Clinical Utility of Cabozantinib in the Treatment of Locally Advanced or Metastatic Differentiated Thyroid Carcinoma: Patient Selection and Reported Outcomes.

Treatment of differentiated thyroid cancer (DTC) is multidisciplinary and begins with surgical intervention. Often, radioactive iodine is used as the prototype targeted therapy to ablate any residual thyroid tissue or metastatic deposits. While these initial therapeutic modalities are often curative with no need for further treatment, many patients develop radioactive-iodine refractory (RAIR) disease. When patients present with progressive RAIR disease, they often require systemic therapy. Several multikinase inhibitors have been approved for treatment of DTC, with sorafenib and lenvatinib employed in frontline treatment settings since approvals in 2013 and 2015, respectively. While patients have benefited from such treatment, progression is inevitable, and until recently, there were no established second-line options. Cabozantinib was recently approved for treatment of patients with DTC who have progressed on either frontline sorafenib or lenvatinib. Molecular testing for driver mutations or gene fusions, such as BRAF V600E or RET or NTRK fusions, has become standard recommendations for RAIR DTC patients due to excellent treatment options with highly selective targeted therapies, most RAIR DTC patients do not harbor such aberrations or have so-called "undruggable" mutations, making rendering cabozantinib an attractive and feasible treatment option for many patients.

Comparison of real-world outcomes following immunotherapy in recurrent or metastatic head and neck squamous cell carcinoma with outcomes of randomized controlled trials.

OBJECTIVES: Evaluate outcomes of patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy (IO). METHODS: Among patients with R/M HNSCC treated with IO in this retrospective single-institution cohort, Cox regression was used to compare overall survival (OS) for those with platinum-refractory disease and those treated in the first-line setting with OS from KEYNOTE-040/048, respectively. Multivariable Cox regression was used to identify predictors of OS. RESULTS: There was no significant OS difference for those treated in the platinum-refractory setting when compared to patients on KEYNOTE-040 (HR = 1.22, p = 0.27), nor for the first-line setting compared to KEYNOTE-048 (HR = 1.23, p = 0.19). ECOG-PS 1 (HR = 2.00, p = 0.02) and ECOG-PS 2 (HR = 3.13, p < 0.01) were associated with worse OS. Higher absolute lymphocyte count (ALC) was associated with improved OS (HR = 0.93 per 100 cells/µL, p = 0.03). CONCLUSIONS: Real-world outcomes of IO in R/M HNSCC are similar to outcomes in randomized control trials, with performance status and ALC correlating with OS.

Immunotherapy in HPV-Related Oropharyngeal Cancers.

OPINION STATEMENT: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) incidence has been increasing in recent decades. Treatment of the locally advanced HPV-related OPSCC includes a multidisciplinary approach. Immunotherapy with immune checkpoint inhibitors is used in the treatment of patients with recurrent/metastatic head and neck squamous cell carcinomas (HNSCC), including HPV-related OPSCC patients. There is increasing knowledge of the role of HPV in the tumor immune microenvironment. Therefore, HPV status of OPSCC plays an essential role in the design of immunotherapy clinical trials in both curative intent and metastatic settings. Moreover, HPV has become a potential therapeutic target, with vaccines and adoptive T-cell therapies being developed against HPV for the treatment of OPSCC. Several novel studies are designed to target HPV in combination with immune checkpoint inhibitors. Thus, HPV-related OPSCC remains a unique subgroup in the immunotherapy era.

Impact of Socioeconomic Factors on Overall Survival in SCLC.

Objectives: To determine how the incidence and demographics of SCLC have changed over time and to evaluate whether patient demographics, disease presentation, and treatment characteristics affect patient outcomes. Methods: We identified patients with SCLC in the National Cancer Database from 2004 to 2016. Differences in demographics, disease, and treatment characteristics were assessed by year of diagnosis using chi-square test. The effect of age, race, insurance status, income, distance to treatment center, and education level on overall survival (OS) was evaluated by multivariable Cox proportional hazard model. Results: Patients diagnosed after 2010 were significantly older, more frequently treated at academic centers, had more comorbidities, had government payer insurance, had more stage IV disease, and lived further from treatment centers. More females, African Americans, patients without high school diplomas, and those from rural areas were diagnosed after 2010. In patients diagnosed between 2004 and 2010, 5-year OS was 6.8% (95% confidence interval: 6.6-6.9), and after 2010, 5-year OS was 8.7% (95% confidence interval: 8.5-8.9), despite an increase in stage IV disease in the latter group. Older patients, males, Caucasians, patients with stage IV disease, those with government primary payer insurance, and those from rural areas had significantly worse OS. Patients without comorbidities and treated at academic centers had significantly better OS. OS significantly increased with community income and education level. Conclusions: Despite improvement in OS, disparities were noted in demographics which may complicate patient and provider access to health care resources, including rural communities, distance to academic centers, income, insurer, and education level. Efforts to affect these variables will improve outcomes for patients with SCLC.

