Background
Primary squamous cell carcinoma of the thyroid (ThySCC) is a rare cancer, primarily described only in case reports. We aimed to characterize the prognosis of ThySCC and compare its ...oncologic behavior to other thyroid malignancies.
Methods
The National Cancer Database was queried to identify patients with ThySCC, papillary, tall cell variant, poorly differentiated (PDTC), and anaplastic (ATC) subtypes of thyroid cancer treated from 2004 to 2015. Demographics, tumor characteristics, and treatments were compared by tumor type and assessed to identify independent predictors of overall survival (OS).
Results
Of 123,684 patients included, 314 had ThySCC. ThySCC patients had a 5-year OS of 17.7%, more closely resembling ATC (8.3%) than PDTC or PTC. ThySCC and ATC patients had similar demographics, except ThySCC patients who were younger (68.0 vs. 70.2 years,
p
< 0.01). ThySCC tumors were smaller (mean 53.5 ± 45.7 vs. 69.5 ± 75.2 mm) with less frequent extrathyroidal extension (ETE) (64.0% vs. 73.8%), lymphovascular invasion (8.3% vs. 12.3%), and positive margins (22.0% vs. 28.3%) compared to ATCs (
p
< 0.05). ETE HR 3.1 (95% CI 1.5–6.4),
p
< 0.05 and lymph node metastases HR 2.2 (95% CI 1.2–4.0)
p
< 0.05 were independently associated with worse OS for ThySCC patients. Both ThySCC and ATC patients had similar surgical success rates, with R1 resection possible in 37.3% versus 35.0% of patients, respectively (
p
< 0.05). However, in contrast to ATC patients, adjuvant therapy was not associated with improved OS for ThySCC patients after complete resection.
Conclusions
ThySCC has a poor prognosis, similar to ATC, but with fewer aggressive features and no apparent survival benefit with adjuvant therapy after complete macroscopic surgical resection.
Background Alpha-blockade is the standard management preoperatively to prevent intraoperative hemodynamic instability (IHD) during resection of a pheochromocytoma. Calcium channel blockers also have ...been shown to lessen the risk of IHD. We aim to determine differences between these classes of antihypertensive agents in minimizing IHD. Methods This was a retrospective analysis from a tri-institutional database. Inclusion criteria were unilateral transabdominal adrenalectomy for pheochromocytomas between 2002 and 2012. IHD was defined as at least one systolic blood pressure (SBP) measurement >160 mm Hg and at least one episode of mean arterial pressure 60 mm Hg. Results A total of 155 patients were included: 110 receiving calcium channel blockers, 41 alpha-blockade, and 4 no medication. Intraoperatively, mean maximal SBP was less after alpha-blockade ( P < .0001) as well as the incidence and duration of episodes of SBP >200 mm Hg ( P < .01); however, severe hypotensive episodes (MAP <60 mm Hg) were more frequent ( P < .001) and longer ( P < .0001) with alpha-blockade. Consequently, intraoperative vasoactive drugs were used more frequently ( P = .03), and mean fluid volume infused was larger ( P < .001). Fifty-four patients had IHD, but these were independent of type of preoperative medication used. Familial disease was the only independent predictor of IHD. Conclusion IHD was independent of type of preoperative medical management but was dependent on familial disease. These findings broaden options for clinicians in the preoperative management of pheochromocytoma.
Poorly differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors, including papillary thyroid cancer ...(PTC) and ATC, are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1-targeting agents for the treatment of aggressive cancer. We developed a third-generation chimeric antigen receptor (CAR) targeting ICAM-1 to leverage adoptive T-cell therapy as a new treatment modality.
ICAM-1 CAR T cells were applied to multiple malignant and nonmalignant target cells to investigate specific target cell death and "off-tumor" toxicity
therapeutic efficacy of ICAM-1 CAR T cells was examined in ATC mouse models established from a cell line and patient-derived tumors that rapidly develop systemic metastases.
ICAM-1 CAR T cells demonstrated robust and specific killing of PTC and ATC cell lines
Interestingly, although certain ATC cell lines showed heterogeneous levels of ICAM-1 expression, addition of cytotoxic CAR T cells induced increased ICAM-1 expression such that all cell lines became targetable. In mice with systemic ATC, a single administration of ICAM-1 CAR T cells mediated profound tumor killing that resulted in long-term remission and significantly improved survival. Patient-derived ATC cells overexpressed ICAM-1 and were largely eliminated by autologous ICAM-1 CAR T cells
and in animal models.
