Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report.

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

Early improvement of global longitudinal strain after iron deficiency correction in heart failure with reduced ejection fraction.

BACKGROUND: Iron deficiency correction with ferric carboxymaltose improves symptoms and reduces rehospitalization in patients with reduced left ventricular ejection fraction. The mechanisms underlying these improvements are poorly understood. This study aimed to determine changes in left ventricular contractility after iron treatment as reflected in global longitudinal strain. METHODS: Prospective single-center study including 43 adults with reduced ejection fraction, non-anemic iron deficiency, and functional class II-III heart failure despite optimal medical treatment. Global longitudinal strain through speckle-tracking echocardiography was measured at baseline and 4 weeks after ferric carboxymaltose. RESULTS: A significant improvement in global longitudinal strain was detected (from -12.3% ± 4.0% at baseline to -15.6% ± 4.1%, p < .001); ferritin and transferrin saturation index had increased, but ejection fraction presented no significant changes (baseline 35.7% ± 4.6%, follow-up 37.2% ± 6.6%, p = .073). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, the correction of iron deficiency with ferric carboxymaltose is associated with an early improvement in global longitudinal strain, possibly suggesting a direct effect of iron correction on myocardial contractility.

Turnover of the mTOR inhibitor, DEPTOR, and downstream AKT phosphorylation in multiple myeloma cells, is dependent on ERK1-mediated phosphorylation.

DEPTOR is a 48 kDa protein upregulated in multiple myeloma (MM) cells. DEPTOR inhibits mTOR and, by repressing a negative feedback loop, promotes AKT activation. We previously identified a compound that binds to DEPTOR in MM cells and induces its proteasomal degradation. To identify the mechanism of degradation, here, we screened for drug-induced posttranslational modifications and identified reduced phosphorylation of DEPTOR on serine 235 (S235). We show that an S235 phosphomimetic DEPTOR mutant was resistant to degradation, confirming the importance of this posttranslational modification. In addition, a DEPTOR mutant with a serine-to-alanine substitution at S235 could only be expressed upon concurrent proteasome inhibition. Thus, S235 phosphorylation regulates DEPTOR stability. Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay. Inhibition of ERK1 also downregulated AKT phosphorylation. To test if DEPTOR phosphorylation mediated this crosstalk, MM cells were transfected with WT or phosphomimetic DEPTOR and exposed to ERK inhibitors. Although WT DEPTOR had no effect on the inhibition of AKT phosphorylation, the phosphomimetic DEPTOR prevented inhibition. These results indicate that ERK1 maintains AKT activity in MM cells via phosphorylation of DEPTOR. We propose that DEPTOR-dependent crosstalk provides MM cells with a viability-promoting signal (through AKT) when proliferation is stimulated (through ERK).

Roles and Regulation of BCL-xL in Hematological Malignancies.

Members of the Bcl-2 family are proteins that play an essential role in the regulation of apoptosis, a crucial process in development and normal physiology in multicellular organisms. The essential mechanism of this family of proteins is given by the role of pro-survival proteins, which inhibit apoptosis by their direct binding with their counterpart, the effector proteins of apoptosis. This family of proteins was named after the typical member Bcl-2, which was named for its discovery and abnormal expression in B-cell lymphomas. Subsequently, the structure of one of its members BCL-xL was described, which allowed one to understand much of the molecular mechanism of this family. Due to its role of BCL-xL in the regulation of cell survival and proliferation, it has been of great interest in its study. Due to this, it is important to research its role regarding the development and progression of human malignancies, especially in hematologic malignancies. Due to its variation in expression in cancer, it has been suggested that BCL-xL can or cannot play a role in cancer depending on the cellular or tissue context. This review discusses recent advances in its transcriptional regulation of BCL-xL, as well as the advances regarding the activities of BCL-xL in hematological malignancies, its possible role as a biomarker, and its possible clinical relevance in these malignancies.

Role of MicroRNA-7 (MiR-7) in Cancer Physiopathology.

miRNAs are non-coding RNA sequences of approximately 22 nucleotides that interact with genes by inhibiting their translation through binding to their 3' or 5' UTR regions. Following their discovery, the role they play in the development of various pathologies, particularly cancer, has been studied. In this context, miR-7 is described as an important factor in the development of cancer because of its role as a tumor suppressor, regulating a large number of genes involved in the development and progression of cancer. Recent data support the function of miR-7 as a prognostic biomarker in cancer, and miR-7 has been proposed as a strategy in cancer therapy. In this work, the role of miR-7 in various types of cancer is reviewed, illustrating its regulation, direct targets, and effects, as well as its possible relationship to the clinical outcome of cancer patients.

