinoma Gallbladder.

Objective The aim of this study is to investigate the effects of gemcitabine maintenance on progression-free survival (PFS) in patients with metastatic gallbladder cancer (GBC). Materials and Methods Sixty patients with unresectable or metastatic GBC having ongoing response to treatment with initial six cycles of gemcitabine and a platinum-based doublet chemotherapy were prospectively randomized on day 21 of the 6th cycle in 1:1 fashion to receive either maintenance gemcitabine 1 g/m 2 intravenously on day 1 and day 8 of three weekly cycle or observation. Survival analysis was performed using the Kaplan-Meier method and comparisons by the log-rank test. A p -value < 0.05 was considered as statistically significant. Results Of 60 patients, a total of 56 were available for final analysis. The median PFS was 4.7 months (3.1-6.3) in gemcitabine arm and 2.6 months (2.4-2.8) in observation arm, hazard ratio (HR) 0.196 (95% confidence interval [CI]: 0.1-0.39), p < 0.001. Median overall survival in gemcitabine arm was 12.4 months (9.15-15.6) as opposed to 9.9 months (8.29-11.5) in observation arm, HR 0.76 (95% CI: 0.43-1.35), p = 0.354. The grade 3 or 4 side effects in maintenance arm were transaminitis (17.9%), thrombocytopenia (17.8%), neutropenia (14.2%), and febrile neutropenia (7.1%). Conclusions Maintenance gemcitabine therapy in unresectable/metastatic GBC patients responding to first-line gemcitabine and platinum treatment contributes to increase PFS with minimal and manageable side effects.

Droplet digital polymerase chain reaction offers an improvisation over conventional immunohistochemistry and fluorescent in situ hybridization for ascertaining Her2 status of breast cancer.

BACKGROUND: Droplet digital polymerase chain reaction (DDPCR) is a recent modality for detecting Her2 expression which is quantitative, cheaper, easier to standardize, and free from interobserver variation. PURPOSE: The purpose of this study is to incorporate DDPCR in the current diagnostic paradigm with clinical benefit. MATERIALS AND METHODS: Fifty-four consecutive patients were tested by immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and DDPCR. With FISH result as gold standard, receiver operating characteristic curves for DDPCR ratio were analyzed to label Her2-negative, equivocal, and positive cases as DDPCR score 1, 2, and 3, respectively. Proportion of patients labeled unequivocally as Her2 positive or negative was defined to have "clinically benefitted" from the test. Drawing parallel to inter-relationships between DDPCR, IHC, and FISH in the test cohort, four diagnostic pathways were defined - (1) initial IHC followed by FISH, (2) initial DDPCR followed by FISH, (3) initial IHC followed by DDPCR followed by FISH, and (4) initial DDPCR followed by IHC followed by FISH. RESULTS: Clinical benefit of DDPCR as an initial test in the test cohort was 57%, while it was 65% if used as a second-line test among those with an initial inconclusive IHC result. Sensitivity analysis in the simulation cohort revealed that if DDPCR cost was ≤0.6 times the cost of IHC, then a three-step pathway with DDPCR upfront would near certainly prove most cost beneficial. If DDPCR cost was >0.6 but ≤2 times the cost of IHC, then a three-step pathway with DDPCR as second-line test had a higher probability to prove most cost beneficial. If DDPCR cost was >2 times the cost of IHC, then conventional pathway had a higher probability to prove most cost-effective. CONCLUSION: Incorporating DDPCR in the current clinical diagnostic paradigm has the potential to improve its cost-effectiveness and benefit.

Clinical validation of an immunohistochemistry-based CanAssist-Breast test for distant recurrence prediction in hormone receptor-positive breast cancer patients.

