Biosimilars: From Production to Patient.

Biologic drugs are large, complex molecules produced through biotechnology. A biosimilar is a biologic product that is highly similar to an already approved biologic (reference product), with no clinically meaningful differences in purity, safety, or efficacy; as such, a biosimilar does not need to undergo the same level of study in a clinical trial program as the original reference product. Due to the potential impact of biosimilars on patient access and health care systems, the US Food and Drug Administration introduced an abbreviated pathway for approving biosimilars (351[k]) in 2009. There is strong evidence that switching from a reference product to a biosimilar does not reduce treatment effectiveness or increase the risk of adverse events. Biosimilars may reduce costs and increase patient access to biologic therapies. Biosimilar use in the United States has increased, as have the associated biosimilar cost savings, which are expected to reach $104 billion between 2020 and 2024. Yet, a need remains for increased knowledge among health care professionals and patients. Prescriber confidence is key to patient acceptance of biosimilars and minimizing the incidence of the nocebo effect. Infusion nurses are well positioned to help educate patients and to improve clinical outcomes across a range of diseases.

"Just Be There": Desired Partner Behaviors Among Pregnant People Living With Opioid Use Disorder, a Qualitative Study.

OBJECTIVES: Elicit how partners impact pregnant peoples experience living with opioid use disorder (OUD) during pregnancy and summarize participant recommendations to improve partner support from people engaged in treatment for OUD during pregnancy. METHODS: In this qualitative study, we completed 20 in-depth interviews in pregnant people with OUD at an outpatient clinic in Tennessee. We employed inductive and deductive coding based on a relationship intimacy model and thematic analysis to elicit the perspectives, attitudes, and experiences that shaped desired partner behaviors during their pregnancy. We placed our findings in a modified relationship intimacy model of couple adaptation to OUD. Finally, we summarized interviewed participants' recommendations on how to best educate and involve their partners. RESULTS: Our analysis generated 24 codes and 5 themes. Previous lived experience and interpersonal factors influenced participants' experiences with relationship-compromising and relationship-enhancing behaviors. They also reported that positive, or relationship-enhancing behaviors, could mitigate some of their negative intrapersonal feelings such as self-stigma. Participants agreed that partners should display emotional intelligence and empathy, provide supportive logistic and physical behaviors, and be open to improve. Participants also suggested that partners be equipped with information about expected physiological changes during pregnancy, supportive behavior examples, and information about OUD treatment. CONCLUSIONS: Additional input from pregnant people and partners in future projects can build on these findings and guide the creation and assessment of comprehensive interventions to improve care for pregnant people with OUD.

Ultraviolet-B Radiation Represses Primary Root Elongation by Inhibiting Cell Proliferation in the Meristematic Zone of Arabidopsis Seedlings.

In Arabidopsis thaliana plants, exposure to UV-B induces an inhibition of primary root elongation. Different mutants have been isolated that are deficient in this response; however, little is known about the cellular and molecular mechanisms that regulate inhibition of root elongation in seedlings exposed to UV-B. In this work, we investigated the effect UV-B irradiation of different organs on primary root elongation. Our results demonstrate that irradiation of the leaves and shoots only induce a partial inhibition of primary root elongation, while when only roots are exposed to this radiation, primary root inhibition is similar as that measured when the complete seedling is irradiated. The consequences of exposure at different root developmental stages and times after the end of the treatment was also studied. We here show that inhibition of primary root elongation is a consequence of a decrease in cell proliferation in the meristematic zone of the primary roots, while the elongation zone size is not affected by the treatment. The decrease in cell number after UV-B exposure is partially compensated by an increase in cell length in the root meristem; however, this compensation is not enough to maintain the meristem size. We also here demonstrate that, similarly as what occurs in developing leaves, GROWTH REGULATING FACTOR 3 (GRF3) transcription factor regulates cell proliferation in UV-B irradiated roots; however, and in contrast to what occurs in the leaves, this response does not depend on the presence of MITOGEN ACTIVATED PROTEIN KINASE 3 (MPK3). Inhibition of primary root elongation by UV-B under our experimental conditions is also independent of the UV-B photoreceptor UV RESISTANT LOCUS 8 (UVR8) or ATAXIA TELANGIECTASIA MUTATED (ATM); but a deficiency in ATM AND RAD3-RELATED (ATR) expression increases UV-B sensitivity in the roots. Finally, our data demonstrate that UV-B affects primary root growth in various Arabidopsis accessions, showing different sensitivities to this radiation.