[Pharmacogenomics of vitamin K antagonists]. / Farmacogenómica de los anticoagulantes orales: la importancia de establecer algoritmos de dosificación en población chilena.

There is an important interindividual variability in dose requirement for coumarinic anticoagulants, which could be explained by genetic and non-genetic factors. Among hereditary factors, there are gene polymorphisms that code the therapeutic target and the main enzyme responsible for their metabolism. However, there are other candidate genes that could modulate dose requirements. The is a paucity of pharmacogenomic platforms to determine dose requirements of coumarinics in the Chilean population. Therefore, algorithms considering different variables to adjust individual dosages are required. Herein, we analyze the available evidence about factors that can modify the effects of vitamin K antagonists and that should be incorporated to dosing algorithms.

Case 270.

History A 54-year-old woman presented with typical chest pain during physical training at the gym. She had a history of hypertension controlled with hydrochlorothiazide, without any other cardiovascular risk factor and with neither personal nor family history of ischemic heart disease. She was postmenopausal and had a long-standing history of migraine headaches without hormonal or drug therapy. The patient had no history of clinically important thoracic trauma or invasive chest interventions. Initial electrocardiography (ECG) showed signs of ongoing anterior ST segment elevation myocardial infarction, and emergent coronary angiography with angioplasty and intravascular US were performed ( Fig 1 ). Maximal level of high-sensitive T troponins was 820 ng/L (normal, <13 ng/L), while echocardiography showed a normal left ventricular ejection fraction, with no apparent regional wall motion abnormalities. General physical examination findings were unremarkable, excluding ligamentous hyperlaxity and joint instability. C-reactive protein, rheumatoid factor, antinuclear antibody, cytoplasmic antineutrophil cytoplasmic antibody, and angiotensin-converting enzyme blood test results were negative. For further evaluation, arterial phase ECG-synchronized CT angiography from the skull base to the pubis symphysis was performed ( Fig 2 ). Figure 1a: Coronary angiography of the left anterior descending (LAD) and left circumflex (LCX) arteries (30° right anterior oblique and 20° caudally angulated projection) and intravascular US of the LCX artery were performed. (a) Initial coronary angiography projection. (b) Coronary angiography projection after LAD stent placement. (c, d) Intravenous US images of the distal (c) and proximal (d) LCX artery obtained after b. Figure 1b: Coronary angiography of the left anterior descending (LAD) and left circumflex (LCX) arteries (30° right anterior oblique and 20° caudally angulated projection) and intravascular US of the LCX artery were performed. (a) Initial coronary angiography projection. (b) Coronary angiography projection after LAD stent placement. (c, d) Intravenous US images of the distal (c) and proximal (d) LCX artery obtained after b. Figure 1c: Coronary angiography of the left anterior descending (LAD) and left circumflex (LCX) arteries (30° right anterior oblique and 20° caudally angulated projection) and intravascular US of the LCX artery were performed. (a) Initial coronary angiography projection. (b) Coronary angiography projection after LAD stent placement. (c, d) Intravenous US images of the distal (c) and proximal (d) LCX artery obtained after b. Figure 1d: Coronary angiography of the left anterior descending (LAD) and left circumflex (LCX) arteries (30° right anterior oblique and 20° caudally angulated projection) and intravascular US of the LCX artery were performed. (a) Initial coronary angiography projection. (b) Coronary angiography projection after LAD stent placement. (c, d) Intravenous US images of the distal (c) and proximal (d) LCX artery obtained after b. Figure 2a: Arterial phase electrocardiography-synchronized CT angiography from the skull base to the pubis symphysis was performed after coronary angiography, subsequent interventional procedures, and intravenous US. (a, b) Axial oblique slab maximum intensity projection image at the level of the left (a) and right (b) renal arteries. (c) Coronal volume-rendering image shows an anterior view of the renal arteries. Figure 2b: Arterial phase electrocardiography-synchronized CT angiography from the skull base to the pubis symphysis was performed after coronary angiography, subsequent interventional procedures, and intravenous US. (a, b) Axial oblique slab maximum intensity projection image at the level of the left (a) and right (b) renal arteries. (c) Coronal volume-rendering image shows an anterior view of the renal arteries. Figure 2c: Arterial phase electrocardiography-synchronized CT angiography from the skull base to the pubis symphysis was performed after coronary angiography, subsequent interventional procedures, and intravenous US. (a, b) Axial oblique slab maximum intensity projection image at the level of the left (a) and right (b) renal arteries. (c) Coronal volume-rendering image shows an anterior view of the renal arteries.

