Ashish V. Chintakuntlawar

Expression of PD-1 and PD-L1 in anaplastic thyroid cancer patients treated with multimodal therapy: Results from a retrospective study

Context Anaplastic thyroid cancer (ATC) is rare and a highly fatal malignancy. The role of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) as prognostic and/or predictive markers in ATC is unknown. Objective Multimodal therapy offers the best chance at tumor control. The objective of this study was to detect potential associations of PD-1/PD-L1 axis variables with outcome data in ATC. Design Retrospective study of a uniformly treated cohort. Setting Single institution retrospective cohort study. Patients or Other Participants Sixteen patients who received intensity-modulated radiation therapy (15 had preceding surgery) were studied. Main Outcome Measure Patients treated with multimodal therapy were followed and assessed for overall survival (OS) and progression-free survival (PFS). Results All samples demonstrated PD-1 expression in inflammatory cells whereas tumor cells were primarily negative. PD-L1 was expressed on ATC tumor cells in most samples and showed mainly membranous staining. High PD-1 expression (>40% staining) in inflammatory cells was associated with worse overall survival (OS; hazard ratio, 3.36; 95% confidence interval, 1.00 to 12.96; P < 0.05) and trended toward worse PFS, whereas high PD-L1 expression in tumor cells (>33% staining) trended toward worse PFS and OS. Conclusion PD-1/PD-L1 pathway proteins are highly expressed in ATC tumor samples and appear to represent predictive markers of PFS and OS in multimodality-treated ATC patients.

High-grade transformation of acinic cell carcinoma: an inadequately treated entity?

OBJECTIVE Acinic cell carcinoma (AcCC) is an uncommon salivary gland malignancy. We aim to characterize the clinical and pathologic characteristics of AcCC with and without high-grade transformation (HGT). Importantly, cases of mammary analogue secretory carcinoma, a recently described histologic mimic of AcCC, have been excluded by using cytogenetics and molecular studies. STUDY DESIGN Archival surgical pathology material was obtained for patients diagnosed with AcCC at Mayo Clinic Rochester between 1990 and 2010. Tumors harboring the ETV6-NTRK3 fusion transcript were excluded from analysis by using cytogenetics and molecular studies. Tumors with HGT were characterized by areas with an infiltrative growth pattern, nuclear anaplasia, prominent nucleoli, brisk mitotic activity, geographic necrosis, and stromal desmoplasia. Demographic and clinical data were extracted from the medical records. RESULTS AcCC with HGT was seen in 8 of 48 cases (17%). Patients with AcCC with HGT were significantly older than patients without HGT (median 69 vs 54 years; P = .04). Angiolymphatic invasion was more common in AcCC with HGT (P = .02). Relapse-free survival and overall survival were significantly worse for cases of AcCC with HGT (hazard ratio 10.4 and 9.3, respectively; P < .0001 for both comparisons). Locoregional recurrence-free survival was not significantly different (P = .12), but distant metastases-free survival was significantly worse in patients with HGT compared with non-HGT patients (P < .0001). CONCLUSIONS Prognosis for overall survival and distant relapse for AcCC patients with HGT is significantly worse than that for patients without HGT.

Survival in Response to Multimodal Therapy in Anaplastic Thyroid Cancer

Context Historical outcomes in anaplastic thyroid cancer (ATC) have been dismal. Objective To determine whether an initial intensive multimodal therapy (MMT) is associated with improved ATC survival. Design MMT was offered to all patients with newly diagnosed ATC treated at the Mayo Clinic from 2003 through 2015; MMT vs care with palliative intent (PI) was individualized considering clinical status and patient preferences. Outcomes were retrospectively analyzed by American Joint Committee on Cancer stage and treatments compared with patient cohort data from 1949 through 1999. Patients Forty-eight patients (60% male; median age, 62 years); 18 treated with PI, 30 with MMT. Main Outcome Measure Overall survival (OS) and progression-free survival determined by Kaplan-Meier method. Results Median OS and 1-year survival for the later cohort were 9 months [95% confidence interval (CI), 4 to 22 months] and 42% (95% CI, 28% to 56%) vs 3 months and 10% for the earlier cohort. Median OS was 21 months compared with 3.9 months in the pooled MMT vs PI groups for the later cohort [hazard ratio (HR), 0.32; P = 0.0006]. Among only patients in the later cohort who had stage IVB disease, median OS was 22.4 vs 4 months (HR, 0.12; 95% CI, 0.03 to 0.44; P = 0.0001), with 68% vs 0% alive at 1 year (MMT vs PI). Among patients with stage IVC cancer, OS did not differ by therapy. Conclusion MMT appears to convey longer survival in ATC among patients with stage IVA/B disease.

