Updates and new directions in the use of radiation therapy for the treatment of pancreatic adenocarcinoma: dose, sensitization, and novel technology.

Panc reatic ductal adenocarcinoma (PDAC) is a devastating malignancy. There have been few advances that have substantially improved overall survival in the past several years. On its current trajectory, the deaths from PDAC are expected to cross that from all gastrointestinal cancers combined by 2030. Radiation therapy is a technically very complex modality that bridges multiple different treatment strategies. It represents a hybrid among advanced diagnostic imaging, local (often ablative) intervention, and heterogeneous biological mechanisms contributing to normal and oncologic cell kill. In this article, we bring an overview of the several promising strategies that are currently being investigated to improve outcomes using radiation therapy for patients with PDAC.

Total Neoadjuvant Therapy for Operable Pancreatic Cancer.

BACKGROUND: Overall survival (OS) for operable pancreatic cancer (PC) is optimized when 4-6 months of nonsurgical therapy is combined with pancreatectomy. Because surgery renders the delivery of postoperative therapy uncertain, total neoadjuvant therapy (TNT) is gaining popularity. METHODS: We performed a retrospective cohort study of patients with operable PC and compared TNT with shorter course neoadjuvant therapy (SNT). Primary outcomes of interest included completion of neoadjuvant therapy (NT) and resection of the primary tumor, receipt of 5 months of nonsurgical therapy, and median OS. RESULTS: We reviewed 541 consecutive patients from 2009 to 2019 including 226 (42%) with resectable PC and 315 (58%) with borderline resectable (BLR) PC. The median age was 66 years (IQR [59, 72]), and 260 (48%) patients were female. TNT was administered to 89 (16%) patients and SNT was administered to 452 (84%). Both groups were equally likely to complete intended NT and surgery (p = 0.90). Patients who received TNT and surgical resection were more likely to have a complete pathologic response (8% vs 4%, p < 0.01) and were more likely to receive at least 5 months of nonsurgical therapy (67% vs 45%, p < 0.01). The median OS was 26 months [IQR (15, 57)]; not reached among patients treated with TNT, and 25 months [IQR (15, 56)] among patients treated with SNT (p = 0.19). CONCLUSIONS: TNT ensures the delivery of intended systemic therapy prior to a complicated operation without decreasing the chance of successful surgery; a window of operability was not lost. Patients who can tolerate SNT will likely benefit from TNT.

Epoxy Fatty Acids: From Salt Regulation to Kidney and Cardiovascular Therapeutics: 2019 Lewis K. Dahl Memorial Lecture.

Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.

Impact of Neoadjuvant Chemoradiation on Pathologic Response in Patients With Localized Pancreatic Cancer.

Introduction/Background: Multimodal neoadjuvant therapy has resulted in increased rates of histologic response in pancreatic tumors and adjacent lymph nodes. The biologic significance of the collective response in the primary tumor and lymph nodes is not understood. Methods: Patients with localized PC who received neoadjuvant therapy and surgery with histologic assessment of the primary tumor and local-regional lymph nodes were included. Histopathologic response was classified using the modified Ryan score as follows: no viable cancer cells (CR), rare groups of cancer cells (nCR), residual cancer with evident tumor regression (PR), and extensive residual cancer with no evident tumor regression (NR). Nodal status was defined by number of lymph nodes (LN) with tumor metastases: N0 (0 LN), N1 (1-3), N2 (≥4). Results: Of 341 patients with localized PC who received neoadjuvant therapy and surgery, 107 (31%) received chemoradiation alone, 44 (13%) received chemotherapy alone, and 190 (56%) received chemotherapy and chemoradiation. Histopathologic response consisted of 15 (4%) CRs, 59 (17%) nCRs, 188 (55%) PRs, and 79 (23%) NRs. Patients who received chemotherapy alone had the worst responses (n = 21 for NR, 48%) as compared to patients who received chemoradiation alone (n = 25 for NR, 24%) or patients who received both therapies (n = 33 for NR, 17%) (Table 1; p = 0.001). Median overall survival for all 341 patients was 39 months; OS by histopathologic subtype was not reached (CR), 49 months (nCR), 38 months (PR), and 34 months (NR), respectively (p = 0.004). Of the 341 patients, 208 (61%) had N0 disease, 97 (28%) had N1 disease, and 36 (11%) had N2 disease. In an adjusted hazards model, modified Ryan score of PR or NR (HR: 1.71; 95% CI: 1.15-2.54; p = 0.008) and N1 (HR: 1.42; 95% CI: 1.1.02-2.01; p = 0.04), or N2 disease (HR: 2.54, 95% CI: 1.64-3.93; p < 0.001) were associated with increased risk of death. Conclusions: Neoadjuvant chemotherapy alone is associated with lower rates of pathologic response. Patients with CR or nCR have a significantly improved OS as compared to patients with PR or NR. Nodal status is the most important pathologic prognostic factor. Neoadjuvant chemoradiation may be an important driver of pathologic response.