Case 270: Spontaneous Coronary Artery Dissection Associated with Fibromuscular Dysplasia.

HistoryA 54-year-old woman presented with typical chest pain during physical training at the gym. She had a history of hypertension controlled with hydrochlorothiazide, without any other cardiovascular risk factor and with neither personal nor family history of ischemic heart disease. She was postmenopausal and had a long-standing history of migraine headaches without hormonal or drug therapy. The patient had no history of clinically important thoracic trauma or invasive chest interventions. Initial electrocardiography (ECG) showed signs of ongoing anterior ST segment elevation myocardial infarction, and emergent coronary angiography with angioplasty and intravascular US were performed. Maximal level of high-sensitive T troponins was 820 ng/L (normal, <13 ng/L), while echocardiography showed a normal left ventricular ejection fraction, with no apparent regional wall motion abnormalities. General physical examination findings were unremarkable, excluding ligamentous hyperlaxity and joint instability. C-reactive protein, rheumatoid factor, antinuclear antibody, cytoplasmic antineutrophil cytoplasmic antibody, and angiotensin-converting enzyme blood test results were negative. For further evaluation, arterial phase ECG-synchronized CT angiography from the skull base to the pubis symphysis was performed.

Anemia and iron deficiency in heart failure: a review of echocardiographic features.

Anemia and iron deficiency are often associated with heart failure, influencing the symptoms and prognosis. Correction of anemia and iron deficiency improves functional capacity and decreases hospitalizations. Many studies have analyzed echocardiographic parameters in iron deficiency and anemia and their evolution after iron treatment; however, the heterogeneity of the results makes it difficult to draw conclusions. The aim of this paper is to review the echocardiographic parameters during anemia and iron deficiency, and their evolution after treatment. Available data suggest that they lead to ventricular and atrial remodeling, a decrease in ventricular contractility, and an alteration of ventricular relaxation, although in heart failure with preserved ejection fraction these changes are not significant. Anemia and iron deficiency also increase systolic pulmonary artery pressure. There is consistent evidence that correction of these comorbidities leads to a reduction in preload and left ventricular cavity dimensions, an improvement in diastolic and load-independent ventricular systolic function parameters, and a decrease in systolic pulmonary artery pressure. However, the evidence is less consistent about the changes produced in ventricular hypertrophy, load-dependent systolic function parameters, and E-wave. Generally, anemia and iron deficiency affect the echocardiographic findings, and correcting these conditions often results in improvement in the affected echocardiographic parameters.

Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract Obesity.

Inhibition of Notch signaling via systemic drug administration triggers conversion of white adipocytes into beige adipocytes (browning) and reduces adiposity. However, translation of this discovery into clinical practice is challenged by potential off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Here, we demonstrate an alternative approach to stimulate browning using nanoparticles (NPs) composed of FDA-approved poly(lactide-co-glycolide) that enable sustained local release of a Notch inhibitor (dibenzazepine, DBZ). These DBZ-loaded NPs support rapid cellular internalization and inhibit Notch signaling in adipocytes. Importantly, focal injection of these NPs into the inguinal white adipose tissue depots of diet-induced obese mice results in localized NP retention and browning of adipocytes, consequently improving the glucose homeostasis and attenuating body-weight gain of the treated mice. These findings offer new avenues to develop a potential therapeutic strategy for clinical treatment of obesity and its associated metabolic syndrome.

Comparison of perinatal outcomes following frozen embryo transfer cycles using autologous versus donor oocytes in women 40 to 43 years old: analysis of SART CORS data.