Our findings are the first demonstration of CAR T therapy against both a metastatic, thyroid cancer cell line and advanced ATC patient-derived tumors that exhibit dramatic therapeutic efficacy and survival benefit in animal studies.
.
Context:
The RAF inhibitor vemurafenib has provided a major advance for the treatment of patients with BRAF-mutant metastatic melanoma. However, BRAF-mutant thyroid cancer is relatively resistant to ...vemurafenib, and the reason for this disparity remains unclear. Anti-cancer therapy induced autophagy can trigger adaptive drug resistance in a variety of cancer types and treatments. To date, role of autophagy during BRAF inhibition in thyroid cancer remains unknown.
Objective:
In this study, we investigate if autophagy is activated in vemurafenib treated BRAF-mutant thyroid cancer cells, and whether autophagy inhibition improves or impairs the treatment efficacy of vemurafenib.
Design:
Autophagy level was determined by western blot assay and transmission electron microscopy. The combined effects of autophagy inhibitor and vemurafenib were assessed in terms of cell viability in vitro and tumor growth rate in vivo. Whether the endoplasmic reticulum (ER) stress was in response to vemurafenib-induced autophagy was also analyzed.
Results:
Vemurafenib induced a high level of autophagy in BRAF-mutant thyroid cancer cells. Inhibition of autophagy by either a pharmacological inhibitor or interfering RNA knockdown of essential autophagy genes augmented vemurafenib-induced cell death. Vemurafenib-induced autophagy was independent of MAPK signaling pathway and was mediated through the ER stress response. Finally, administration of vemurafenib with the autophagy inhibitor hydroxychloroquine promoted more pronounced tumor suppression in vivo.
Conclusions:
Our data demonstrate that vemurafenib induces ER stress response-mediated autophagy in thyroid cancer and autophagy inhibition may be a beneficial strategy to sensitize BRAF-mutant thyroid cancer to vemurafenib.
Background
Risks of thyroidectomy for multinodular goiter (MNG) in older and frail patients are unclear, particularly regarding hematoma and recurrent laryngeal nerve (RLN) palsy.
Methods
MNG ...patients undergoing total thyroidectomy were reviewed in the ACS-NSQIP procedure-targeted database (2016–2017). Outcomes were analyzed between adult (age <65), older-adult (age ≥65 and <80), and oldest-old (age ≥80) patients. Five-factor modified frailty index (mFI-5) was calculated based on functional status, diabetes, COPD, CHF, and hypertension, and used in comparative analyses.
Results
A total of 2189 adult, 635 older-adult, and 59 oldest-old patients were included. Compared to adult patients, older-adult and oldest-old patients had higher mFI-5 ≥0.4 rates (14% vs. 22% vs. 31%, respectively,
p
< 0.001). The overall complication rate was 17.0% and similar between groups; however, oldest-old patients had higher rates of surgical site infection (3.4% vs. 0.3% vs. 0.4%), pneumonia (5.1% vs. 0.3% vs. 0.2%), and readmission (10.2% vs. 2.4% vs. 2.6%) compared to older-adult and adult patients, respectively (
p
< 0.05). On multivariable analyses of thyroidectomy-specific complications, mFI-5 ≥0.4 (OR 2.5, 95%-CI 1.4–4.4) and bleeding disorder (OR 4.6, 95%-CI 1.3–16.3) were predictive of hematoma, whereas vessel-sealant device usage (OR 0.4, 95%-CI 0.3–0.7) was protective. mFI-5 ≥ 0.4 (OR 1.5, 95%-CI 1.1–2.2), bleeding disorder (OR 2.8, 95%-CI 1.04–7.8), parathyroid autotransplantation (OR 1.7, 95%-CI 1.2–2.6), and prolonged operative time (OR 1.4, 95%-CI 1.02–1.8) were predictive of RLN palsy. Age was not a significant predictor of hematoma or RLN palsy.
Conclusions
Patients ≥80 years old are at increased risk for systemic complications and readmission after thyroidectomy for MNG. Frailty index better risk-stratifies patients than age for thyroidectomy-specific complications.
