Serum fibulin-3 as a diagnostic and prognostic biomarker in patients with knee osteoarthritis.

BACKGROUND: Osteoarthritis is a chronic degenerative disorder with rising prevalence. Early detection of structural damage is difficult. Consequently, there is a pressing demand for reliable biomarkers that enable an earlier diagnosis of osteoarthritis. The aim is to investigate the level of serum fibulin-3 in patients with primary knee osteoarthritis and its correlation with disease severity. SUBJECTS AND METHODS: A case-control study was conducted at the Baqubah Teaching Hospital from November 2023 to January 2024. One hundred twenty persons participated in this study (eighty females with the diagnosis of knee osteoarthritis in its early and late stages, and forty age-matched, apparently healthy control. Serum fibulin-3, ESR, CRP, and calcium levels were measured for all participants. Ethical approval was obtained. SPSS was used for data analysis. RESULTS: Patients with osteoarthritis had considerably higher serum levels of fibulin-3. In patients with late-stage knee osteoarthritis, this rise was greater than in earlier stages. Serum fibulin and ESR are positively correlated. Fibulin's area under the curve is 0.830 for diagnosis and 0.709 for differentiating between osteoarthritis's early and late stages. CONCLUSION: Serum levels of fibulin-3 can act as diagnostic markers for OA and may be useful in determining the severity of knee osteoarthritis.

Effect of Levothyroxine Therapy on the Lipid Profile of Patients With Hypothyroidism: A Systematic Review.

Hypothyroidism, also known as underactive thyroid, is a condition where the thyroid gland does not produce enough thyroid hormone. Deficiency or lack of thyroid hormone causes patients to have a slower metabolism, which may lead to secondary medical issues such as weight gain, fatigue, depression, and increased cardiovascular risk. This systematic review aims to explore the effect of levothyroxine therapy on the lipid profile of hypothyroid patients. Through a comprehensive search, 3096 articles were retrieved using keywords such as Hypothyroidism, Levothyroxine, Lipid, Dyslipidemia, and Cholesterol from PubMed, PubMed Central, Google Scholar, and ScienceDirect databases. The Medical Subject Headings (MeSH) strategy was also leveraged to extensively search the PubMed database. Research articles that were published from the year 2020 until May 2024, including randomized control trials, observational studies, meta-analyses, systematic reviews, literature reviews, and case reports, were included in the research. Research papers published before 2020, written in languages other than English, and animal studies were excluded. The 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were used in the design of the systematic review. Levothyroxine therapy is the treatment of choice in patients suffering from hypothyroidism, and based on our review, the treatment has a positive impact, leading to a significant decrease in total cholesterol, low-density lipoproteins, and triglyceride values in hypothyroid patients. The research highlights the importance of starting timely levothyroxine therapy in hypothyroid patients to maintain normal lipid levels and reduce the associated cardiovascular risk.

Exploring the Effect of Thyroid Hormone on Serum Lipoprotein (a) Levels in Patients With Thyroid Hormone Dysfunction: A Systematic Review.

Genetic variations among people mainly determine the blood levels of lipoprotein (a) (Lp(a)), and it is relatively stable throughout one's lifetime. Nevertheless, there could still be other factors that control the Lp(a) level. Thyroid hormones are known to influence the serum lipid level by regulating the expression of key enzymes that are involved in lipid metabolism. Both hypo and hyperthyroidism are associated with changes in lipid levels. Even though thyroid hormone abnormalities have been shown to alter traditional lipid parameters like low-density lipoprotein (LDL-C), its influence on Lp(a) has not been established. This review aims to identify the relationship between Lp(a) and thyroid hormones by reviewing data from correlative studies and observing treatment-related Lp(a) level changes in thyroid disorders from interventional studies. We searched MEDLINE, Cochrane, and Google Scholar databases with predefined search criteria and search strategies for paper identification. Individual reviewers reviewed identified papers for selection. Finalized papers were reviewed for Lp(a) levels and their responses to treatment in patients with thyroid disorders to establish the relationship between Lp(a) and thyroid hormone. We concluded that the data were limited and sometimes contradicted one another to establish a clear relationship between Lp(a) and thyroid hormones. Even though correlative studies data showed strong indications that overt-hypothyroidism was associated with high Lp(a) levels, thyroid hormone replacement studies did not show any significant changes in Lp(a) levels compared to pre-treatment in patients with both overt-hypothyroidism and subclinical hypothyroidism. More clinical trials focusing on Lp(a) with longer periods of treatment and follow-up in thyroid patients are needed to establish the relationship between the two. The possibility of dose-related Lp(a) responses to thyroid hormone treatment should also be explored.