E2Fb and E2Fa transcription factors independently regulate the DNA damage response after ultraviolet B exposure in Arabidopsis.

Ultraviolet (UV)B radiation affects plant growth inhibiting cell proliferation. This inhibition is in part controlled by the activity of transcription factors from the E2F family. In particular, the participation of E2Fc and E2Fe in UV-B responses in Arabidopsis plants was previously reported. However, the E2Fa and E2Fb contribution to these processes has still not been investigated. Thus, in this work, we provide evidence that, in Arabidopsis, both E2Fa and E2Fb control leaf size under UV-B conditions without participating in the repair of cyclobutane pyrimidine dimers in the DNA. Nevertheless, in UV-B-exposed seedlings, E2Fa, but not E2Fb, regulates primary root elongation, cell proliferation, and programmed cell death in the meristematic zone. Using e2fa mutants that overexpress E2Fb, we showed that the role of E2Fa in the roots could not be replaced by E2Fb. Finally, our results show that E2Fa and E2Fb differentially regulate the expression of genes that activate the DNA damage response and cell cycle progression, both under conditions without UV-B and after exposure. Overall, we showed that both E2Fa and E2Fb have different and non-redundant roles in developmental and DNA damage responses in Arabidopsis plants exposed to UV-B.

Diagnosis and management of IgG4-related disease.

IgG subclass 4-related disease (IgG4-RD) is a rare but increasingly recognised fibroinflammatory condition known to affect multiple organs. IgG4-RD is characterised by unique histological features of lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis. In this review we describe the pancreaticobiliary manifestations of IgG4-RD, with particular emphasis on type 1 autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC). AIP and IgG4-SC can pose diagnostic challenges to the clinician as they may mimic pancreatic cancer and primary sclerosing cholangitis, respectively. We discuss current knowledge, clinical diagnostic criteria and recent advances and summarise the evidence base for current therapeutic approaches for AIP and IgG4-SC.

Arabidopsis E2Fc is required for the DNA damage response under UV-B radiation epistatically over the microRNA396 and independently of E2Fe.

UV-B radiation inhibits plant growth, and this inhibition is, to a certain extent, regulated by miR396-mediated repression of Growth Regulating Transcription factors (GRFs). Moreover, E2Fe transcription factor also modulates Arabidopsis leaf growth. Here, we provide evidence that, at UV-B intensities that induce DNA damage, E2Fc participates in the inhibition of cell proliferation. We demonstrate that E2Fc-deficient plants show a lower inhibition of leaf size under UV-B conditions that damage DNA, decreased cell death after exposure and altered SOG1 and ATR expression. Interestingly, the previously reported participation of E2Fe in UV-B responses, which is a transcriptional target of E2Fc, is independent and different from that described for E2Fc. Conversely, we here demonstrate that E2Fc has an epistatic role over the miR396 pathway under UV-B conditions. Finally, we show that inhibition of cell proliferation by UV-B is independent of the regulation of class II TCP transcription factors. Together, our results demonstrate that E2Fc is required for miR396 activity on cell proliferation under UV-B, and that its role is independent of E2Fe, probably modulating DNA damage responses through the regulation of SOG1 and ATR transcript levels.

Outcome of long interval radiological surveillance of side branch pancreatic duct-involved intraductal papillary mucinous neoplasm in selected patients.

