A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: Palbociclib, a cyclin D kinase 4 (CDK4)/6 inhibitor, has shown radiosensitizing effects in preclinical studies. There is a strong rationale for adding palbociclib to cetuximab and radiotherapy in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), especially in p16-negative HNSCC. PATIENTS AND METHODS: We conducted a phase I dose-escalation study (NCT03024489) using a classical 3+3 design to determine safety, tolerability, and MTD of palbociclib, cetuximab, and intensity-modulated radiotherapy (IMRT) combination. At the recommended phase II dose (RP2D), additional p16-negative patients were enrolled. RESULTS: Twenty-seven patients with LA-HNSCC (13 in dose escalation, 14 in expansion) with oropharyngeal (41%) and hypopharyngeal (30%) cancers were enrolled. The MTD was not reached, and the RP2D of palbociclib was established at the full standard palbociclib dose of 125 mg/day for 21 days per cycle, administered for two cycles during IMRT. The most common grade 3-4 toxicities were mucositis (59%), radiation dermatitis (22%), and neutropenia (22%), with a febrile neutropenia rate of 7%. Common genomic alterations included mutations in TP53 (57%), GNAQ (35%), and PIK3CA (17%), and copy-number gains in CCND1 (22%), CCND2 (9%), and EGFR (9%). Overall, p16 expression was positive in 15% of patients. No correlation was observed between p16 status, genomic alterations, and preliminary efficacy. The objective response rate was 84%. The rates for 2-year locoregional control, event-free survival, and overall survival were 73%, 48%, and 71%, respectively. CONCLUSIONS: The palbociclib, cetuximab, and IMRT combination was well tolerated. The RP2D was established, while no MTD was determined. The regimen demonstrated promising preliminary efficacy, suggesting further investigation is warranted in patients with cisplatin-ineligible p16/human papilloma virus-unrelated LA-HNSCC.

Bone Mineral Density and Trabecular Bone Score in Predicting Vertebral Fractures in Male Employees of the Electricity Generating Authority of Thailand.

Purpose: Osteoporotic VF is frequently asymptomatic and affects not only women but also men. Identifying patients at risk is essential for early management and prevention. BMD and the TBS are measurements of bone strength and trabecular microarchitecture, respectively. Their role in VF prediction in men is less well-studied. We determined the BMD and TBS predictive ability for osteoporotic VF in men. Methods: A total of 115 male participants of the Electricity Generating Authority of Thailand (EGAT) cohorts without a history of VF who completed the baseline BMD and TBS measurements in 2012 and a thoracolumbar spine radiograph in 2017 were recruited. The VF was assessed using the Genant semiquantitative method. Logistic regression analysis was performed to identify factors associated with the fracture. The area under the receiving operator curve (AUC) was analyzed to define VF predictive ability. Results: Forty subjects (34.78%) had VFs. The unadjusted relative risks (95% confidence interval) for VF for one standard deviation decrease in the TBS and low TBS were 1.319 (1.157-1.506) and 2.347 (1.496-3.682), respectively, and remained significant after BMD and age adjustment. For VF prediction, combined models had a greater AUC than models predicted from a single variable. The use of low TBS, femoral neck BMD, and age provided the best AUC (0.693). Conclusion: BMD and the TBS could predict osteoporotic VF in male EGAT employees. The use of both BMD and the TBS in the VF prediction process improved predictive ability.

Risk-stratified papillary thyroid microcarcinoma: post-operative management and treatment outcome in a single center.