Hypothyroidism in Head and Neck Squamous Cell Carcinoma Patients Receiving Radiotherapy With or Without Immune Checkpoint Inhibitors.

OBJECTIVES/HYPOTHESIS: Hypothyroidism is a relatively common complication of head and neck squamous cell carcinoma (HNSCC) treatment. The objective of this study was to determine whether the addition of programmed death ligand-1 (PD-1) or programmed death ligand-1 (PD-L1) inhibition (anti-PD-1/PD-L1 therapy) to standard treatment increases the risk of hypothyroidism in HNSCC. STUDY DESIGN: Retrospective Cohort. METHODS: This is a retrospective, single institutional cohort study. Patients who received radiotherapy (RT) for HNSCC were identified in the electronic medical record. Patient factors collected include age, sex, body mass index (BMI), smoking status, alcohol use, Charlson comorbidity index, and HNSCC treatment records. The rate of hypothyroidism for patients with HNSCC receiving RT (+/- chemotherapy and surgery) (RT group, n = 101) was compared to that of HNSCC patients receiving RT (+/- chemotherapy and surgery) + anti-PD-1/PD-L1 therapy, either concurrently or after RT (RT + anti-PD-1/PD-L1 group, n = 38). RESULTS: There was no significant difference in the rate of clinical or subclinical hypothyroidism between the two groups. Multinomial logistic regression found no significant difference in hypothyroidism based on age, sex, or BMI. CONCLUSIONS: The addition of anti-PD-1/PD-L1 therapy to standard HNSCC treatment does not significantly increase the risk of developing hypothyroidism. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E2413-E2419, 2021.

Determining the molecular landscape and impact on prognosis in HPV-associated head and neck cancer.

BACKGROUND: Human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than HNSCC due to other risk factors. However, there is significant heterogeneity within HPV-associated HNSCC and 25% of these patients still do poorly despite receiving aggressive therapy. We currently have no good molecular tools to differentiate and exclude this "high-risk" sub-population and focus on "low-risk" patients for clinical trials. This has been a potential barrier to identifying successful de-escalation treatment strategies in HPV-associated HNSCC. We conducted an analysis of molecular markers with a well-known role in the pathogenesis of HPV-associated HNSCC and hypothesized that these markers could help independently predict recurrence and prognosis in these patients and therefore help identify at the molecular level "low-risk" patients suitable for de-escalation trials. METHODS: We analyzed 24 tumor specimens of patients with p16+ HNSCC who underwent definitive resection as primary treatment. Tissue microarray (TMA) was generated from the 24 pathology blocks and immunohistochemistry (IHC) was performed using highly specific antibodies for our chosen biomarkers (PI3K-PTEN, AKT pathway, mTOR, 4EBP1, S6, and pAMPK, ERCC-1). Transcriptome data was also obtained for 7 p16+ HNSCC patients from The Cancer Genome Atlas (TCGA). Data from the TMA and TCGA were analyzed for association of relapse-free survival (RFS) and overall survival (OS) with protein and gene expression of the chosen biomarkers. RESULTS: Increased pAMPK protein activity by IHC and AMPK gene expression by TCGA gene expression data was correlated with improved RFS with a trend towards statistical significance. CONCLUSIONS: This data suggests that increased pAMPK activity and expression may portend a better prognosis in HPV-associated HNSCC undergoing primary definitive resection. However, these findings require validation in larger studies.

Salvage cryotherapy in patients undergoing endoscopic eradication therapy for complicated Barrett's esophagus.

Background and study aims Some patients with dysplastic Barrett's esophagus (BE) experience suboptimal response to radiofrequency ablation (RFA), endoscopic mucosal resection (EMR), or the combination. Cryotherapy has been used as salvage therapy in these patients, but outcomes data are limited. We aimed to assess clinical outcomes among a large cohort of patients with dysplastic BE whose condition had failed to respond to RFA and/or EMR. Patients and methods This was a retrospective cohort study of consecutive cases of dysplastic BE or intramucosal carcinoma (IMC) treated with salvage cryotherapy at a tertiary-care academic medical center. The primary goal of cryotherapy treatment was eradication of all neoplasia. The secondary goal was eradication of all intestinal metaplasia. The proportion of patients undergoing salvage cryotherapy who achieved complete eradication of dysplasia (CE-D) and metaplasia (CE-IM), as well as the time to CE-D and CE-IM were calculated. Results Over a 12-year period, 46 patients received salvage cryotherapy. All patients underwent RFA prior to cryotherapy, either at our center or prior to referral, and 50 % of patients underwent EMR. A majority of patients (54 %) had high-grade dysplasia (HGD) at referral, while 33 % had low-grade dysplasia (LGD), and 13 % had IMC. Overall, 38 patients (83 %) reached CE-D and 21 (46 %) reached CE-IM. Median time to CE-D was 18 months, median number of total interventions (RFA, cryotherapy, and EMR) was five, and median number of cryotherapy sessions was two. Conclusion Salvage cryotherapy appears safe and effective for treating BE that is refractory to RFA and/or EMR.