Characterization of the oropharynx: anatomy, histology, immunology, squamous cell carcinoma and surgical resection

Understanding the structure and function of the oropharynx is paramount for providing excellent patient care. In clinical oncology, the oropharynx is generally divided into four distinct components: (i) the base of the tongue; (ii) the soft palate; (iii) the palatine tonsillar fossa; and (iv) the pharyngeal wall. The oropharyngeal mucosa is distinct from other mucosal surfaces in the body, as it is composed of a reticulated epithelium with a discontinuous basement membrane, also known as lymphoepithelium. This review describes the anatomy, histology, immunology and surgical resection of the oropharynx as they relate to oncological care.

Toxoplasmosis in patients with hematologic malignancies

Toxoplasmosis is one of the most common parasitic infections [1] and is caused by a protozoan, Toxoplasma gondii . Clinically signifi cant toxoplasmosis is a well-recognized opportunistic infection usually due to reactivation of a latent infection [2]. Adults with intact immunity usually have a self-limited infection; however, in immunocompromised patients, it can cause a life-threatening central nervous system (CNS) or disseminated infection. Th e frequency of this opportunistic infection in patients treated with antineoplastic chemotherapy in the modern era is unknown, as most series were published in patients with bone marrow transplant, and before the widespread use of trimethoprim – sulfamethoxazole prophylaxis or the advent of immunotherapy, including rituximab (R) [3 – 5]. Here we report a case of CNS toxoplasmosis after treatment with R and bendamustine (B) in a patient with Waldenstr o m macroglobulinemia (WM), and describe three other cases of toxoplasmosis in patients with hematologic malignancies treated at our institution from 2000 to 2013. A 79-year-old female presented with progressive fatigue and dyspnea on exertion for the past year. She noted easy bruising and several episodes of epistaxis over the preceding 2 months. Physical examination revealed palpable lymphadenopathy. Excisional lymph node biopsy demonstrated that the lymph node architecture was partially eff aced by an infi ltrate of neoplastic lymphoplasmacytoid cells that were positive for CD20, bcl-2 and immunoglobulin kappa light chains, suggesting a diagnosis of lymphoplasmacytic lymphoma. Laboratory studies showed hemoglobin 7.7 g/dL (12.0 – 15.5 g/dL), M-spike 4.6 g/dL, immunoglobulin M (IgM) 6910 mg/dL (37 – 286 mg/dL) and viscosity of 3.2 cP ( 1.5 cP). Bone marrow biopsy showed a hypercellular marrow with 60% involvement by lymphoplasmacytic lymphoma; monoclonal kappa light chain-restricted B-cell lymphocytes were present. Th e diagnosis of WM with hyperviscosity syndrome was made. After initial therapeutic apheresis, she was treated with B and R (BR) at 90 mg/m 2 /day (day 1 and 2) and 375 mg/m 2 (day 1) of body surface area, respectively, every 4 weeks. Following the completion of four cycles of BR, hemoglobin was 10.9 g/dL, M-spike was 1.9 g/dL and IgM was 2690 mg/dL, and observation was recommended. At that time, she was able to perform all activities of daily living independently and had a steady improvement in energy levels. Eight weeks after her last chemotherapy cycle, her family noted intermittent episodes of mild cognitive dysfunction which progressed to frank confusion and visual hallucinations. Th ere were no reported falls, seizures or symptoms suggestive of infection, including fevers and chills. She was admitted to our institution for further work-up. On initial examination, vital signs were normal. Mucous membranes were dry. Lymph nodes, heart, lung, abdomen and extremities were unremarkable. Her pupils were equal, round and reactive to light. She was restless and only partially oriented to person (only able to say her fi rst name), but not oriented to time or place. Strength, sensation, coordination and gait could not be evaluated, but refl exes were brisk throughout, with Babinski fl exor bilaterally. Laboratory examination revealed hemoglobin of 12.5 g/ dL, leukocyte count 6.4 10 9 /L, with normal absolute neutrophil and lymphocyte counts. Serum viscosity and IgM levels were 1.2 cP and 2760 mg/dL, respectively. Fungal, human immunodefi ciency virus (HIV) and syphilis serologies were negative. Magnetic resonance imaging (MRI) showed innumerable peripherally enhancing lesions of variable size, many at the gray – white junction. A mild to moderate mass eff ect was noted on the right frontal horn (Figure 1). Cerebrospinal fl uid (CSF) analysis showed glucose of 51 mg/dL (blood sugar 93 mg/dL), total protein of 239 mg/dL (0 – 35 mg/dL) and a cell count of 239 cells/ μ L (94% lymphocytes). Cytology was negative for malignancy, and fl ow cytometry showed no monotypic B-cells. CSF cultures were negative for bacteria, fungi and mycobacteria. CSF polymerase chain reaction (PCR) was positive for T. gondii . Th erapy with both intravenous trimethoprim – sulfamethoxazole and oral pyrimethamine with folinic acid was initiated due to concerns about erratic oral intake. Intravenous trimethoprim – sulfamethoxazole was later changed to sulfadiazine when oral therapy could be given reliably. Follow-up examination and MRI 6 weeks later