PURPOSE: This article aims to review and assess the post-operative management and treatment outcomes of papillary thyroid microcarcinoma (PTMC) in risk-stratified patients. METHODS: We retrospectively analyzed the data of PTMC patients who underwent thyroid surgery with or without radioactive iodine treatment (RAI) in a single center between January 2011 and December 2017. Demographic and clinicopathologic data were collected. Risk stratification according to the 2015 American Thyroid Association guideline was applied. RESULTS: Three hundred forty PTMC patients were included. Post-operative RAI was performed in 216/340 (63.53%) patients. In the non-RAI scenario, there were 122 low-risk and two intermediate-risk patients. In total, 261 (76.77%), 57 (16.76%), and 22 (6.47%) patients were classified as low, intermediate, and high risk, respectively. With a median follow-up time of 36 months (interquartile range: 23, 52), we found unfavorable outcomes (evidenced by imaging or out-of-range serum tumor marker levels: high thyroglobulin [Tg] or rising Tg antibody [TgAb] levels) in 8/340 (2.35%) patients, all of which received RAI. PTMC patients with unfavorable outcomes were stratified as low risk (4/261 [1.53%]), intermediate risk (1/57 [1.75%]), or high risk (3/22 [13.64%]). One death occurred in a patient with initial distant metastasis in the high-risk group. Initial high-risk stratification and initial stimulated Tg (of at least 10 ng/mL) were demonstrated as independent predictors for PTMC unfavorable outcomes (persistent or recurrent disease). Five patients with unfavorable outcomes (four with persistent disease and one with recurrent disease) had abnormal Tg or TgAb values despite unremarkable imaging findings. Moreover, 79/124 (63.71%) patients in the non-RAI scenario were only followed up with neck ultrasound. CONCLUSIONS: In general, at least 98% of low-risk and intermediate-risk PTMC patients showed favorable outcomes without persistent or recurrent disease, defined by either imaging or serum tumor markers. Nevertheless, aggressive disease could occur in few PTMC patients. Decisions on post-operative management and follow-up may be guided by initial high-risk stratification and initial stimulated Tg levels (≥10 ng/mL) as independent predictors for PTMC unfavorable outcomes. Monitoring using both imaging and serum tumor markers is crucial and should be implemented for patients with PTMC.

Precision and Effects of a Small Meal on DXA-Derived Visceral Adipose Tissue, Appendicular Lean Mass, and Other Body Composition Estimates In Nonobese Elderly Men.

BACKGROUND: Information on precision errors and the least significant change (LSC) of dual energy X-ray absorptiometry (DXA)-derived body composition estimates is scarce, particularly for the appendicular lean mass (ALM) and appendicular lean mass index (ALMI). Overnight fasting is recommended for body composition measurements but has not been well tolerated by some elderly patients. This study aimed to establish precision errors and LSC values of body composition estimates in all regions-including visceral adipose tissue (VAT) and ALM-and the ALMI to assess the effect of a small meal on body composition and to estimate the changes it incurred. METHODOLOGY: Our institutional review board approved the study protocol. Altogether, 36 non-obese men aged ≥60 years, having given written informed consent, underwent body composition assessment after fasting overnight except for water. They underwent DXA scans three times, each time with repositioning (to simulate the clinical setting), the last after consuming a standardized meal (210-250 g and 200 cc of water). RESULTS: Precision errors and LSC values of DXA-derived body composition estimates in these elderly men tended to be higher than those in reports on younger subjects. Coefficients of variation (CVs (%)) of total bone mass (Tb.BMC) and total lean mass (Tb.LM) were <1%, whereas those of total fat mass (Tb.FM) and total %fat mass (Tb.%FM) were <2%, with LSCs of 45.8 g, 706.52 g, 731.4 g, and 1.15%, respectively. The CVs (LSC) of VAT, ALM, and ALMI were 8.9% (150.65 g), 0.93% (501 g), and 0.94% (0.19), respectively. After meal consumption, the mean changes in Tb.FM, Tb.BMC, and Tb.LM were -100, -8.2, and 440 g, respectively. CONCLUSIONS: Effects of a small meal on most parameters were trivial, including those for VAT, ALM, and ALMI, where changes were not statistically significant. None exceeded the LSC of ALM and ALMI, suggesting that a small meal is allowable before these measurements.

Iodine-131 metaiodobenzylguanidine (131I-mIBG) treatment in relapsed/refractory neuroblastoma.