INTRODUCTION: Side branch IPMN (SB-IPMN) of the pancreas has a malignancy rate between 10 and 20%. We hypothesized that surveillance at longer intervals on selected patients with SB-IPMN might be indicated. METHODS: This is a retrospective study of prospectively collected data of 276 patients presenting from 2000 to 2010. After 2007, we opted to screen our patients with longer intervals, initially at 12 months then 24 months using MR if no "worrisome features" were present. RESULTS: Complete data sets for 261 patients were analysed and patients were aged 78 (40-91) years. 232 patients had sole SB-IPMN while 92% were incidental (n = 209) and 8% were symptomatic (n = 24). Single SB-IPMN accounted for 84% (n = 195) of all cases; maximum diameter of 15.5 (5-60) mm. The median follow up duration was 46 (32-53) months. Short interval radiological surveillance (3-9 months) was 39% (n = 90), while long interval surveillance (12-36 months) was performed in 61% (n = 142). The rate of pancreatic resection, due to concern for the development of pancreatic cancer, in the short and long interval surveillance groups was 4.4% (n = 4) and 3.5% (n = 5) respectively; p = 0.78. CONCLUSION: Our data suggests no difference in outcome between long and short interval MR surveillance of SB-IPMN patients.

Lymphoepithelial cysts of the pancreas:a management dilemma.

Pancreatic lymphoepithelial cysts (LECs) are rare, benign lesions that are typically unexpected post-operative pathological findings. We aimed to review clinical, radiological and pathological features of LECs that may allow their pre-operative diagnosis. Histopathology databases of two large pancreatic units were searched to identify LECs and notes reviewed to determine patient demographic details, mode of presentation, investigations, treatment and outcome. Five male and one female patients were identified. Their median age was 60 years. Lesions were identified on computed tomography performed for abdominal pain in two patients, and were incidentally observed in four patients. Five LECs were located in the tail and one in the body of the pancreas, with a median cyst size of 5 cm. Obtaining cyst fluid was difficult and a largely acellular aspirate was yielded. The pre-operative diagnosis was mucinous cystic neoplasm in all patients. This series of patients were treated distal pancreatectomy and splenectomy. A retrospective review of radiological examinations suggested that LECs have a relatively low signal on T2 imaging and a high signal intensity on T1 weighted images. LECs appear more common in elderly males, and are typically incidental, large, unilocular cysts. Close attention to signal intensity on MRI may allow pre-operative diagnosis of these lesions.

Xanthogranulomatous cholecystitis: a European and global perspective.

INTRODUCTION: Xanthogranulomatous cholecystitis (XGC) is often mistaken for, and may predispose to, gallbladder carcinoma (GB Ca). This study reviews the worldwide variation of the incidence, investigations, management and outcome of patients with XGC. METHODS: Data from 29 studies, cumulatively containing 1599 patients, were reviewed and results summarized by geographical region (Europe, India, Far East and Americas) with 95% confidence intervals (CIs) to present variability within regions. The main study outcomes were incidence, association with GB Ca and treatment of patients with XGC. RESULTS: Overall, the incidence of XGC was 1.3-1.9%, with the exception of India where it was 8.8%. The incidence of GB Ca associated with XGC was lowest in European studies (3.3%) varying from 5.1-5.9% in the remaining regions. Confusion with or undiagnosed GB Ca led to 10.2% of patients receiving over or under treatment. CONCLUSIONS: XGC is a global disease and is associated with GB Ca. Characteristic pathological, radiological and clinical features are shared with GB Ca and contribute to considerable treatment inaccuracy. Tissue sampling by pre-operative endoscopic ultrasound or intra-operative frozen section is required to accurately diagnose gallbladder pathology and should be performed before any extensive resection is performed.

Detection of colorectal metastases in patients being treated with chemotherapy utilising SPIO-MRI: a radiological-pathological study.