Detection of germline variants using expanded multigene panels in patients with localized pancreatic cancer.

BACKGROUND: Current guidelines recommend genetic testing for all patients with pancreatic cancer (PC). METHODS: Patients with localized PC who received neoadjuvant therapy between 2009 and 2018 were identified. Genetic consultation (including personal and family history of cancer), genetic testing, and variant data were abstracted. RESULTS: Of 510 patients identified, 163 (32%) underwent genetic counseling and genetic testing was performed in 127 (25%). Patients who underwent genetic testing were younger (median age: 63 vs. 67, p = 0.01). Multi-gene testing was performed in 114 (90%) of 127 patients, targeted gene testing was performed in 8 (6%), and not specified in 5 (4%). Of 127 patients who underwent genetic testing, 20 (16%) had pathogenic (P)/likely pathogenic (LP) variants, observed in ATM (n = 7/105,7%), CHEK2 (n = 3/98, 3%), BRCA1 (n = 2/117, 2%), BRCA2 (n = 2/122, 2%), PALB2 (n = 1/115, 1%), MUTYH (n = 1/98, 1%), CDKN2A (n = 1/94, 1%), STK11 (n = 1/97, 1%), NBN (n = 1/98, 1%), and MSH6 (n = 1/97, 1%). Of 20 patients with either a P/LP variant, nine (45%) had a prior cancer, three (15%) had a first-degree relative with PC, and six (30%) had an any-degree relative with PC. CONCLUSION: Pathogenic/likely pathogenic variants were identified in 16% of patients who underwent genetic testing, 60% of which occurred in the homologous recombination pathway.

Management of Acute Cholecystitis during Neoadjuvant Therapy in Patients with Pancreatic Adenocarcinoma.

BACKGROUND: Patients with localized pancreatic cancer (PC) can develop acute cholecystitis during neoadjuvant therapy; optimal management remains undefined. METHODS: Consecutive patients with localized PC who had indwelling biliary stents and received neoadjuvant therapy were reviewed. Time from stent placement to the development of acute cholecystitis was calculated. Patients were categorized as having surgical versus nonoperative management of cholecystitis. Time to PC resection was defined as the time from the start of treatment to pancreatic resection. RESULTS: Of the 283 patients with indwelling biliary stents, acute cholecystitis occurred in 17 (6%) patients. The median time from the date of stent placement to the development of cholecystitis was 2.3 months [interquartile range (IQR) 4.6 months]. Acute cholecystitis was managed with cholecystostomy tube placement in 15 (88%) patients and cholecystectomy in 2 (12%). In total, 189 (67%) of the 283 patients completed all intended neoadjuvant therapy and surgery; 10 (59%) of the 17 patients with cholecystitis (10 of 15 managed with a cholecystostomy tube and 0 of 2 managed with cholecystectomy) and 179 (67%) of the 266 patients without cholecystitis (p = 0.47). The median time to PC resection was 3.2 months for the 179 patients without cholecystitis and 3.6 months for the 10 patients with cholecystitis (p = 1.00). CONCLUSIONS: Acute cholecystitis occurred in 6% of patients with indwelling biliary stents during neoadjuvant therapy. Management with a cholecystostomy tube did not delay the completion of neoadjuvant therapy and surgery and should be considered the optimal management of this complication.