BACKGROUND: I-meta-iodo-benzylguanidine (I-mIBG) therapy has been used in treatment of for advanced neuroblastoma for many years with promising results. There are several studies regarding predictors and outcomes of I-mIBG therapies in relapsed/refractory neuroblastoma patients. OBJECTIVE: To identify the predictors and outcomes of I-mIBG treatment in relapsed/refractory neuroblastoma. METHODS: This study was a retrospective review of 22 patients with high risk stage IV relapsed/refractory neuroblastoma who received at least one cycle of I-mIBG therapy. Patient' characteristics, hematologic toxicity, scintigraphic semi-quantitative scoring, and overall survival were recorded. Factors predicting survival were analyzed. RESULTS: Twenty-two patients (50% male) with mean age of 3.7 years (4.8 months to 8.3 years) received I-mIBG therapies at an average of 3.8 and mean dose of 136 mCi (5032 MBq) per treatment. Most common acute hematologic toxicity was thrombocytopenia. Overall 5-year survival rate was 37% (95% confidence interval: 16.3-58.0) and median survival time was 2.8 year (95% confidence interval: 1.38-6.34). Patients with rising Curie score of ≥25% upon the second therapy were major determinants of overall survival with poorer response to treatment. At least three treatments of I-mIBG were needed to identify some degrees of survival prolongation (crude hazard ratio: P-value = 0.003). Age, sex, metastatic status, and baseline Curie scoring system were good predictors associated with survival. Seven patients (32%) demonstrated objective responses. CONCLUSION: Despite multimodality therapy, high risk neuroblastoma had a propensity of treatment failure in terms of relapsed or refractory, with some objective responses after I-mIBG treatments. The declined or non-rising Curie score upon second post-treatment total body scan was an important predictor of survival and aided a decision whether or not to proceed with bone marrow transplantation.

Errors in Patient Positioning for Bone Mineral Density Assessment by Dual X-Ray Absorptiometry: Effect of Technologist Retraining.

Improper positioning is one of the factors that can lead to incorrect bone mineral density (BMD) results. This study aimed to assess the frequencies of erroneous positioning during three periods: before retraining of the technologists (BR), after retraining (AR), and at the current timepoint 8 years after retraining (C). The BMD images of the first 150 consecutive patients who underwent DXA of the lumbar spine and hip during each of the three periods were retrospectively reviewed. Patients were excluded if they had severe scoliosis, rendering proper positioning impossible. Each BMD image was assessed by an International Society of Clinical Densitometry certified clinical densitometrist who was blinded to the date of the initial examination. For the lumbar spine in the BR group, the criteria frequently not met were inclusion of both iliac crests (33.8%), straightness (30.3%), and midline positioning (20.4%); the respective frequencies were significantly reduced to 0.8%-5.6%, 2.1%-3.0%, and 0%-2.8% in the AR and C groups (p < 0.05). For the hip in the BR group, the criteria frequently not met were straightness (52.8%) and internal rotation (21.8%); the respective frequencies were significantly reduced to 0%-4.2% and 8.3%-8.4% in the AR and C groups (p < 0.05). Overall improper positioning in the BR group was 49.3% and 57.3% at the lumbar spine and the hip, respectively; the respective frequencies were reduced to 9.3% and 12.7% in the AR group, and to 2.7% and 7.3% in the C group. The least significant change values for the lumbar spine, femoral neck, and total hip also became smaller after retraining. Retraining the technologists improved patient positioning, as evidenced by the decreased frequencies of erroneous positioning and the improved least significant change values after the retraining.

Simulated increased soft tissue thickness artefactually decreases trabecular bone score: a phantom study.