OBJECTIVE: To study the differences in perinatal outcomes after frozen embryo transfer cycles using autologous or donor oocytes in women of advanced maternal age. DESIGN: Historical cohort study. SETTING: US national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 2009 to 2013. PATIENT(S): Women at 40-43 years of age undergoing autologous frozen embryo transfers (a-FET) or donor oocyte frozen embryo transfers (d-FET) resulting in singleton pregnancies that were entered in the SART CORS database from 2009 to 2013. RESULTS: a-FET resulted in 4402 singleton live births whereas d-FET resulted in 2703 singleton live births. d-FET resulted in a higher risk of preterm births (< 37 weeks), with adjusted odds ratio (aOR) 1.33 (95% CI 1.02-1.75), but similar risk of small for gestational age (SGA), with aOR 1.75 (95% CI 0.85-3.7), when compared to a-FET. However, when only single blastocyst transfer cycles are considered, d-FET and a-FET showed no difference in preterm births or other adverse perinatal outcomes. CONCLUSIONS: Singletons resulting from d-FET are at increased risk for perinatal morbidity. However, the risk was diminished in single blastocyst transfer cycles. Our study supports the current American Society for Reproductive Medicine (ASRM) guidelines of transferring a single blastocyst in d-FET cycles.

Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction.

DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast. This therapeutic (compound B) also prevented DEPTOR/mTOR binding in MM cells and was selectively cytotoxic to MM cells. We now present a structure-activity relationship (SAR) study around this compound as a follow-up report of this previous work. This study has led to the discovery of five new leads - namely compounds 3g, 3k, 4d, 4e and 4g - all of which have anti-myeloma cytotoxic properties superior to compound B. Due to their targeting of DEPTOR, these compounds activate mTORC1 and selectively induce MM cell apoptosis and cell cycle arrest.

IVF outcomes in average- and poor-prognosis infertile women according to the number of embryos transferred.

Outcome measures of IVF success, which account for effectiveness of IVF and perinatal outcome risks, have recently been described. The association between number of embryos transferred in average and poor-prognosis IVF patients, and the chances of having good or poor IVF and perinatal outcomes, was investigated. Good IVF and perinatal outcome was defined as the birth of a live, term, normal-weight infant (≥2500 g). Poor IVF and perinatal outcome was defined as no live birth or birth of a very low weight neonate (<1500 g) or severe prematurity (birth at <32 weeks gestation). Each neonate was analysed as a separate outcome. A total of 713 IVF cycles in 504 average and poor-prognosis patients from January 2010 to December 2013 were identified. The odds of having good IVF and perinatal outcomes increased by 28% for each additional embryo transferred. The odds of poor IVF and perinatal outcome decreased by 32% with an additional embryo transferred. The likelihood of live birth with good perinatal outcome in average- and poor-prognosis patients after IVF increases with additional embryos being transferred. These data add to recently reported evidence in favour of multiple embryo transfer in older women and those with average or poor IVF prognosis.

Insulin Resistance and ß-cell Function Calculated by Homeostasis Model Assessment in Lean, Overweight, and Obese Women with Polycystic Ovary Syndrome.

OBJECTIVE: To evaluate the homeostasis model assessment (HOMA) measurement of insulin resistance (IR) and pancreatic ß-cell function (%ß) and compare those values between groups of healthy-weight, over-weight, and obese women with polycystic ovary syndrome (PCOS). STUDY DESIGN: Retrospective cohort study of women aged 24-48 with PCOS, diagnosed according to 2004 Rotterdam criteria. Participants were grouped by BMI. Quantitative variables were compared by one-way ANOVA and the Tukey method. Analysis for power to detect a difference between means was conducted. Pearson correlation was used to test differences in frequency distribution. RESULTS: By BMI category, 29 participants were of healthy weight, 11 were overweight, and 11 were obese. HOMA-IR was significantly higher in obese women as compared to overweight and healthy-weight patients (2.88 ± 2.09, 1.13 ± 0.73, 0.84 ± 0.49, respectively; p <0.0001). Moreover, HOMA-%ß was significantly increased in obese women as compared to overweight and healthy-weight patients (186.89 ± 131.62, 106.83 ± 46.77, 86.60 ± 40.91, respectively; p<0.0001). Adequate statistical power was not present to distinguish a difference between overweight and normal-weight participants. A positive linear correlation was found between log HOMA-IR and BMI, and between log HOMA-%ß and BMI. CONCLUSION: Obese PCOS patients have a higher risk of elevated insulin resistance and ß-cell function than do those with BMI <30.

Day 3 Biopsy and Blastulation Rates.