While the majority of thyroid cancer patients are easily treatable, those with anaplastic or poorly differentiated recurrent thyroid carcinomas have a very poor prognosis with a median survival of ...less than a year. Previously, we have shown a significant correlation between ICAM-1 overexpression and malignancy in thyroid cancer, and have pioneered the use of ICAM-1 targeted CAR T cells as a novel treatment modality. For clinical translation of this novel modality, we designed CAR T cells possessing micromolar rather than nanomolar affinity to ICAM-1 to avoid cytotoxicity in normal cells with basal levels of ICAM-1 expression. Herein, we report the automated process of CAR T cell manufacturing with CliniMACS Prodigy (Miltenyi Biotec) using cryopreserved peripheral blood leukocytes from apheresis collections. Using Prodigy, thawed leukopak cells were enriched for CD4
and CD8
T cells, subjected to double transduction using lentiviral vector, and expanded in culture for a total of 10 days with a final yield of 2-4 × 10
cells. The resulting CAR T cells were formulated for cryopreservation to be used directly for infusion into patients after thawing with no further processing. We examined cross-reactivity of CAR T cells toward both human and murine ICAM-1 and ICAM-1 expression in human and mouse tissues to demonstrate that both efficacy and on-target, off-tumor toxicity can be studied in our preclinical model. Selective anti-tumor activity in the absence of toxicity provides proof-of-concept that micromolar affinity tuned CAR T cells can be used to target tumors expressing high levels of antigen while avoiding normal tissues expressing basal levels of the same antigen. These studies support the initiation of a phase I study to evaluate the safety and potential efficacy of micromolar affinity tuned CAR T cells against newly diagnosed anaplastic and refractory or recurrent thyroid cancers.
Background
Population-based analyses of 30-day outcomes after parathyroidectomy for renal secondary hyperparathyroidism are limited. We sought to identify risk factors associated with prolonged ...length of stay (LOS) and readmission in this patient population.
Methods
Patients with secondary hyperparathyroidism who underwent parathyroidectomy were reviewed in the ACS-NSQIP database (2011–2016). Patients were identified by ICD codes specific to secondary hyperparathyroidism of renal origin and the ACS-NSQIP variable for current preoperative dialysis. Multivariable logistic regression was used to identify independent factors associated with prolonged LOS and 30-day readmission after parathyroidectomy.
Results
The cohort included 1846 patients with secondary hyperparathyroidism on dialysis who underwent parathyroidectomy. There were 416 (22.5%) patients classified under the prolonged LOS group. On multivariable analysis, factors associated with prolonged LOS included elevated preoperative alkaline phosphatase OR 3.13 (95%-CI 2.09–4.70),
p
< 0.001, decreased preoperative hematocrit OR 1.83 (95%-CI 1.25–2.68),
p
= 0.002, unplanned reoperation (OR 5.02 95%-CI 2.22–11.3,
p
< 0.001) and any postoperative complication OR 6.12 (95%-CI 3.31–11.3),
p
< 0.001. The overall 30-day readmission rate was 15.0%. Hypocalcemia and hungry bone syndrome accounted for 47.0% (
n
= 93/198) of readmissions. On multivariable analysis, patients with a history of hypertension and those undergoing unplanned reoperation were at risk of readmission 2.16 (95%-CI 1.21–3.87),
p
= 0.009, and 2.40 (95%-CI 1.15–5.02),
p
= 0.020, respectively, whereas reoperative parathyroidectomy was inversely associated with readmission (OR 0.24, 95%-CI 0.07–0.80,
p
= 0.021).
Conclusion
In patients undergoing parathyroidectomy for renal secondary hyperparathyroidism, several readily available preoperative biochemical markers, including those of increased bone turnover and anemia, are associated with prolonged postoperative LOS. Unplanned reoperation was predictive of both increased LOS and readmission.
Background
Although the role of prophylactic central neck lymph node dissection (CNLD) in the treatment of papillary thyroid carcinoma (PTC) is controversial, many surgeons perform routine ...prophylactic CNLD. The present study compares local recurrence rates in PTC patients undergoing total thyroidectomy with and without prophylactic CNLD.
Materials and Methods
A retrospective review of 206 patients undergoing thyroidectomy for PTC was conducted at two tertiary referral centers. Of these, 81 patients had total thyroidectomy for PTC and a follow-up between 2 and 9 years with a mean of 3.1 years. Of these 81 patients, 45 underwent routine prophylactic CNLD and 36 did not. For those two groups, demographics, clinical and pathologic findings, radioactive iodine (RAI) treatment, and the incidence of recurrence were compared. Univariate statistical analysis was performed.