Acute Hyperglycemia and Its Impact on Mortality of Acute Coronary Syndrome Patients: A Systematic Review.

Acute hyperglycemia or stress hyperglycemia is a frequent finding in patients with acute coronary syndrome (ACS). Several studies have demonstrated the association between acute hyperglycemia with short- and long-term mortality in ACS patients. But the evidence is not concrete. We gathered 1056 articles from three databases, i.e., PubMed, Google Scholar, and Science Direct using different search strategies and filters. We then removed duplicates and 919 articles were screened with title abstract and full text. After a full-text screening of 169 articles, we removed 116 articles. We then applied eligibility criteria and did a quality assessment of articles and finally, we included 21 articles in our study. The 21 articles spanned years 2014 to 2024. Of them, 16 articles were observational studies, two were systematic reviews and meta-analyses, and three were review articles. Six articles used stress hyperglycemia ratio (SHR) alone, seven articles used admission blood glucose (ABG) alone, two used fasting plasma glucose (FPG) alone and one used SHR, ABG, and FPG together as a parameter to measure acute hyperglycemia. Short-term poor outcomes (in-hospital, <30 days) were studied in 12 studies, and long-term poor outcomes (>30 days-1 year, >1 year) were studied in six studies. A positive correlation between acute hyperglycemia and short- and long-term mortality was found in our 21 included studies. The three parameters which are used to quantify acute or stress hyperglycemia in our study, i.e., SHR, ABG, and FPG predict both short- and long-term mortality in ACS patients. Further study is needed to determine the accurate cutoff level of hyperglycemia to be called acute hyperglycemia in diabetics. We tried to review the recent literature on this topic to deepen our understanding of this topic and to provide a base for future research.

A review of recent advancements in Actinium-225 labeled compounds and biomolecules for therapeutic purposes.

In nuclear medicine, cancers that cannot be cured or can only be treated partially by traditional techniques like surgery or chemotherapy are killed by ionizing radiation as a form of therapeutic treatment. Actinium-225 is an alpha-emitting radionuclide that is highly encouraging as a therapeutic approach and more promising for targeted alpha therapy (TAT). Actinium-225 is the best candidate for tumor cells treatment and has physical characteristics such as high (LET) linear energy transfer (150 keV per µm), half-life (t1/2 = 9.92d), and short ranges (400-100 µm) which prevent the damage of normal healthy tissues. The introduction of various new radiopharmaceuticals and radioisotopes has significantly assisted the advancement of nuclear medicine. Ac-225 radiopharmaceuticals continuously demonstrate their potential as targeted alpha therapeutics. 225 Ac-labeled radiopharmaceuticals have confirmed their importance in medical and clinical areas by introducing [225 Ac]Ac-PSMA-617, [225 Ac]Ac-DOTATOC, [225 Ac]Ac-DOTA-substance-P, reported significantly improved response in patients with prostate cancer, neuroendocrine, and glioma, respectively. The development of these radiopharmaceuticals required a suitable buffer, incubation time, optimal pH, and reaction temperature. There is a growing need to standardize quality control (QC) testing techniques such as radiochemical purity (RCP). This review aims to summarize the development of the Ac-225 labeled compounds and biomolecules. The current state of their reported resulting clinical applications is also summarized as well.

Insight into prognostics, diagnostics, and management strategies for SARS CoV-2.