Utility of the Medtronic microvascular plug™ as a transcatheter implantable and explantable pulmonary artery flow restrictor in a swine model.

BACKGROUND: A surgical pulmonary artery band (PAB) is used to control excessive pulmonary blood flow for certain congenital heart diseases. Previous attempts have been made to develop a transcatheter, implantable pulmonary flow restrictor (PFR) without great success. We modified a microvascular plug (MVP) to be used as a PFR. The objectives of this study were to demonstrate feasibility of transcatheter implantation and retrieval of the modified MVP as a PFR, and compare PA growth while using the PFR versus PAB. METHODS AND RESULTS: The PFR was implanted in eight newborn piglets in bilateral branch pulmonary arteries (PAs). Immediately post-PFR implantation, the right ventricular systolic pressure increased from a median of 20-51 mmHg. Transcatheter retrieval of PFR was 100% successful at 3, 6, and 9 weeks and 50% at 12-weeks post-implant. A left PAB was placed via thoracotomy in four other newborn piglets. Debanding was performed 6-weeks later via balloon angioplasty. On follow-up, the proximal left PA diameters in the PFR and the PAB groups were similar (median 8 vs. 7.1 mm; p = 0.11); albeit the surgical band sites required repeat balloon angioplasty secondary to recurrent stenosis. By histopathology, there was grade II vessel injury in two pigs immediately post-retrieval of PFR that healed by 12 weeks. CONCLUSIONS: Transcatheter implantation and retrieval of the MVP as a PFR is feasible. PA growth is comparable to surgical PAB, which is likely to require reinterventions. The use of the MVP as a PFR in humans has to be trialed before recommending its routine use.

A phase III, multicenter, prospective, single-blinded, noninferiority, randomized controlled trial on the performance of a novel esophageal stent with an antireflux valve (with video).

BACKGROUND AND AIMS: Self-expanding metal stents (SEMSs) when deployed across the gastroesophageal junction (GEJ) can lead to reflux with risks of aspiration. A SEMS with a tricuspid antireflux valve (SEMS-V) was designed to address this issue. The aim of this study was to evaluate the efficacy and safety of this stent. METHODS: A phase III, multicenter, prospective, noninferiority, randomized controlled trial was conducted on patients with malignant dysphagia requiring SEMSs to be placed across the GEJ. Patients were randomized to receive SEMSs with no valve (SEMS-NV) or SEMS-V. Postdeployment dysphagia score at 2 weeks and Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) questionnaire score at 4 weeks were measured. Patients were followed for 24 weeks. RESULTS: Sixty patients were randomized (SEMS-NV: 30 patients, mean age 67 ± 13 years; SEMS-V: 30 patients, mean age 65 ± 12 years). Baseline dysphagia scores (SEMS-NV, 2.5 ± .8; SEMS-V, 2.5 ± .8) and GERD-HRQL scores (SEMS-NV, 11.1 ± 8.2; SEMS-V, 12.8 ± 8.3) were similar. All SEMSs were successfully deployed. A similar proportion of patients in both arms improved from advanced dysphagia to moderate to no dysphagia (SEMS-NV, 71%; SEMS-V, 74%; 95% confidence interval, 1.93 [-17.8 to 21.7]). The dysphagia scores were also similar across all follow-up time points. Mean GERD-HRQL scores improved by 7.4 ± 10.2 points in the SEMS-V arm and by 5.2 ± 8.3 in the SEMS-NV group (P = .96). The GERD-HRQL scores were similar across all follow-up time points. Aspiration pneumonia occurred in 3.3% in the SEMS-NV arm and 6.9% in the SEMS-V arm (P = .61). Migration rates were similar (SEMS-NV, 33%; SEMS-V, 48%; P = .29). Two SEMS-V spontaneously fractured. There was no perforation, food impaction, or stent-related death in either group. CONCLUSIONS: The SEMS-V was equally effective in relieving dysphagia as compared with the SEMS-NV. Presence of the valve did not increase the risks of adverse events. GERD symptom scores were similar between the 2 stents, implying either that the valve was not effective or that all patients on proton pump inhibitors could have masked the symptoms of GERD. Studies with objective evaluations such as fluoroscopy and/or pH/impedance are recommended. (Clinical trial registration number: NCT02159898.).