Drug–drug interaction between bosutinib and warfarin

Bosutinib (SKI-606) is an orally bioavailable tyrosine kinase inhibitor (TKI) with potent activity against Src and Abl kinases, but not c-kit or platelet derived growth factor receptor kinases [1]. Bosutinib was recently approved for the treatment of chronic, accelerated or blast phase Philadelphia chromosome-positive (Ph ) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy [2]. Here we describe a case illustrating potential drug – drug interaction between bosutinib and warfarin that led to clinically signifi cant bleeding in a patient with CML. Th e patient was an 84-year-old Caucasian male who was initially diagnosed with chronic lymphocytic leukemia (CLL) 20 years ago; the patient was asymptomatic with Rai stage 0 disease; disease risk stratifi cation based on interphase fl uorescence in situ hybridization (FISH) revealed a sole del(13q) abnormality. He was managed expectantly with observation only. Approximately 12 years after the CLL diagnosis, he presented with fatigue and decreased appetite. His physical examination showed lymphadenopathy and splenomegaly. Complete blood count showed hemoglobin of 13.7 g/dL, platelet count of 353 10 9 /L and white blood cell count of 123.7 10 9 /L, with 36% neutrophils, 28% lymphocytes, 17% monocytes and 5% basophils, suggestive of an evolving myeloid malignancy. Peripheral blood FISH revealed the BCR – ABL1 fusion in 50% of nuclei, and another 50% carried del(13q), thereby confi rming concurrent development of chronic phase CML in the background of CLL. He was treated with imatinib 400 mg daily and achieved a complete hematologic response (CHR) but subsequently lost the response. Testing at the time of relapse (approximately 18 months following treatment initiation) confi rmed the presence of BCR – ABL1 p190 transcript by reverse transcription polymerase chain reaction (RT-PCR) and the M244V mutation on kinase domain sequencing. Th e patient was thereafter treated with dasatinib and again achieved a CHR, however had signifi cant problems with drug-induced cytopenias and recurrent pleural eff usions, requiring temporary discontinuation of drug and sequential dose reduction from 100 mg to 70 mg to 25 mg daily to 25 mg every other day. Ultimately, dasatinib was permanently discontinued due to recurrent and treatmentrefractory pleural eff usions, approximately 24 months after initiation. Th e patient had hematological relapse after dasatinib discontinuation; the third TKI he received was nilotinib, initially at the dose of 300 mg twice daily. He rapidly achieved CHR but required dose reduction following temporary drug hold for grade 4 thrombocytopenia. Eventually, he was managed at a dose of 150 mg daily alternating with 150 mg twice daily for 2 years. Th e treatment was discontinued due to the development of accelerated atherosclerosis with peripheral arterial occlusive disease, with bilateral ischemic leg ulcers and gangrene of the left toes. Th e patient required left peroneal angioplasty in addition to other conservative treatment measures.