OBJECTIVE: To determine if blastomere biopsy affects the rate of blastulation as compared to intact embryos. STUDY DESIGN: Retrospective age-matched cohort study. RESULTS: Forty-one patients with 41 in vitro fertilization (IVF) cycles and 329 embryos who under- went cleavage-stage biopsy with preimplantation genet- ic screening using array com- parative genomic hybridiza- tion were compared to 41 IVF cycles with 352 embryos eligible for biopsy but who did not undergo biopsy January 2011-July 2013. The proportion of embryos that developed to the blastocyst stage was significantly lower in the case group than in the control group (46.5% vs. 59.9%; p=0.0134). This was most evident in the age group >35 years old (43.2% vs. 58.8%; p=0.035). No significant difference was detected in proportions that developed to fully expanded' or hatching blastulation between cases and controls (28.0% vs. 24.4%, p=0.56). There was a statistically .significant difference in the proportion of euploid embryos available for transfer when comparing day 3 vs. day 5 biopsy (20.9% vs. 13.1%, p=0.0003). CONCLUSION: Cleavage stage biopsy for genetic testing lowers the overall proportion of embryos that develop to the blastocyst stage by 25% (from 59.9% to 46.5%). When compared to trophectoderm biopsy, cleavage stage biopsy allows for a larger cohort of euploid embryos to be available for selection and transfer.

Inhibition of tumor progression during allergic airway inflammation in a murine model: significant role of TGF-ß.

INTRODUCTION: TGF-ß is an important mediator of pulmonary allergic inflammation, and it has been recently reported to be a potential inhibitor of lung tumor progression. The correlation between cancer and allergic inflammatory diseases remains controversial. Thus, the aim of the present study was to evaluate the effects of pulmonary allergic inflammation and in particular the role of TGF-ß on cancer progression. METHODS: Cancer cells were implanted in a BALB/c mice model of allergic airway inflammation, and tumor growth was measured. Apoptosis was evaluated by TUNEL assay, and TGF-ß was measured by ELISA. Expression of proliferating cell nuclear antigen, TGF-ß, TGF-ß receptors I and II, phospho-Smad2 and phospho-Smad4 was evaluated by immunohistochemistry and quantified using digital pathology. The effect of a TGF-ß activity inhibitor and recombinant TGF-ß on tumor growth was analyzed. The effect of exogenous TGF-ß on cell proliferation and apoptosis was evaluated in vitro. RESULTS: Mice with allergic airway inflammation exhibited decreased tumor volumes due to cell proliferation inhibition and increased apoptosis. TGF-ß was increased in the sera and tumor tissues of allergic mice. TGF-ß activity inhibition increased tumor progression in allergic mice by enhancing proliferation and decreasing apoptosis of tumor cells. The administration of TGF-ß resulted in reduced tumor growth. CONCLUSION: This study is the first to establish an inverse relationship between allergic airway inflammation and tumor progression. This effect appears to be mediated by TGF-ß, which is overexpressed in tumor cells during pulmonary allergic inflammation. This study indicates that TGF-ß is a potential target for antitumor therapy.

Gonadotropin surge-inhibiting/attenuating factors: a review of current evidence, potential applications, and future directions for research.

Animal studies in the 1980s suggested the existence of an ovarian hormone, termed gonadotropin surge-inhibiting/attenuating factor (GnSIF/AF), that modulates pituitary secretion of luteinizing hormone (LH). Given the importance of identifying regulatory factors of the hypothalamic-pituitary-ovarian axis and the accumulating data suggesting its existence, we conducted a comprehensive literature search using PubMed, Web of Science, Scopus, and Embase to identify articles related to GnSIF/AF. The search generated 161 publications, of which 97 were included in this study. Several attempts have been made to identify and characterize this hormone and several candidates have been identified, but the protein sequences of these putative GnSIF/AF factors differ widely from one study to another. In addition, while the RF-amide RFRP-3 is known foremost as a neuropeptide, some research supports an ovarian origin for this non-steroidal hormone, thereby suggesting a role for RFRP-3 either as a co-modulator of GnSIF/AF or as a gonadotropin-inhibiting factor in the hypothalamus (GnIH). Discovery of the KNDy neurons that modulate GnRH secretion, on the other hand, further encourages the search for substance(s) that modulate their activity and that indirectly affect LH secretion and the hypothalamic-pituitary-ovarian axis. While it has remained an elusive hormone, GnSIF/AF holds many potential applications for contraception, in vitro fertilization, and/or cancer as well as for understanding polycystic ovary syndrome, metabolic diseases, and/or pubertal development. In this review, we rigorously examine the available evidence regarding the existence of GnSIF/AF, previous attempts at its identification, limitations to its discovery, future directions of research, and potential clinical applications.