The foremost challenge in countering infectious diseases is the shortage of effective therapeutics. The emergence of coronavirus disease (COVID-19) outbreak has posed a great menace to the public health system globally, prompting unprecedented endeavors to contain the virus. Many countries have organized research programs for therapeutics and management development. However, the longstanding process has forced authorities to implement widespread infrastructures for detailed prognostic and diagnostics study of severe acute respiratory syndrome (SARS CoV-2). This review discussed nearly all the globally developed diagnostic methodologies reported for SARS CoV-2 detection. We have highlighted in detail the approaches for evaluating COVID-19 biomarkers along with the most employed nucleic acid- and protein-based detection methodologies and the causes of their severe downfall and rejection. As the variable variants of SARS CoV-2 came into the picture, we captured the breadth of newly integrated digital sensing prototypes comprised of plasmonic and field-effect transistor-based sensors along with commercially available food and drug administration (FDA) approved detection kits. However, more efforts are required to exploit the available resources to manufacture cheap and robust diagnostic methodologies. Likewise, the visualization and characterization tools along with the current challenges associated with waste-water surveillance, food security, contact tracing, and their role during this intense period of the pandemic have also been discussed. We expect that the integrated data will be supportive and aid in the evaluation of sensing technologies not only in current but also future pandemics.

Functionalized thiazolidone-decorated lanthanum-doped copper oxide: novel heterocyclic sea sponge morphology for the efficient detection of dopamine.

Herein, we synthesized lanthanum (La)-doped sea sponge-shaped copper oxide (CuO) nanoparticles and wrapped them with novel O-, N- and S-rich (2Z,5Z)-3-acetyl-2-((3,4-dimethylphenyl)imino)-5-(2-oxoindolin-3-ylidene)thiazolidin-4-one (La@CuO-DMT). The shape and composition of the designed materials were confirmed by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and Raman spectroscopy. The graphitic pencil electrode (GPE) fabricated using La@CuO-DMT showed excellent sensing efficacy against dopamine (DA) with good selectivity, reproducibility and ideal stability. The unique morphology and massive surface defects by La@CuO offer good accessibility to DA and enhance smooth and robust channeling of electrons at the electrode-electrolyte interface. Consequently, these properties resulted in improved reaction kinetics and robust DA oxidation with an amplified faradaic response. Meanwhile, O-, N-, and S-enriched carbon support, i.e. DMT, inhibited the leaching of electrode matrixes, resulting in a superior detection limit of 423 nm and an improved sensitivity of 13.9 µA µM-1 cm-2 in the linear range of 10 µM to 1500 µM. Additionally, the developed sensing interface was successfully employed to analyze DA from tear samples with excellent percentage recoveries. We expect that such engineered morphology-based nanoparticles with a O-, N-, and S-rich C support will facilitate the development of DA sensors for in vitro screening of rarely studied tear samples with good sensitivity and selectivity.

Vasitis Nodosa: A Rare Diagnosis for Inguinal Swelling.

Vasitis nodosa involves benign, reactive spindle-shaped nodular thickening of the ductal epithelium of vas deferens. We report the case of a 21-year-old male with a history of bilateral undescended testes and left orchidopexy. The patient presented with the complaint of a non-tender left inguinal swelling. The definitive diagnosis of vasitis nodosa was made based on clinical evaluation and imaging findings. We suggest that this rare entity should be considered as a differential diagnosis of inguinal swelling during the assessment of the male urogenital system.

Role of Multidetector Computed Tomography with Multiplanar and Curved Multiplanar Reformations in the Detection of Cause of Intestinal Obstruction: A Tertiary Care Experience.