Characteristics and long-term outcomes of head and neck squamous cell carcinoma after solid organ transplantation

INTRODUCTION Immunosuppression after solid organ transplant prevents graft rejection, but leads to increased incidence of various malignancies including head and neck squamous cell carcinoma (HNSCC). Outcomes of patients with post-transplant HNSCC are unknown. MATERIALS AND METHODS We retrospectively identified patients who developed HNSCC after solid organ transplant between 1995 and 2010. Adults with pathology-proven HNSCC and adequate follow up were included. Median overall survival and progression free survival were analyzed using the Kaplan-Meier method. The prognostic effect of variables was studied with Cox proportional hazards models. RESULTS Thirty-three patients met study inclusion criteria. The median time to diagnosis of HNSCC after transplant was 5.9years. The primary site was oral cavity in 15 patients, oropharynx in 10, larynx in 3, hypopharynx in 2, parotid in 2 and unknown in 1 patient. Eighty-eight percent underwent upfront surgical resection. Of those, sixty-six percent received adjuvant therapy. Six percent of patients had definitive chemoradiation. Treatment was well tolerated and did not lead to graft rejection. The 5-year overall survival rate was 45% and 37% for localized and locally advanced disease respectively. Seventy-five percent of patients with oropharyngeal tumors were HPV-positive and they had better outcomes (5-year overall survival rate of 67%). In multivariate analysis, age ≥60years was a negative predictor of survival (HR 2.7; 95% CI, 1.1-6.5; P=0.03). CONCLUSIONS Patients with post-transplant HNSCC have relatively poor survival and high risk of locoregional and distant recurrence. HPV- positive oropharyngeal tumors continue to have better outcomes in this population.

Esthesioneuroblastoma with distant metastases: Systematic review & meta-analysis

The purpose of this study was to determine the clinical outcomes and review the management strategies for metastatic esthesioneuroblastoma.

OPTIMIZING LENVATINIB THERAPY IN PATIENTS WITH METASTATIC RADIOACTIVE IODINE-RESISTANT DIFFERENTIATED THYROID CANCERS

OBJECTIVE Lenvatinib is approved for use in advanced radioactive iodine-resistant differentiated thyroid cancers (RAIR-DTCs). Its efficacy is indisputable, but toxicities are great, creating daunting challenges for patients and providers. Few data regarding early adverse events and impact on quality of life (QOL) exist; we sought to clarify these issues by analyzing our initial postapproval lenvatinib experience. METHODS Standardized patient education was implemented, providing detailed instructions and expert provider contacts to facilitate timely reporting of toxicities and guide responsive actions. Early adverse events, QOL outcomes, and response data from 25 consecutively treated DTC patients (02/2015 and 05/2016) were retrospectively analyzed. RESULTS The median age was 55 years (range 27-81); 52% were female. Fourteen (56%) were on antihypertensive medication(s) at baseline. Most patients (21/25, 84%) developed adverse events during the first month of therapy. Hypertension arose in 16/25 (64%), requiring antihypertensive dose adjustment/addition in 6 (24%)/12 (48%) patients, respectively, during the first month of therapy. Dose reduction was required in 11 (44%) due to multiple adverse events; the median time to first dose reduction was 33 days (range 11-84); 8 (32%) required multiple dose reductions. Therapy interruption >3 weeks occurred in 4 (16%). The median change in patient-reported fatigue score was +2 (worsening, range -2 to +10, P<.007; 0-10 scales), but the median QOL change was 0 (range +4 to -9, P = .57). The mean duration of lenvatinib therapy was 6.5 months (range 1-12); median overall and progression-free survival have not yet been reached. Lenvatinib was discontinued in 7 (28%) patients; among 20 patients with available RECIST (Response Evaluation Criteria In Solid Tumors) measurements, 10 (50%) achieved partial response. CONCLUSION Lenvatinib has promising efficacy in RAIR-DTC, but toxicities require frequent early interventions. QOL can be maintained on lenvatinib therapy. ABBREVIATIONS DTC = differentiated thyroid cancer; LASA = linear analog self-assessment; PR = partial response; QOL = quality of life; RAI = radioactive iodine; RAIR = RAI-resistant; RECIST = Response Evaluation Criteria In Solid Tumors; Tg = thyroglobulin; VEGFR = vascular endothelial growth factor receptor.