P38 MAPK expression and activation predicts failure of response to CHOP in patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: The p38 MAPK is constitutively activated in B-NHL cell lines and regulates chemoresistance. Accordingly, we hypothesized that activated p38 MAPK may be associated with the in vivo unresponsiveness to chemotherapy in B-NHL patients. METHODS: Tissue microarrays generated from eighty untreated patients with Diffused Large B Cell Lymphoma (DLBCL) were examined by immunohistochemistry for the expression of p38 and phospho p38 (p-p38) MAPK. In addition, both Bcl-2 and NF-κB expressions were determined. Kaplan Meier analysis was assessed. RESULTS: Tumor tissues expressed p38 MAPK (82 %) and p-p38 MAPK (30 %). Both p38 and p-p38 MAPK expressions correlated with the high score performance status. A significant correlation was found between the expression p-p38 and poor response to CHOP. The five year median follow-up FFS was 81 % for p38(-) and 34 % for p38(+) and for OS was 83 % for p38(-) and 47 % for p38(+). The p-p38(+) tissues expressed Bcl-2 and 90 % of p-p38(-) where Bcl-2(-). The coexpression of p-p38 and Bcl-2 correlated with pool EFS and OS. There was no correlation between the expression of p-p38 and the expression of NF-κB. CONCLUSION: The findings revealed, for the first time, that a subset of patients with DLBCL and whose tumors expressed high p-p38 MAPK responded poorly to CHOP therapy and had poor EFS and OS. The expression of p38, p-p38, Bcl2 and the ABC subtype are significant risk factors both p38 and p-p38 expressions remain independent prognostic factors.

Comparison of perioperative outcomes and complication rates between conventional versus robotic-assisted laparoscopy in the evaluation and management of early, advanced, and recurrent stage ovarian, fallopian tube, and primary peritoneal cancer.

OBJECTIVE: The objective of this study was to examine perioperative outcomes, including complication rates, of conventional laparoscopy (CL) versus robotic-assisted laparoscopy (RALS) in the evaluation and management of early, advanced, and recurrent ovarian, fallopian tube, and peritoneal cancer. METHODS: This is a retrospective analysis of a prospectively maintained database of surgery performed from July 2008 to December 2012. Sixty-three women had 83 surgeries performed; 22 surgeries for early-stage disease (International Federation of Gynecology and Obstetrics stage I) and 61 for advanced and/or recurrent disease. RESULTS: Of the 22 for early stage, 10 were CL, 9 were RALS, and 3 were laparoscopy converted to laparotomy (LP). There was no significant difference between CL and RALS in estimated blood loss (EBL, P = 0.27) or length of stay (LOS, P = 0.43); however, both had significantly less EBL (P = 0.03 and 0.03, respectively) and LOS (P = 0.03 and 0.03) than LP. There was no difference in OR time among the groups (P = 0.79). One patient (33%) had an intraoperative complication in LP. One patient (10%) had a postoperative complication in CL, 2 (22%) in RALS, and 1 (33%) in LP, with no significant difference (P = 0.61).Among the 42 patients with advanced/recurrent disease, 61 surgeries were performed: 14 diagnostic procedures and 47 cytoreductive surgeries. Of the 47, there was no difference in operating room time (P = 0.10). There was no difference in EBL or LOS between CL and RALS (P = 0.82, P = 0.87); however, both were less in CL (P < 0.001 and P = 0.02) and RALS (P = 0.01 and P = 0.02) compared with LP. There were 5 (63%) intraoperative transfusions in LP and none in CL or RALS. When including all surgeries for advanced/recurrent disease, there was 1 intraoperative complication (12%) in LP. There was no difference in postoperative complications between groups (P = 0.89); 8 patients (19%) had postoperative complications in CL, 2 (18%) in RALS, and 2 (25%) in LP. Overall, there were no grade 4 or 5 complications and no perioperative or intraoperative deaths. CONCLUSIONS: In our experience, perioperative outcomes are comparable between CL and RALS in both early and advanced/recurrent disease and not inferior to laparotomy, making CL and RALS an acceptable approach in selected patients.