Objective To determine the role of multidetector computed tomography (MDCT) with multiplanar (MPR) and curved multiplanar reformations (CMPR) in the detection of the cause of intestinal obstruction. Materials and methods A retrospective analysis of 200 patients with a clinical suspicion of intestinal obstruction referred to the department of radiology, Dr. Ziauddin University Hospital, Clifton campus, from September 2016 to October 2019, was done. All patients who underwent an MDCT scan with oral and intravenous (I/V) contrast were included in the study. Patients with deranged serum creatinine and an allergic reaction to contrast were excluded from the study. MPR and CMPR images were acquired in each patient in addition to routine axial images. The causes of intestinal obstruction as determined by a computed tomography (CT) scan were confirmed on surgery and colonoscopy. The CT scans were analyzed by an independent radiologist with five years of experience blinded to the surgical and colonoscopy findings in detecting the cause of bowel obstruction using the axial, MPR, and CMPR images. Data analysis was done on IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY). Results Out of 200 patients with a clinical suspicion of intestinal obstruction, 120 patients with intestinal obstruction was confirmed on CT scan. Fifty-eight patients were males (48.33%) and 62 patients were females (51.66%) with a male-to-female ratio of 1:1.06. The mean age of the patients was 54.7 years (age range from 06 years to 85 years). Abdominal distension was the most common presentation seen in 37 patients (30.83%) followed by vomiting in 25 patients (20.83%). Small bowel obstruction was seen in 96 patients (80.00%) with the ileum being the most common site of obstruction seen in 76 patients (63.33%). Among the patients with the ileum being the site of obstruction, distal ileal obstruction was seen in the majority of patients (30 patients, with a frequency of 25.00%). Twenty-three patients (19.16%) had a large bowel obstruction, with sigmoid colon involvement seen as the most common site in 10 patients (8.33%). Adhesions were the leading extrinsic cause of bowel obstruction seen in 32 patients (26.6%). Intraluminal causes of obstruction were seen in 36 patients (30.0%) with carcinoma being the commonest cause (12 patients with a frequency of 10.0%). A foreign body is the primary cause of intraluminal obstruction (three patients, with a frequency of 2.5%). The sensitivity, specificity, positive predictive value, and negative predictive value of MDCT were 86.2%, 92.7%, 90.1%, and 96.4%, respectively. Conclusion MDCT has high sensitivity and specificity to diagnose and determine the cause of bowel obstruction. It not only determines the site of obstruction but also the cause of obstruction, including intrinsic, extrinsic, and intraluminal causes.

Right Scapular Swelling Revealed to Be a Spontaneous Lateral Chest Wall Hematoma: An Intriguing Case Report.

Chest wall hematoma commonly occurs as a result of blunt thoracic trauma. We report an intriguing case of spontaneous lateral chest wall hematoma that presented with right scapular swelling and tenderness on palpation having hemodynamic instability without any prior history of recent trauma or surgery. Chest x-ray and ultrasound were carried out at the time of admission to evaluate the swelling, followed by contrast-enhanced CT (CECT) of the chest to identify and localize the bleeder. Transcatheter arterial embolization (TAE) of the intercostal artery was performed to treat the condition successfully. CECT is found to be vitally important in localizing bleeders. Other possible options include exploratory thoracotomy, video-assisted thoracic surgery (VATS) exploration, and angiography.

Diagnostic Accuracy of Echo-planar Diffusion-weighted Imaging in the Diagnosis of Intra-cerebral Abscess by Taking Histopathological Findings as the Gold Standard.

Objective To determine the diagnostic accuracy of echo-planar diffusion-weighted imaging (DWI) in the diagnosis of intra-cerebral abscesses by taking histopathological findings as the gold standard. Subject and methods A retrospective cross-sectional study was performed from July 2014 to June 2015 at a tertiary care hospital in Karachi. A total of 462 patients, who were referred for magnetic resonance imaging (MRI) brain, presenting with clinical suspicion of an intra-cerebral abscess on the basis of clinical signs and symptoms, were included in this study. MR imaging was performed. All patients subsequently underwent surgery. The histopathological findings of these patients were collected and compared with echo-planar diffusion-weighted MRI findings. A proforma was used to record the findings. Results The mean age of the patients was 47.39±13.54 years. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of echo-planar diffusion-weighted MRI in the diagnosis of intra-cerebral abscesses was 85.64%, 95.88%, 93.82%, 90.14%, and 91.56%, respectively. Conclusion Brain abscesses and necrotic tumors are, most of the time, difficult to differentiate on routine conventional imaging, and prompt diagnosis is important, as an untreated brain abscess could be lethal. Diffusion imaging can aid in the diagnosis and further management plan so as to help in improved patient care. Although this sequence has high sensitivity and specificity, it should be used in addition to conventional imaging and not as a replacement of histopathology.

Role of Ultrasound in the Diagnosis of Chronic Kidney Disease and its Correlation with Serum Creatinine Level.

