Impact of initial imaging with gallium-68 dotatate PET/CT on diagnosis and management of patients with neuroendocrine tumors.

BACKGROUND: Somatostatin analog functional imaging with gallium-68 (Ga-68) dotatate positron emission tomography/computed tomography (PET/CT) has demonstrated superiority in lesion detection in patients with neuroendocrine tumors (NETs). The clinical impact of this imaging modality on US surgical and medical oncology practices has not been established. METHODS: Consecutive patients with NET at our institution who received an initial Ga-68 dotatate PET/CT between July 2017 and September 2018 were included. Ga-68 dotatate PET/CT was compared with prior imaging. RESULTS: Among 101 eligible patients, 51 of 50 were female/male, site of origin was gastroenteropancreatic (75%), unknown primary (13%), lung (8%), thymus (2%), and other (2%). All NETs were histologically well/moderately differentiated. Ga-68 dotatate imaging findings altered management in 36 (35.6%) patients: documentation of progression led to the initiation of systemic therapy in 14 patients, obviated the need for biopsy in four patients, and altered surgical plans in 7 of 14 (50%) patients referred for surgery. In 11 patients, decisions regarding peptide receptor radionucleotide therapy and somatostatin analogs were altered. CONCLUSIONS: In this series, Ga-68 dotatate PET/CT altered diagnosis and management in one-third of patients and changed operative plans in half of the patients who were referred for surgical evaluation. These results support the routine use of this imaging in the care of patients with early-stage and advanced NETs.

The impact of neoadjuvant chemoradiotherapy on perioperative outcomes, tumor pathology, and survival in clinical stage II and III esophageal cancer.

BACKGROUND: The purpose of this study was to evaluate the impact of neoadjuvant chemoradiotherapy (NCR) on perioperative outcomes, tumor pathology, and survival following surgical resection of clinical stage II and III esophageal cancer. METHODS: Patients undergoing esophagectomy for clinical stage II and III cancer were divided into two groups: those who received NCR and those who underwent primary surgery (1991-2011). RESULTS: A total of 173 (50.9%) of 340 stage II/III patients received NCR, 108 (31.8%) patients underwent primary surgery, and 59 (17.4%) underwent neoadjuvant chemotherapy followed by surgery. Patients who received NCR were younger but had a similar Charlson comorbidity index and incidence of adenocarcinoma. There were no differences between groups in the incidence of complications, in-hospital mortality, and ICU stay, but patients who received NCR demonstrated a reduced length of hospital stay. NCR was associated with a reduced the incidence of positive pathological lymph node status and positive resection margin (3.1 vs. 21.1%) in stage III esophageal cancer. No overall survival benefit was seen with use of NCR, although a nonsignificant improvement in survival of 22 months (p = 0.06) was noted in patients with adenocarcinoma. Negative resection margin was associated with an improved survival in both stage II and III patients. CONCLUSIONS: This study highlights the importance of planning operations to optimize the opportunity to provide negative surgical resection margins and to identify patients not responding to NCR to allow them to proceed directly to surgery. Additional assessment of the effect of NCR on patients with adenocarcinoma is warranted.

A Community-based study on the prevalence and predisposing factors of Parkinson's disease in Barangay Mangilag Sur, Quezon Province, Philippines.

Introduction: Prevalence of Parkinson's Disease (PD) in the Philippines has been estimated to be < 1 % based on a 2007 nationwide survey conducted by the Philippine Neurological Association, but without case ascertainment. Since there is still paucity of data, we aim to determine the prevalence of PD in a rural community and the possible predisposing factors on the development of the disease. Methods: This is a two-phase descriptive study which investigated the prevalence of PD and associated risk factors in a randomly selected rural community in Candelaria, Quezon Province. A validated screening questionnaire was utilized, and case ascertainment was done in eligible respondents. Results: A total of 365 respondents aged ≥ 20 years were randomly surveyed from 2016 to 2017. Two cases of PD aged ≥ 60 years were reported. Thus, the prevalence of PD in the community was 0.55 %. Age-specific prevalence of PD among individuals ≥ 60 years was 4.35 %.Insecticide use was infrequent in the community and was recorded in one PD patient. Protective factors like smoking and drinking tea were not observed in both cases whereas coffee intake was reported in one PD patient. Conclusion: This community-based epidemiologic study on PD is consistent with a nationwide study. The study portrayed certain demographic and environmental features inherent in a community, which are potential confounding variables in PD development. Future larger population studies be recommended to establish PD in the advancing age and to further support the link of various factors with PD.