Distal splenorenal and mesocaval shunting at the time of pancreatectomy.

BACKGROUND: When pancreatic neoplasms occlude or encase the superior mesenteric-portal-splenic vein confluence with abutment of the posterior lateral wall of the superior mesenteric artery, a mesocaval shunt with or without a distal splenorenal shunt allows for safe dissection of the porta hepatis and separation of the pancreatic tumor from the superior mesenteric artery. Herein we report long-term results of the largest known series of portosystemic shunts performed at the time of pancreatectomy. METHODS: All patients who underwent pancreatic resection with a mesocaval shunt or distal splenorenal shunt were identified from our prospective database. Demographics, perioperative treatment, and outcomes were reviewed. RESULTS: A total of 34 patients underwent mesocaval shunt or distal splenorenal shunt, including 25 at the time of pancreatoduodenectomy, 6 during total pancreatectomy, and 3 after prior pancreatectomy. There were 15 mesocaval shunts, 16 distal splenorenal shunts, 2 combined mesocaval/distal splenorenal shunts, and 1 distal splenoadrenal vein shunt. The mesocaval group included 11 temporary and 6 permanent (3 delayed) shunts. Median operative time was 9 hours (range 6.5-13), median estimated blood loss was 950 mL (range 200-5,000), and median duration of hospital stay was 11 days (range 7-35). Four patients experienced complications that required intervention (Clavien-Dindo grade ≥III), but there were no 90-day mortalities. For patients with adenocarcinoma, median overall survival was 31 months at a median follow-up of 19 months. All but 1 shunt (distal splenorenal) were patent at last follow-up. CONCLUSION: Mesenteric venous shunting facilitates a safe and complete tumor resection in patients who require a complex pancreatectomy, many of whom would otherwise be deemed inoperable.

Locally advanced pancreas cancer: Staging and goals of therapy.

BACKGROUND: Patients with locally advanced pancreatic cancer have historically been considered inoperable. The purpose of this report was to determine resectability rates for patients with locally advanced pancreatic cancer based on our recently described definitions of type A and type B locally advanced pancreatic cancer. METHODS: An institutional prospective pancreas cancer database was queried for consecutive patients with locally advanced pancreatic cancer treated between January 2009 and June 2017. All pretreatment imaging was re-reviewed and patients were categorized as locally advanced pancreatic cancer type A or type B. Demographics, induction therapy, resection type, and outcomes were reviewed. RESULTS: We identified 108 consecutive patients; 12 were excluded from analysis due to the absence of available pretreatment imaging or they had not yet completed all intended neoadjuvant therapy. Of the remaining 96 patients (45 type A, 51 type B), disease progression occurred in 19 (20%) during induction therapy and 30 (31%) were deemed inoperable at final preoperative restaging. Therefore, 47 (49%) of 96 patients were taken to surgery and 40 (42%) underwent successful resection (28 [62%] of 45 type A and 12 [24%] of 51 type B); an RO resection was achieved in 32 (80%). Metastatic disease was found intraoperatively (6 at laparoscopy, 1 at laparotomy) in 7 (15%) of 47 patients. There were no mortalities; 6 (15%) patients experienced major postoperative complications. Resected patients had a median overall survival of 38.9 months. CONCLUSION: Locally advanced pancreatic cancer can be dichotomized into type A and B with distinctly different probabilities of completing all therapy to include surgery; thereby allowing goals of therapy to be established at the time of diagnosis. Multimodality therapy that includes surgery can be accomplished in selected patients with locally advanced pancreatic cancer and is associated with a median overall survival that approximates earlier stages of disease. (Surgery 2017;160:XXX-XXX.).