OBJECTIVE: We aimed to study the role of ultrasound in the diagnosis of chronic kidney disease (CKD) and its correlation with serum creatinine level. MATERIALS AND METHODS: This was a retrospective cross sectional study conducted in the ultrasound department of Dr. Ziauddin Hospital Clifton campus, Karachi from April 6, 2017 to October 6, 2017 for a period of six months. A total of 200 patients with CKD and glomerular filtration rate (GFR) determined to be < 60 ml/min were included in this study. Blood tests were gathered from the chosen patients, serum creatinine estimation was done for those patients and they underwent ultrasonography on the same day to assess echogenicity, parenchymal thickness, cortical thickness, and longitudinal length. This information was noted in the pro forma. RESULTS: The average age of the patients was 54.62±13.3 years. Mean serum creatinine was significant among echogenicity grades [p=0.0005]. Mean parenchymal thickness was also significant among echogenicity grades (p=0.0005). Mean longitudinal length was also significant among echogenicity grades (p=0.0005). Mean corticomedullary distinction was also significant among echogenicity grades (p=0.0005). A statistically significant highly positive correlation was observed between serum creatinine and cortical echogenicity grading (r=0.915 P = 0.0005). CONCLUSION: The best sonographic parameter that correlates with serum creatinine is renal cortical echogenicity and its grading in comparison to longitudinal length, parenchymal thickness, and cortical thickness in patients of CKD. Since renal cortical echogenicity has the advantage of being irreversible in comparison to serum creatinine levels, it can be used as a parameter of renal function.

Diagnostic Accuracy of Multidetector Computed Tomography in Detection of Esophageal Varices.

Objective To determine the diagnostic accuracy of multidetector computed tomography (MDCT) in the detection of esophageal varices by taking endoscopy as the reference standard. Materials and methods This was a cross-sectional prospective study conducted at the Department of Radiology, Aga Khan University Hospital, (AKUH) Karachi, for the duration of 12 months from August 1, 2014 to July 31, 2015. One hundred ninety-six patients with a suspicion of chronic liver disease/cirrhosis undergoing 64 slice MDCT were enrolled in our study and underwent computed tomography (CT) scanning in the Department of Radiology at AKUH. Biphasic CT was performed with images obtained during the hepatic arterial phase (30-second delay) and the portal venous phase (65-second delay) after the intravenous (IV) injection of 120 mL of nonionic contrast material at a rate of 3.5 mL/s. The presence of esophageal varices was evaluated on MDCT with endoscopy as gold standard. The sensitivity, specificity, negative predictive value and positive predictive value, and accuracy of MDCT were assessed against the gold standard. Results Our results yielded an MDCT sensitivity of 98.96%, specificity of 100%, positive predictive value (PPV) of 100%, negative predictive value (NPV) of 66.67%, and diagnostic accuracy of 98.97% for esophageal varices in chronic liver disease (CLD) patients. Conclusion The rate of detection of esophageal varices in patients with chronic liver disease on MDCT in our country is comparable to the international data and we advocate that MDCT should be used as a screening tool in patients with chronic liver disease to exclude esophageal varices.

Detection of Transition Zone in Bowel Obstruction via Curved Multiplanar Reformations with Multidetector Computed Tomography.

Objective We conducted this study to determine the added value of curved multiplanar reformations (CMPR) and multiplanar reformations (MPR) of multidetector computed tomography (MDCT) scan in the visualization and localization of the zone of transition in patients with intestinal obstruction. Materials and methods A total of 100 patients with suspected bowel obstruction were evaluated in a retrospective cross-sectional study from September 2016 to September 2018 at Dr. Ziauddin University Hospital, Clifton Campus. All patients underwent multidetector computed tomography (CT) scans with oral and intravenous contrast before surgical exploration. CMPR and MPR were acquired at the time of examination in each patient in addition to routine axial images. The CT scans were analyzed by two independent, experienced radiologists skilled at detecting the zones of transition in patients with bowel obstruction using the axial images alone, followed by axial images along with MPR, and then MPR plus CMPR. Patient data were masked to the radiologists. The CT scan findings were compared with surgical findings to determine the accuracy of CMPR in detecting the zone of transition between distended and collapsed bowel loops. The added CMPR showed high accuracy in the diagnosis of intestinal obstruction with a remarkable advantage over the conventional axial images. Data analysis was done on IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY). Cohen's kappa statistics were obtained to show the measure of agreement between the two readers. McNemar's test was also applied to determine the homogeneity. Results Two radiologists, one with two years of experience and the other with five years of experience were 80% and 81% accurate, respectively, in identifying the zones of transition using axial images alone. Using axial images plus MPR, their accuracy was 88% and 92%, respectively. Using MPR plus CMPR, their accuracy was 96% and 98%, respectively. The accuracy of MPR plus CMPR views was significantly increased when compared to the accuracy using axial images alone. CT findings were compared to surgical findings in terms of diagnostic performance. The kappa value of 0.6 indicates moderate association and substantial agreement between two radiologists. McNemar's test showed homogeneity in the number of valid cases. Conclusion CMPR is an important and accurate technique for evaluating intestinal obstruction in addition to MPR as it helps in better localization of the zone of transition and in determining the cause of obstruction. This insight provides guidance for the appropriate treatment.