Phase II Trial of Carfilzomib Plus Irinotecan in Patients With Small-cell Lung Cancer Who Have Progressed on Prior Platinum-based Chemotherapy.

INTRODUCTION: The purpose of this study was to evaluate the efficacy and tolerability of carfilzomib plus irinotecan (C/I) in patients with relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC who progressed after 1 platinum-containing regimen for recurrent or metastatic disease were eligible. Patients were stratified as: sensitive (SS) (progressive disease > 90 days after chemotherapy) or refractory (RS) (progressive disease 30 to 90 days after chemotherapy) and received up to 6 cycles of C/I; imaging was performed every 2 cycles. The primary endpoint was 6-month overall survival (OS). RESULTS: All 62 patients enrolled were evaluable for efficacy and adverse events. 6-month OS was 59% in the platinum SS and 54% in the platinum RS. The overall response rate was 21.6% (2.7% complete response, 18.9% partial response) in SS (n = 37) and 12.5% (all partial response) in RS (n = 25). The disease control rate was 68% (SS) and 56% (RS). Progression-free survival and OS were 3.6 months (95% confidence interval [CI], 2.6-4.6 months) and 6.9 months (95% CI, 4.3-12.3 months) in SS, and 3.3 months (95% CI, 1.8-3.9 months) and 6.8 months (95% CI, 4.1-11 months) in RS. Twenty-nine (47%) patients experienced ≥ grade 3 adverse events; 8 (12.9%) subjects had grade 4 toxicities. Three treatment-related deaths occurred: myocardial infarction (possible), lung infection (possible), and sepsis (probable). CONCLUSION: In patients with relapsed SCLC, C/I was effective in the treatment of SS and RS. With 4.8% grade 5 toxicity, C/I is a viable option for relapsed patients with SCLC with performance status 0 to 1, particularly in platinum-resistant patients, or subjects who cannot receive immunotherapy.

Validation of the severity index by cardiac catheterization and Doppler echocardiography in patients with aortic sclerosis and stenosis.

The severity index is a new echocardiographic measure that is thought to be an accurate indicator of aortic leaflet pathology in patients with AS. However, it has not been validated against cardiac catheterization or Doppler echocardiographic measures of AS severity nor has it been applied to patients with aortic sclerosis. The purposes of this study were to compare the severity index to invasive hemodynamics and Doppler echocardiography across the spectrum of calcific aortic valve disease, including aortic sclerosis and AS. 48 patients with aortic sclerosis and AS undergoing echocardiography and cardiac catheterization comprised the study population. The aortic valve leaflets were assessed for mobility (scale 1 to 6) and calcification (scale 1 to 4) and the severity index was calculated as the sum of the mobility and calcification scores according to the methods of Bahler et al. The severity index increased with increasing severity of aortic valve disease; the severity indices for patients with aortic sclerosis, mild to moderate AS and severe AS were 3.38 +/- 1.06, 6.45 +/- 2.16 and 8.38 +/- 1.41, respectively. The aortic jet velocity by echocardiography and the square root of the maximum aortic valve gradient by cardiac catheterization correlated well with the severity index (r = 0.84, p < 0.0001; r = 0.84, p < 0.0001, respectively). These results confirm that the severity index correlates with hemodynamic severity of aortic valve disease and may prove to be a useful measure in patients with aortic sclerosis and AS.

Association between progression of aortic valve calcification and coronary calcification: assessment by electron beam tomography.