BACKGROUND: Trabecular bone score (TBS), which has been proposed to be used in complementary with bone mineral density (BMD) to improve the assessment of fracture risk, is negatively associated with body mass index (BMI). The effect of soft tissue, which is expected to be thicker in subjects with high BMI, on TBS was studied using three scan types: Hologic with fast array mode (Hfa), Hologic with high definition mode (Hhd), and GE-Lunar iDXA. METHODS: A spine phantom provided by Hologic for routine quality control procedure was scanned using three scan types: Hfa, Hhd, and iDXA. The phantom was scanned with an overlying soft tissue equivalent material (bolus used in radiotherapy) of 0 (without), 1, 2.5, 3.5, 5 and 7.5 cm thick. For each setting, 30 acquisitions were performed in the same way as for the quality control procedure. TBS was calculated using TBS iNsight® software version 2.1 on the same regions of interest as those used for lumbar spine BMD. RESULTS: Mean ± SD TBS of the phantom (without overlying soft tissue) were 1.379 ± 0.018, 1.430 ± 0.009, and 1.423 ± 0.005 using Hfa, Hhd, and iDXA, respectively. A one-way repeated measures ANOVA showed that there were statistically differences in TBS due to different thicknesses of soft tissue equivalent materials for all three scan types (p < 0.001). A Tukey post-hoc test revealed that the decrease in TBS was statistically significant (p < 0.001) when the soft tissue thickness was 1 cm (-0.0246 ± 0.0044, -0.0319 ± 0.0036, and -0.0552 ± 0.0015 for Hfa, Hhd, and iDXA, respectively). Although to a lesser degree, the effects were also statistically significant for BMD (p < 0.05): an increase for Hfa and Hhd but a decrease for iDXA. However, these changes did not exceed the least significant change (LSC) derived from patients. CONCLUSIONS: Increased soft tissue thickness results in lower TBS value. Although BMD is also affected, it is unlikely to pose a clinical problem because the change is unlikely to exceed the patient-derived LSC.

Incidental Gallbladder Cancer Visualized From Posttreatment 131I Whole-Body Scan.

A 72-year-old woman with papillary thyroid cancer post-total thyroidectomy was referred for post-I treatment whole-body scan. Images revealed focal uptake within the gallbladder. Cholecystectomy was subsequently performed, and the pathology report showed well-differentiated adenocarcinoma. Given a history of papillary thyroid cancer, the iodine uptake was reasonably explained as metastasis; however, gallbladder metastasis was extremely infrequent. Literature described the incidental radioiodine retention in the gallbladder as false-positive findings, which can be normal variants or benign hepatobiliary conditions. Primary gallbladder malignancy could be counted for another possibility despite controversial mechanism of uptake.

Factors affecting disease-free status of differentiated thyroid carcinoma patients.

PURPOSE: The study aim was to assess factors that impact on the outcome of radioiodine therapy in patients diagnosed with differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: We performed a retrospective cohort study on 256 patients with DTC who underwent thyroidectomy and received radioiodine therapy during December 2003 to January 2012. All patients were followed up for at least 1 year. They were considered disease- free by the criteria of the revised American Thyroid Association Management Guideline for Patients with Thyroid nodules and DTC (ATA guideline 2009). RESULTS: On Cox univariate analysis, factors associated with disease-free status were age<45, stage I tumor, low risk group by histopathology, unifocal tumor involvement, stimulated serum Tg level at 1st dose of radioiodine therapy and no distant metastasis from 1st post-treatment WBS (post RxWBS). On multivariate analysis, stage I tumor and stimulated serum Tg level at 1st dose of radioiodine therapy<30 ng/mL were the significant prognostic factors that increased disease-free rate by 1.73 times and 2.60 times, respectively (P-value<0.05). CONCLUSIONS: Factors affecting the outcome of radioiodine therapy in our study were age, stage, risk of recurrence by histopathology, unifocal tumor involvement and 1st postRxWBS findings. From these factors, stage I tumor and stimulated serum Tg level at 1st dose of radioiodine therapy were independent prognostic factors that substantial increase the disease-free rate.

Unexpectedly expected fetal thyroid function on posttreated radioiodine (131I) SPECT/CT of a patient with differentiated thyroid cancer.

We present a 25-year-old woman who has a diagnosis of differentiated thyroid cancer, a 2.5-cm papillary carcinoma in the right lobe, and presence of minimal extrathyroid invasion. 131I ablation and/or treatment of 150 mCi was given orally 3 months after total thyroidectomy. A fetus with radioiodine uptake in the fetal thyroid was unsuspectedly detected by SPECT/CT after 131I treatment.