Development of a high risk pancreatic screening clinic using 3.0 T MRI.

Selective screening for pancreatic cancer (PC) has been proposed. We describe the establishment of a comprehensive multidisciplinary screening program using 3.0 T MRI. Criteria for screening included the presence of PC in: ≥ 2 first degree relatives (FDR), 1 FDR and 1 s degree relative (SDR), ≥ 3 any degree relatives (ADR), or any known hereditary cancer syndrome with increased PC risk. Imaging with 3.0 T MRI was performed routinely and endoscopic ultrasound was used selectively. Screening was completed in 75 patients (pts). Hereditary cancer syndromes were present in 42 (56%) of the 75 pts: BRCA2 (18), ATM (8), BRCA1 (6), CDKN2A (4), PALB2 (3), Lynch (2), and Peutz-Jeghers (1). A family history of PC was present in ≥ 2 FDR in 12 (16%) pts, 1 FDR and 1 SDR in 5 (7) pts, and ≥ 3 ADR in 16 (21%) pts. Of the 65 pts who received screening MRI, 28 (43%) pts had pancreatic cystic lesions identified, including 1 (1%) patient in whom a cholangiocarcinoma was diagnosed as well. No patient underwent surgical resection. Using a 3.0 T MRI to screen patients at high risk for developing PC identified radiographic abnormalities in 43% of patients, which were stable on subsequent surveillance. Specific guidelines for the frequency of surveillance and indications for surgery remain areas of active investigation as the global experience with high risk screening continues to mature.

Is Adjuvant Therapy Necessary for All Patients with Localized Pancreatic Cancer Who Have Received Neoadjuvant Therapy?

BACKGROUND: Among patients with localized pancreatic cancer (PC), the benefit of adjuvant therapy after neoadjuvant therapy and surgery is unknown. METHODS: Patients with localized PC who completed all intended neoadjuvant therapy and surgery were categorized based on the receipt of adjuvant therapy and by pathologic lymph node status (LN-/LN+). RESULTS: Data was available from 234 consecutive patients, 121 (52%) with resectable and 113 (48%) with borderline resectable PC. Of the 234 patients, 92 (39%) were LN+ and 142 (61%) were LN-. The median overall survival (OS) for the 234 patients was 39 months, 42.3 months for patients who received any adjuvant therapy and 34.1 months for those who did not (p = 0.29). Of the 92 LN+ patients, the median OS with and without adjuvant therapy was 29.5 and 23.2 months, respectively (p = 0.02). Of the142 LN- patients, the median OS was 45 months with or without adjuvant therapy (p = 0.86). In an adjusted hazard model, additional adjuvant therapy had a significant protective effect among LN+ patients (HR 0.39; 95% CI 0.21-0.70; p = 0.002) but not in LN- patients (HR 0.89; 95% CI 0.53-1.52; p = 0.68). CONCLUSION: Among patients with localized PC who received neoadjuvant therapy and surgery, the benefit of adjuvant therapy was limited to those with node-positive disease.

A Novel Protocol Obviates Endoscope Sampling for Carbapenem-Resistant Enterobacteriaceae: Experience of a Center with a Prior Outbreak.