CanAssist-Breast (CAB) is an immunohistochemistry (IHC)-based prognostic test for early-stage Hormone Receptor (HR+)-positive breast cancer patients. CAB uses a Support Vector Machine (SVM) trained algorithm which utilizes expression levels of five biomarkers (CD44, ABCC4, ABCC11, N-Cadherin, and Pan-Cadherin) and three clinical parameters such as tumor size, grade, and node status as inputs to generate a risk score and categorizes patients as low- or high-risk for distant recurrence within 5 years of diagnosis. In this study, we present clinical validation of CAB. CAB was validated using a retrospective cohort of 857 patients. All patients were treated either with endocrine therapy or chemoendocrine therapy. Risk categorization by CAB was analyzed by calculating Distant Metastasis-Free Survival (DMFS) and recurrence rates using Kaplan-Meier survival curves. Multivariate analysis was performed to calculate Hazard ratios (HR) for CAB high-risk vs low-risk patients. The results showed that Distant Metastasis-Free Survival (DMFS) was significantly different (P-0.002) between low- (DMFS: 95%) and high-risk (DMFS: 80%) categories in the endocrine therapy treated alone subgroup (n = 195) as well as in the total cohort (n = 857, low-risk DMFS: 95%, high-risk DMFS: 84%, P < 0.0001). In addition, the segregation of the risk categories was significant (P = 0.0005) in node-positive patients, with a difference in DMFS of 12%. In multivariate analysis, CAB risk score was the most significant predictor of distant recurrence with hazard ratio of 3.2048 (P < 0.0001). CAB stratified patients into discrete risk categories with high statistical significance compared to Ki-67 and IHC4 score-based stratification. CAB stratified a higher percentage of the cohort (82%) as low-risk than IHC4 score (41.6%) and could re-stratify >74% of high Ki-67 and IHC4 score intermediate-risk zone patients into low-risk category. Overall the data suggest that CAB can effectively predict risk of distant recurrence with clear dichotomous high- or low-risk categorization.

Ki-67 labeling index as a predictor of response to neoadjuvant chemotherapy in breast cancer.

AIMS: To investigate Ki-67 index with regard to its ability to predict achievement of pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) in breast cancer patient. MATERIAL AND METHODS: It was a prospective observational study, conducted in Department of Medical Oncology, Rajiv Gandhi Cancer Institute & Research Center (RGCIRC), New Delhi from February 2014 to March 2016. A total of 134 patients with Stage II/III breast cancer who underwent NACT followed by surgery at our center were enrolled and analyzed. Before starting the treatment, clinical, tumor-related and treatment-related factors were recorded. Response evaluation was done clinically and radiologically after completion of NACT and pathologically on the surgical specimen. We calculated Ki-67 cut-off of 35% to label it as high by area under Receiver operating characteristic curve analysis for prediction of pCR. RESULTS: Clinical complete response (cCR) was observed in 35/134 (26.1%) patients while pCR was observed in 32/134 (23.9%) patients. On univariate analysis, higher grade (III), high Ki-67 index (>35%) and number of chemotherapy cycles (>3) were associated with better CCR rates. On multivariate analysis, number of chemotherapy cycles (>3) and high Ki-67 index (>35%) were independent predictive factors. For the predictive factors of pCR, univariate analysis showed grade (III), estrogen receptor/progesterone receptor negativity, HER-2 positivity, number of chemotherapy cycles (>3), TNBC and high Ki-67 index (>35%) to be associated with higher pCR rates. On multivariate analysis, Ki-67 index >35% and HER-2 positivity were the only independent predictive factors of pCR. CONCLUSIONS: We suggest 35% as best cut-off for Ki-67 expression for predicting response to NACT and achievement of pCR. Validation of this cut-off is required in larger studies.

Case report of everolimus-induced sustained partial response in metastatic renal epithelioid angiomyolipoma.

Epithelioid variant of angiomyolipoma (EAML) is a newly defined entity and a close mimicker of renal cell carcinoma. There is a growing body of evidence to suggest its aggressive behavior in terms of local recurrence, metastasis and death. The treatment for this subset of patients has posed challenges for the experts. Chemotherapy plays little active role and so molecular profiling to identify genomic alterations amenable to targeted therapies has paved the way. Recently, tyrosine kinase inhibitors and mTOR inhibitors have been utilised both in adjuvant and neoadjuvant settings and have shown promising results in terms of survival. We present a case of a metastatic epithelioid angiomyolipoma treated sequentially with imatinib, crizotinib and now maintaining a sustained partial response with everolimus.