RATIONALE AND OBJECTIVES: It has been demonstrated that aortic valve calcification (AVC) shares many similarities with coronary atherosclerosis, including risk factors and pathologic characteristics. We sought to examine the relationship of AVC to coronary artery calcification (CC), to assess whether similar risk factors affect the process in a similar way. MATERIALS AND METHODS: The study included 620 asymptomatic persons (513 men and 107 women, mean age 59 years range [30-82]) who underwent two consecutive electron beam tomography (EBT) scans at least 1 year apart (mean 3.3 years). Calcification scores were obtained by summation of Agatston and volumetric scores. Stabilization of calcium was defined as no increase in score per year or positive percent change in score 1%/year. Of 106 with AVC, 105 (99%) had CC. Sixty-five patients had an AVC >10 on initial scan, and 50 (77%) demonstrated progression on the follow-up scan. Of 394 participants with CC >10 on initial scan, follow-up scans showed CC stabilization in 64 (16.2%) and CC progression in 330 (83.8%). Patients with AVC were significantly older than those with only CC (64.5 versus 56.5 years, P < .0001). The average age of the patient with AVC was 7 years older than the average age with CC. AVC (by volumetric score) progressed more rapidly in patients with diabetes (P = .036) and smoking (P = .042) than those without. RESULTS: We found no difference in the degree of change in the CC scores (by Agatston or volumetric methods) over time between men and women, or in any baseline cardiac risk factor (P > .05 for all measures). In 65 patients with both AVC and CC >10, there was a significant association between progression of AVC and CC (P = .047); the absolute rate of change of AVC was 24.5 +/- 43.2 %/year, and CC was 28.0 +/- 49.1 %/year. CONCLUSION: Virtually all patients with AVC had CC, potentially explaining the coronary risk associated with AVC. There is substantially parallel development between rates of progression of EBT-assessed AVC and CC.

Usefulness of aortic valve calcium scores by electron beam computed tomography as a marker for aortic stenosis.

This study was undertaken to determine whether aortic valve calcium (AVC) scores measured by electron beam tomography can identify patients with echocardiographically defined aortic stenosis. Electron beam tomography is increasingly being used to detect coronary artery calcium. AVC can also be measured on electron beam tomographic (EBT) scans obtained to screen for coronary calcium. Whether EBT AVC scores correlate with the presence of aortic stenosis, as assessed by echocardiography, is unknown. Results of this study suggest that AVC scores should be calculated routinely for coronary calcium screening EBT scans, and that patients with Agatston AVC scores above a certain level (e.g., >150) should be referred for echocardiography.

Protein phosphatase 1 ß paralogs encode the zebrafish myosin phosphatase catalytic subunit.

BACKGROUND: The myosin phosphatase is a highly conserved regulator of actomyosin contractility. Zebrafish has emerged as an ideal model system to study the in vivo role of myosin phosphatase in controlling cell contractility, cell movement and epithelial biology. Most work in zebrafish has focused on the regulatory subunit of the myosin phosphatase called Mypt1. In this work, we examined the critical role of Protein Phosphatase 1, PP1, the catalytic subunit of the myosin phosphatase. METHODOLOGY/PRINCIPAL FINDINGS: We observed that in zebrafish two paralogous genes encoding PP1ß, called ppp1cba and ppp1cbb, are both broadly expressed during early development. Furthermore, we found that both gene products interact with Mypt1 and assemble an active myosin phosphatase complex. In addition, expression of this complex results in dephosphorylation of the myosin regulatory light chain and large scale rearrangements of the actin cytoskeleton. Morpholino knock-down of ppp1cba and ppp1cbb results in severe defects in morphogenetic cell movements during gastrulation through loss of myosin phosphatase function. CONCLUSIONS/SIGNIFICANCE: Our work demonstrates that zebrafish have two genes encoding PP1ß, both of which can interact with Mypt1 and assemble an active myosin phosphatase. In addition, both genes are required for convergence and extension during gastrulation and correct dosage of the protein products is required.

Chemotherapy for metastatic colorectal cancer.

The past decade has seen a significant survival improvement for patients with metastatic colorectal cancer, fueled in large part by the arrival of active novel chemotherapeutic drugs and their incorporation into combination regimens. Several randomized trials have successfully integrated oxaliplatin and irinotecan into previously existing 5-fluorouracil (5-FU)-based regimens for advanced colorectal cancer, resulting in median survivals that have risen from 9 months to almost 2 years. Even as the ideal combinations and sequences of these regimens are elucidated, targeted therapies such as recently approved bevacizumab and cetuximab have been added to treatment protocols, with favorable consequences. We review the evolution of primary chemotherapy for advanced colorectal cancer, focusing on the trials that have led to the new standard first-line treatments. We also review the data on newer targeted therapies, especially in combination with cytotoxic therapy.