BACKGROUND: Numerous published outbreaks, including one from our institution, have described endoscope-associated transmission of multidrug-resistant organisms (MDROs). Individual centers have adopted their own protocols to address this issue, including endoscope culture and sequestration. Endoscope culturing has drawbacks and may allow residual bacteria, including MDROs, to go undetected after high-level disinfection. AIM: To report the outcome of our novel protocol, which does not utilize endoscope culturing, to address our outbreak. METHODS: All patients undergoing procedures with elevator-containing endoscopes were asked to permit performance of a rectal swab. All endoscopes underwent high-level disinfection according to updated manufacturer's guidance. Additionally, ethylene oxide (EtO) sterilization was done in the high-risk settings of (1) positive response to a pre-procedure risk stratification questionnaire, (2) positive or indeterminate CRE polymerase chain reaction (PCR) from rectal swab, (3) refusal to consent for PCR or questionnaire, (4) purulent cholangitis or infected pancreatic fluid collections. Two endoscopes per weekend were sterilized on a rotational basis. RESULTS: From September 1, 2015 to April 30, 2016, 556 endoscopy sessions were performed using elevator-containing endoscopes. Prompted EtO sterilization was done on 46 (8.3%) instances, 3 from positive/indeterminate PCR tests out of 530 samples (0.6%). No CRE transmission was observed during the study period. Damage or altered performance of endoscopes related to EtO was not observed. CONCLUSION: In this pilot study, prompted EtO sterilization in high-risk patients has thus far eliminated endoscope-associated MDRO transmission, although no CRE infections were noted throughout the institution during the study period. Further studies and a larger patient sample will be required to validate these findings.

Multimodality Therapy in Patients With Borderline Resectable or Locally Advanced Pancreatic Cancer: Importance of Locoregional Therapies for a Systemic Disease.

Historically, the clinical staging of pancreatic cancer has centered on the surgical management of the primary tumor, because few effective chemotherapeutic agents were available and long-term survival was only achieved in the context of surgical resection. Such a strategy of complete oncologic surgical care is reasonable when surgery is both the principal therapy and highly effective. However, complex surgery for pancreatic cancer-often performed in older patients after a lengthy period of induction therapy-can be associated with significant morbidity and mortality. The majority of patients with pancreatic cancer present either locally advanced or metastatic disease at the time of diagnosis. In this article, we will discuss the role of multimodality management of patients with borderline resectable and locally advanced pancreatic cancer. Considering that surgery has a modest impact on the natural history of pancreatic cancer in most patients, a neoadjuvant approach to treatment sequencing is favored for patients with borderline resectable pancreatic cancer, and this same rationale has been extended to select patients with locally advanced disease who demonstrate an exceptional response to induction therapy.

Cholangiopancreatoscopy and endoscopic ultrasound for indeterminate pancreaticobiliary pathology.

BACKGROUND: Techniques to confirm suspected pancreaticobiliary (PB) malignancy when index sampling is non-diagnostic include cholangiopancreatoscopy (CP) and endoscopic ultrasound (EUS). However, comparative data are lacking. AIM: The purpose of this study was to compare the yield of EUS and CP for the diagnosis of PB pathology. METHODS: Consecutive patients with indeterminate PB pathology who underwent both CP and EUS within 3 months of each other were retrospectively identified. For CP, tissue sampling included biopsy under direct inspection (cholangioscopy-directed biopsy), biopsy following CP with fluoroscopic guidance (cholangioscopy-assisted biopsy), or brush cytology. For EUS-FNA, lesions included ductal strictures or hypoechoic masses. A comparison of operating characteristics between CP and EUS utilizing tissue confirmation or 12-month clinical course consistent with either benign or malignant disease was performed. RESULTS: Between February 2000 and June 2007, 66 (33 males, 33 females, median age 64.5) patients with indeterminate PB pathology who had undergone both CP and EUS within 3 months of each other were included. Lesions amenable to sampling were noted in 59 CP and 50 EUS patients. On follow-up, 39 patients had neoplasia and 27 were benign. The sensitivity/specificity for the diagnosis of neoplasia for CP and EUS was 48.7/96.3 % and 33.3/96.3 %, respectively (comparison of sensitivities, P = 0.183). The combined (CP and EUS) sensitivity/specificity was 66.7/96.3 % (P = 0.0064 and P = 0.0001 comparing combined sensitivity vs. sensitivity of either CP alone or EUS alone, respectively). CONCLUSIONS: In patients who undergo both EUS and CP for indeterminate PB pathology, the combined yield of EUS and CP to detect neoplasia appears to be higher than either examination alone.