131I-rituximab treatment in patient with relapsed non-Hodgkin's lymphoma: the first case report in Thailand.

Radioimmunotherapy (RIT) with 131-rituximab is a safe and effective treatment in patients with relapsed, refractory follicular lymphoma. The authors demonstrated the first case of 131-rituximab treatment in the patient with relapsed non-Hodgkin's lymphoma (NHL) in Thailand. There was no immediate complication after treatment. Impressive treatment response occurred.

Different distribution of (62) Cu ATSM and (18)F-FDG in head and neck cancers.

PURPOSE: [6²Cu]-diacetyl-bis(N4-methlythiosemicarbazone) (Cu-ATSM) was used to delineate hypoxic tissue in head-and-neck cancer, and its distribution was compared with that of ¹8F-FDG. MATERIALS AND METHODS: Thirty patients with head-and-neck cancer underwent Cu-ATSM and FDG PET within a 1 week interval. Accumulation of tracer for each PET image was converted to SUV. After coregisteration of PET images with individual anatomic images, multiple small ROIs were drawn on the tumor mass and applied to both PET images. SUV values were obtained for all ROIs (SUV(roi)), and the SUV(roi) regression lines between Cu-ATSM and FDG of each tumor were determined. RESULTS: The SUV mean of Cu-ATSM was lower than that of FDG for both squamous cell carcinoma (SCC) and adenocarcinoma (P < 0.05). In 27 patients with SCC, Cu-ATSM accumulated higher in the peripheral region than in the center of the tumor, and FDG showed the other tendency. Thus, the relationship of the SUV(roi) for Cu-ATSM and FDG showed a negative correlation in SCC. However, 3 adenocarcinoma cases showed similar and homogenous accumulation in the tumor mass with a positive SUV(roi) correlation for the 2 tracers. The regression slope means were -0.12 ± 0.08 for SCC (n = 27) and 0.28 ± 0.12 (n = 3) for adenocarcinoma. CONCLUSION: In patients with head-and-neck cancer, intratumoral distribution of Cu-ATSM and FDG showed a negative correlation in SCC and a positive correlation in adenocarcinoma. The 2 tracers represented different pathophysiological microenvironments in different tumors, suggesting that noninvasive hypoxic tissue imaging with Cu-ATSM would be beneficial in the pretreatment evaluation of head-and-neck cancer.

Cancers of the oral cavity and oropharynx: FDG PET with contrast-enhanced CT in the posttreatment setting.

The combined use of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and contrast material-enhanced computed tomography (CT) for posttreatment monitoring of cancers of the oral cavity and oropharynx has steadily increased in recent years. FDG PET/CT offers many advantages for evaluating the effects of therapy, determining whether residual or recurrent disease is present, and assessing the extent of nodal disease. Because of the high negative predictive value of this imaging test, some have advocated the deferral of neck dissection in patients with negative findings at FDG PET/CT after chemotherapy and radiation therapy; positive findings may have a similarly heavy influence on the future course of treatment. Thus, the accuracy of image interpretation is crucial. However, the interpretation of posttreatment FDG PET images is challenging, with multiple potential pitfalls and limitations that could lead to an incorrect analysis. Accuracy depends on a detailed knowledge of the patient's treatment history and a thorough understanding of the kinds of changes that might result from treatment. Awareness of the principles underlying the selection of the optimal interval between the completion of treatment and the first follow-up FDG PET/CT examination is especially important, since an interval that is too short could lead to false-positive or false-negative findings. A period of 12 weeks or more is generally recommended, but the optimal waiting period depends on the extent of therapy and other factors. If recurrence or progression is suspected during the waiting period, contrast-enhanced CT or magnetic resonance imaging should be performed without FDG PET.

PET/CT in oral cavity and oropharyngeal cancer in post therapy setting.

18F-FDG PET/CT is an immerging tool for follow-up a head and neck cancerpatients. Accurate PET/CT interpretation in a post therapy setting is crucial for proper management. However there are many limitations in post therapy settings. For example, variable degree of normal physiologic uptake is noted. Physiologic processes cannot be identified by symmetrical FDG uptake in a post therapy setting. The present article demonstrates case series including asymmetrical, abnormal, or unusual patterns of FDG uptake within the oral cavity and oropharyngeal structures in both benign and malignant conditions.