Diagnostic yield of nondiagnostic thyroid nodules is not altered by timing of repeat biopsy.

BACKGROUND: Guidelines from the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference recommend a repeat fine-needle aspiration biopsy (FNAB) after 3 months for thyroid nodules with a nondiagnostic (ND) result. Our aims were to assess which factors influenced their clinical management and to determine if the timing of the repeat FNAB affects the diagnostic yield. METHODS: A retrospective institutional review of 298 patients from 1/2006 to 12/2007 with an ND FNAB was performed. The factors influencing the next step in management, including age, gender, history of radiation, presence of Hashimoto's thyroiditis, thyroid-stimulating hormone levels, and ultrasound characteristics, were evaluated. The effect of the time of the repeat FNABs on their diagnostic yield was assessed. RESULTS: Of the 298 patients in our cohort, 9% were referred directly for surgery, 76% had a repeat FNAB, and 15% were observed. Tumor size was the only independent variable correlated with treatment strategy after a ND FNAB. There was not a significant difference in diagnostic yields between repeat FNABs performed earlier than 3 months compared to those preformed later (p=0.58). CONCLUSION: The timing of repeat FNAB for an initial ND FNAB does not affect diagnostic yield of the repeat FNAB.

Assessment of chk1 phosphorylation as a pharmacodynamic biomarker of chk1 inhibition.

PURPOSE: Chk1 inhibitors, such as AZD7762, are in clinical development in combination with cytotoxic agents for the treatment of solid tumors, including pancreatic cancers. To maximize the likelihood of their clinical success, it is essential to optimize drug scheduling as well as pharmacodynamic biomarkers in preclinical models. EXPERIMENTAL DESIGN: We tested multiple schedules of administration of gemcitabine and AZD7762 on the survival of pancreatic cancer cells. Potential pharmacodynamic biomarkers including pChk1, pChk2, pHistone H3, and caspase-3 were evaluated in vitro, followed by assessment of promising candidate biomarkers in vivo. We then went on to determine the contributions of PP2A and DNA damage to the mechanism(s) of induction of the identified biomarker, pS345 Chk1. RESULTS: AZD7762 given during and after or after gemcitabine administration produced maximum chemosensitization. In vivo, AZD7762 significantly inhibited the growth of pancreatic tumor xenografts in response to gemcitabine. Of the biomarkers assessed, pS345 Chk1 was most consistently increased in response to gemcitabine and AZD7762 in tumors and normal tissues (hair follicles). pS345 Chk1 induction in response to gemcitabine and AZD7762 occurred in the presence of PP2A inhibition and in association with elevated γH2AX, suggesting that DNA damage is an underlying mechanism. CONCLUSIONS: AZD7762 sensitizes pancreatic cancer cells and tumors to gemcitabine in association with induction of pS345 Chk1. Together these data support the clinical investigation of AZD7762 with gemcitabine in pancreatic cancer under a dosing schedule in which gemcitabine is administered concurrent with or before AZD7762 and in conjunction with skin biopsies to measure pS345 Chk1.

Preoperative basal calcitonin and tumor stage correlate with postoperative calcitonin normalization in patients undergoing initial surgical management of medullary thyroid carcinoma.