The chemokine receptor CCR2 is not required for successful initiation of labor in mice.

Chemokine-driven neutrophil and monocyte recruitment into the uterus and cervix has been proposed to initiate labor. Chemokines that bind CXCR2 direct neutrophil migration and are induced during labor in humans. The chemokine CCL2, induced in the uterus by endocrine and mechanical signals, has been proposed to drive CCR2-dependent monocyte homing to the uterus to contribute to the initiation of labor. However, no direct evidence indicates that chemokines or their receptors play indispensable roles in labor-associated inflammation, and the impact of leukocyte infiltration on labor is unclear. Here, we have quantified expression of the principal monocyte- and neutrophil-attracting chemokines in the uteri of term pregnant (Day 18) and laboring wild-type mice. None of the neutrophil attractants we assayed were up-regulated with labor. Strikingly, however, Ccl2 was markedly increased, and this was concomitant with increased expression of Ccr2, the myeloid marker Itgam (also known as Cd11b), the monocyte/macrophage marker Emr1 (also known as F4/80). Moreover, in CCR2-deficient mice, this labor-associated increase in Itgam and Emr1 was not seen, consistent with the monocyte-trafficking defects that exist in these animals. Nonetheless, laboring CCR2-deficient and wild-type uteri showed similarly enhanced expression of the myometrial activation markers Gja1 and Oxtr (commonly known as connexin 43 and oxytocin receptor, respectively), and CCR2-deficient mice had gestation lengths, litter sizes, and fetal and placental weights no different from those of their wild-type counterparts. Thus, whereas labor is associated with an inflammatory response in gestational tissues, CCR2-dependent leukocyte recruitment into the mouse uterus is dispensable for the initiation of successful labor.

Interdependency of cystathione γ-lyase and cystathione ß-synthase in hydrogen sulfide-induced blood pressure regulation in rats.

BACKGROUND: Hydrogen sulfide (H(2)S), an endogenous vasoactive agent, is produced by cystathionine γ-lyase (CGL) and cystathionine ß-synthase (CBS) enzymes. This study was conducted to evaluate the relative contribution of these enzymes in regulating systemic arterial pressure. METHODS: Sprague-Dawley rats were chronically treated with CGL inhibitor, DL-propargylglycine (PAG, 37.5 mg/kg/day; intraperitoneally, i.p.) or CBS inhibitor, aminooxyacetic acid (AOA, 8.75 mg/kg/day; i.p.) or in combination for 4 weeks and the effects on arterial pressure (tail-cuff plethysmography) and renal excretory function (24 h urine collections using metabolic cages) were assessed once in a week. Changes in renal blood flow (RBF; Ultrasonic flowmetry) and glomerular filtration rate (GFR; Inulin clearance) were assessed in acute experiments in anesthetized rats at the end of treatment period. RESULTS: Compared to vehicle treated control group, only the rats with combination therapy showed a decrease in urinary sulfate excretion rate (248 ± 47 vs. 591 ± 70 nmol/24 h; marker for endogenous H(2)S level) which was associated with an increase in mean arterial pressure (MAP; 130 ± 2 vs. 99 ± 2 mm Hg). Urine flow and sodium excretion were also increased in combination group as consequent to the increase in MAP. GFR did not alter due to these treatments but RBF was lowered (4 ± 0.3 vs. 7 ± 0.4 ml/min/g) only in the combination group compared to the control group. CONCLUSION: These findings indicate that a deficiency in one enzyme's activity could be compensated by the activity of the other to maintain the endogenous H(2)S level, the deficiency of which modulates systemic and renal vascular resistances leading to the development of hypertension.