Results
There was no significant difference in age, gender, multifocality, or extrathyroidal extension for the two groups. Patients with CNLD had an average tumor size of 1.4 cm versus 2 cm in the group without CNLD (
p
< 0.05). Patients who underwent CNLD had an average of 8 nodes removed, and positive nodes were found in 33%. Patients with CNLD received a higher dose of RAI, 102.7 mCi versus 66.3 mCi (
p
< 0.05). The incidence of positive nodes correlated with an increased RAI dose (
r
= 0.55). Rates of parathyroid removal and autotransplantation were higher in the CNLD group, 36 and 16% in the CNLD group versus 22 and 3% in the group without CNLD (
p
= 0.4 and
p
= 0.07). Rates of temporary hypocalcemia were higher in the CNLD group (31 versus 5%;
p
= 0.001), however rates of permanent hypocalcemia were similar, 1/35 in the no CNLD group versus 0/45 in the CNLD group (
p
= 0.4). There was a higher recurrence rate among patients without CNLD 6/36 (16.7%) versus 2/45 (4.4%), although this difference was not statistically significant (
p
= 0.13).
Conclusions
Routine CNLD as an adjunct to total thyroidectomy identifies positive nodes in over 30% of patients with PTC. The discovery of positive nodes is associated with higher doses of RAI for postoperative ablation, and there is a trend toward decreased recurrence in patients undergoing CNLD.
Background
The routine use of external beam radiotherapy (EBRT) is not recommended for parathyroid carcinoma (PC). However, case series have demonstrated a potential benefit in preventing local ...recurrence with EBRT. We aimed to characterize the patient population treated with EBRT and identify any impact of EBRT on overall survival (OS) in parathyroid carcinoma.
Methods
Patients who underwent surgery for PC from 2004 to 2016 were identified from the National Cancer Database. Clinicopathologic variables and OS were compared between patients based on treatment with EBRT. Multivariable logistic and Cox regression models were performed with propensity scores and inverse-probability-weighting (IPW) adjustment to reduce treatment-selection bias in the OS analysis.
Results
A total of 885 patients met the inclusion criteria, with 126 (14.2%) undergoing EBRT. Demographics were similar between the two cohorts (EBRT vs. no EBRT). However, patients treated with EBRT had a higher frequency of regionally extensive disease, nodal metastases, and residual microscopic disease (all
p
< 0.05). On multivariable analysis, Black race, regional tumor extension, nodal metastasis, and treatment at an urban facility were independently associated with EBRT. The 5-year OS was 85.3% with a median follow-up of 60.8 months. EBRT was not associated with a difference in OS in crude, multivariable, or IPW models. More importantly, 10.5% of patients with completely resected localized disease (M0, N0 or Nx) underwent EBRT without a benefit in OS (
p
= 0.183).
Conclusions
EBRT is not associated with any survival benefit in the treatment of PC. Therefore, it may be overutilized, particularly in patients with localized disease and complete surgical resection.
Background Our aim was to determine the learning curve for robotic adrenalectomy and factors that influence operative time and cost. Methods We prospectively evaluated of 100 consecutive patients who ...underwent robotic, unilateral, transperitoneal adrenalectomy. Results The mean operative time for robotic-assisted adrenalectomy was 95 minutes and conversion rate was 5%. Pathology was aldosteronoma ( n = 39), pheochromocytoma ( n = 24), nonfunctional adenoma ( n = 19), Cushing adenoma or hyperplasia ( n = 16), and cyst ( n = 2). Morbidity and mortality rates were 10% and 0%, respectively. The mean operative time decreased by 1 minute every 10 cases. Operative time improved more for junior surgeons than for senior surgeons ( P = .006) after the first 50 cases. By multiple regression analysis, surgeon's experience (−18.9 ± 5.5), first assistant level (−7.8 ± 3.2), and tumor size (3 ± 1.4) were independent predictors of operative time ( P < .001 each). The robotic procedure was 2.3 times more costly than lateral transperitoneal laparoscopic adrenalectomy (€4102 vs €1799). Conclusions Surgeon experience, resident training level, and tumor size are important variables for robotic-assisted, unilateral adrenalectomy and should be taken into account when this approach is evaluated. Controlled studies need to be performed to show potential relevant clinical benefits that could balance costs.
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