BACKGROUND: The optimal initial operative management of medullary thyroid cancer (MTC) and the use of biomarkers to guide the extent of operation remain controversial. We hypothesized that preoperative serum levels of calcitonin and carcinoembryonic antigen (CEA) correlate with extent of disease and postoperative levels reflect the extent of operation performed. METHODS: We assessed retrospectively clinical and pathologic factors among patients with MTC undergoing at least total thyroidectomy; these factors were correlated with biomarkers using regression analyses. RESULTS: Data were obtained from 104 patients, 28% with hereditary MTC. Preoperative calcitonin correlated with tumor size (P < .001) and postoperative serum calcitonin levels (P = .01) after multivariable adjustment for lymph node positivity, extent of operation, and hereditary MTC. No patient with a preoperative calcitonin level of <53 pg/mL (n = 20) had lymph node metastases. TNM stage (P = .001) and preoperative calcitonin levels (P = .04), but not extent of operation, independently correlated with the failure to normalize postoperative calcitonin. Postoperative CEA correlated with positive margins (adjusted P = 04). Neither preoperative nor postoperative CEA was correlated with lymph node positivity or extent of surgery. CONCLUSION: Preoperative serum calcitonin and TMN stage, but not extent of operation, were independent predictors of postoperative normalization of serum calcitonin levels. Future studies should evaluate preoperative serum calcitonin levels as a determinate of the extent of initial operation.

Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair.

The median survival for patients with locally advanced pancreatic cancer treated with gemcitabine and radiation is approximately 1 year. To develop improved treatment, we have combined a Chk1/2-targeted agent, AZD7762, currently in phase I clinical trials, with gemcitabine and ionizing radiation in preclinical pancreatic tumor models. We found that in vitro AZD7762 alone or in combination with gemcitabine significantly sensitized MiaPaCa-2 cells to radiation. AZD7762 inhibited Chk1 autophosphorylation (S296 Chk1), stabilized Cdc25A, and increased ATR/ATM-mediated Chk1 phosphorylation (S345 Chk1). Radiosensitization by AZD7762 was associated with abrogation of the G(2) checkpoint as well as with inhibition of Rad51 focus formation, inhibition of homologous recombination repair, and persistent gamma-H2AX expression. AZD7762 was also a radiation sensitizer in multiple tumor xenograft models. In both MiaPaCa-2- and patient-derived xenografts, AZD7762 significantly prolonged the median time required for tumor volume doubling in response to gemcitabine and radiation. Together, our findings suggest that G(2) checkpoint abrogation and homologous recombination repair inhibition both contribute to sensitization by Chk1 inhibition. Furthermore, they support the clinical use of AZD7762 in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer.

Radiotherapy combined with gemcitabine and oxaliplatin in pancreatic cancer cells.

Clinical evidence suggests that gemcitabine (Gem) plus oxaliplatin (Ox) is superior to gemcitabine alone in advanced pancreatic carcinoma. The addition of radiation to gemcitabine improves response and is a standard treatment for locally advanced disease. We investigated the effect of oxaliplatin on gemcitabine-based chemoradiation by determining whether gemcitabine and oxaliplatin produced synergistic cytotoxicity using median effect analysis and radiosensitization using clonogenic survival assays. We analyzed the effects of gemcitabine and oxaliplatin on cell cycle distribution by DNA content and on radiation-induced DNA damage repair by phosphorylated H2AX (gamma-H2AX). Gemcitabine and oxaliplatin produced schedule-dependent synergistic cytotoxicity in BxPC-3 and Panc-1 cells (combination indices: 0.76 +/- 0.05, 0.61 +/- 0.11). In BxPC-3 cells, oxaliplatin did not affect gemcitabine-mediated radiosensitization (Gem 1.99 +/- 0.27; Gem + Ox 2.38 +/- 0.30). In Panc-1 cells, oxaliplatin significantly enhanced gemcitabine-mediated radiosensitization (Gem 1.31 +/- 0.05; Gem + Ox 2.90 +/- 0.31). Radiosensitization by gemcitabine was accompanied by early S-phase arrest and induction/persistence of gamma-H2AX protein, which were unaltered by oxaliplatin. Addition of oxaliplatin to gemcitabine produces radiosensitization equal to or greater than gemcitabine alone, supporting our clinical investigation of oxaliplatin with gemcitabine-radiation in pancreatic cancer aimed at improving systemic disease control while maintaining local tumor radiosensitization.