High-risk pathological features at the time of salvage surgery predict poor survival after definitive therapy in patients with head and neck squamous cell carcinoma.

OBJECTIVES: Salvage surgical resection is the preferred treatment for head and neck squamous cell carcinoma (HNSCC) patients who develop locally recurrent disease after failing primary therapy. However, salvage surgical resection is not always feasible, and survival outcomes for those that do undergo salvage remain poor. It is well known that patients with adverse pathological features (extracapsular extension (ECE) of lymph nodes (LN), positive margins, perineural invasion (PNI), lymphovascular invasion (LVI), and multiple LN metastases) at the time of primary surgical resection are likely to have relatively poor outcomes. However, the impact of adverse pathological features on outcomes in the salvage setting remains controversial. MATERIALS AND METHODS: We retrospectively analyzed 73 patients at a single institution from 2008 to 2017 who developed recurrence and subsequently underwent salvage surgery (SS) after definitive curative-intent therapy including radiation. Demographic and disease control outcomes were reviewed. Kaplan-Meier curves were used to estimate relapse free survival (RFS) and overall survival (OS). RESULTS: Median age at diagnosis was 61 years (range 40-86), 49/73 (67%) were male, and 55/73 (75%) had smoked. Patients with any adverse pathological features at SS had worse RFS (HR 3.15 p = 0.0008) and worse OS (3.97 p = 0.0008). Patients who relapsed <6 months after initial therapy had worse OS (HR 2.96 p = 0.004). CONCLUSIONS: Patients with adverse pathological features at time of salvage surgery as well as those who have an early recurrence after definitive treatment and salvage surgery have worse outcomes. Prospective studies are necessary to clarify which patients should receive more intense treatment at salvage.

Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade.

Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities. Further investigations indicated that treatment with a pan-PIM kinase inhibitor promoted increased ubiquitination and subsequent degradation of IKZF1 and IKZF3, two transcription factors crucial for survival of myeloma cells. Combining a pan-PIM kinase inhibitor with lenalidomide led to more effective degradation of IKZF1 and IKZF3 in multiple myeloma cell lines as well as xenografts of myeloma tumors. We also demonstrated that treatment with a pan-PIM kinase inhibitor resulted in increased expression of cereblon, and that knockdown of cereblon via a shRNA lentivirus abolished the effects of PIM kinase inhibition on the degradation of IKZF1 and IKZF3 and myeloma cell apoptosis, demonstrating a central role of cereblon in pan-PIM kinase inhibitor-mediated down-regulation of IKZF1 and IKZF3 and myeloma cell killing. These data elucidate the mechanism of pan-PIM kinase inhibitor mediated anti-myeloma effect and the rationale for the synergy observed with lenalidomide co-treatment, and provide justification for a clinical trial of the combination of pan-PIM kinase inhibitors and lenalidomide for the treatment of multiple myeloma.

Senile transthyretin cardiac amyloidosis in patients with plasma cell dyscrasias: importance of cardiac biopsy for making the correct diagnosis.

Amyloidosis refers to a group of widely diverse conditions characterized by the deposition of insoluble protein within the extracellular space, leading to disruption of normal organ function. AL primary amyloidosis is associated with plasma cell dyscrasias and is caused by the deposition of insoluble kappa or lambda light chains. Cardiac involvement by AL primary amyloidosis has a very poor prognosis, and patients are treated with systemic chemotherapy. Clinically, the presence of cardiac amyloidosis in patients with plasma cell disorders is usually presumed to represent AL primary amyloidosis, and they are often managed as such. We reported four cases of elderly patients with plasma cell disorders who were found to have biopsy-proven cardiac senile transthyretin amyloidosis. Our cases demonstrated that cardiac amyloidosis in patients with plasma cell disorders does not necessarily represent AL primary amyloidosis. Cardiac biopsy is important in making the correct diagnosis. Accurate subtyping of the amyloid has significant implications in the management of patients and discussion of prognosis.