PET/CT evaluation of cervical cancer: spectrum of disease.

The prognosis of invasive cervical cancer is based on the stage, size, and histologic grade of the primary tumor and the status of the lymph nodes. Assessment of disease stage is essential in determining proper management in individual cases. In the posttherapy setting, the timely detection of recurrence is essential for guiding management and may lead to increased survival. However, the official clinical staging system of the International Federation of Gynecology and Obstetrics has inherent flaws that may lead to inaccurate staging and improper management. Combined positron emission tomography (PET)/computed tomography (CT) represents a major technologic advance, consisting of two integrated complementary modalities whose combined strength tends to overcome their respective weaknesses. PET/CT has higher sensitivity and specificity than do conventional anatomic modalities and is valuable in determining the extent of disease and detecting recurrent or residual tumor. The combination of 2-[fluorine-18]fluoro-2-deoxy-d-glucose PET with intravenous contrast material-enhanced high-resolution CT has proved useful for avoiding the interpretative weaknesses associated with either modality alone and in increasing the accuracy of staging or restaging. Nonetheless, accurate PET/CT interpretation requires a knowledge of the characteristics of disease spread or recurrence and an awareness of various imaging pitfalls if false interpretations are to be avoided.

FDG PET with contrast-enhanced CT: a critical imaging tool for laryngeal carcinoma.

Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has evolved to be an essential imaging modality in the evaluation of laryngeal carcinoma. Although the modality has limited utility in assessing the extent of the primary tumor, FDG PET has proved to be superior to anatomic modalities in the detection of lymph node and distant metastases. The role of FDG PET in the evaluation of patients with laryngeal tumors that are clinically classified as N0 has not shown consistent usefulness because of the innate resolution limitations of the camera. In the posttherapy setting, however, FDG PET has consistently demonstrated a high negative predictive value in the identification of recurrent disease, both during the course of therapy and during long-term follow-up. In addition, contrast material-enhanced computed tomography (CT) in conjunction with FDG PET has demonstrated a complementary role by allowing for superior anatomic coregistration and therefore more definitive diagnosis. There is sufficient evidence that with further advances in PET technology, this modality will likely become more useful in the detection of small lesions and occult nodal disease, as well as in guiding the management of laryngeal carcinoma.

Correlation between myocardial perfusion imaging findings and cardiac events.

OBJECTIVE: The excellent prognostic value of a normal or near normal stress myocardial perfusion imaging (MPI) has been confirmed in numerous studies. The aim of the present study was to determine the association of MPI findings and cardiac events. MATERIAL AND METHOD: Consecutive patients referred from January 2003 to December 2004 by Nuclear Medicine Unit in Ramathibodi Hospital for myocardial perfusion imaging were studied. Visual scoring of perfusion images used 17-segments and a scale of 0-4 was done. Sum stress score (SSS) was generated Cardiac death, death from any cause and nonfatal acute myocardial infarction (MI) were considered major cardiac events, and chest pain and late revascularization > 60 days after testing were considered minor cardiac events. RESULTS: Of the 320 patients studied, 218 subjects who had complete 1-year follow-up, were enrolled. There were 99 patients with normal MPI (SSS < or = 3) and 119 patients with abnormal MPI (SSS > 3). Statistical significance between cardiac events in two groups (p < 0.001) was detected. Among hard events, there were three cardiac deaths (of these, 1 occurred in a patient with normal MPI and 2 in those with abnormal MPI) and no patients had non-fatal MI in both groups. Among minor cardiac events, 17 patients developed chest pain and 11 patients underwent late revascularization. No patient with normal MPI underwent revascularization (included early and late revascularization) was found. CONCLUSION: These results show that SSS can be used to provide incremental prognostic information beyond clinical data, which confirms the conclusions drawn from the results of previous studies by using nuclear stress test results.