OBJECTIVE: Chemotherapy commonly causes liver injury through sinusoidal obstructive syndrome and steatosis. Chemotherapy-induced liver injury may make it more difficult to detect metastases secondary to reduced contrast between the injured liver and metastases. The aim of this study was to determine the sensitivity of superparamagnetic iron oxide (SPIO) contrast-enhanced imaging in patients who have undergone chemotherapy prior to liver surgery. METHODS: Local ethics committee approval was obtained. Thirty-one patients with hepatic metastases completing preoperative chemotherapy were prospectively recruited. Images were reviewed independently by two blinded observers who identified and localized lesions with a four-point confidence scale. The alternative free-response receiver operator characteristic method was used to analyze the results. RESULTS: The sensitivity in detecting colorectal metastases following chemotherapy was 78% and 76%, respectively, for observers 1 and 2 (95% confidence interval: 71%-85% and 68%-82%). The areas under the alternative free-response receiver operator curves were 0.73 and 0.80 for observers 1 and 2, respectively. CONCLUSION: Compared to previously published work on chemotherapy-naïve patients, it is clear that the sensitivity of SPIO-enhanced magnetic resonance imaging (MRI) in detecting colorectal metastases following chemotherapy is reduced. It is therefore critical that all imaging--pre-, during and postchemotherapy--is reviewed when reporting liver MRI prior to surgery.

Pancreaticopleural fistula: etiology, treatment and long-term follow-up.

BACKGROUND: Pancreaticopleural fistula (PPF) are uncommon. Complex multidisciplinary treatment is required due to nutritional compromise and sepsis. This is the first description of long-term follow-up of patients with PPF. METHODS: Eleven patients with PPF treated at a specialist unit were identified. Causation, investigation, treatment and outcomes were recorded. RESULTS: Pancreatitis was the etiology of the PPF in 9 patients, and in the remaining 2 the PPF developed following distal pancreatectomy. Cross-sectional imaging demonstrated the site of duct disruption in 10 cases, with endoscopic retrograde cholangiopancreatography identifying the final case. Suppression of pancreatic exocrine secretion and percutaneous drainage formed the mainstay of treatment.Five cases resolved following pancreatic duct stent insertion and three patients required surgical treatment for established empyema. There were no complications. In all cases that resolved there has been no recurrence of PPF over a median follow-up of 50 months (range 15-62). CONCLUSIONS: PPF is an uncommon event complicating pancreatitis or pancreatectomy; pancreatic duct disruption is the common link. A step-up approach consisting of minimally invasive techniques treats the majority with surgery needed for refractory sepsis.

Sinusoidal obstructive syndrome diagnosed with superparamagnetic iron oxide-enhanced magnetic resonance imaging in patients with chemotherapy-treated colorectal liver metastases.

PURPOSE: To assess the predictive value of superparamagnetic iron oxide (SPIO) -enhanced T2-weighted gradient echo (GRE) imaging to determine the presence and severity of sinusoidal obstructive syndrome (SOS). PATIENTS AND METHODS: Sixty hepatic resection patients with colorectal metastases treated with chemotherapy underwent unenhanced magnetic resonance imaging (MRI) followed by T2-weighted GRE sequences obtained after SPIO. The images were reviewed in consensus by two experienced observers who determined the presence and severity of linear and reticular hyperintensities, indicating SOS-type liver injury, using a 4-point ordinal scale. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with 95% CIs for the detection of SOS were calculated. RESULTS: Twenty-four of 60 patients had moderate to severe SOS on MRI. MRI achieved a sensitivity of 87% (95% CI, 66% to 97%), specificity of 89% (95% CI, 75% to 97%), PPV of 83% (95% CI, 63% to 95%), and NPV of 92% (95% CI, 77% to 98%). SOS was never found at surgery or histology in patients whose background liver parenchyma was normal on SPIO-enhanced MRI. CONCLUSION: SOS is present in a significant proportion of patients with treated colorectal metastases and is effectively detected on SPIO-enhanced T2-weighted GRE images.

Endoscopic ultrasound guided transgastric stenting of traumatic pancreatic pseudocyst.

CONTEXT: Although there exists multiple modalities of managing traumatic pancreatic pseudocysts it remains a diagnostic and therapeutic challenge. We report herein a case that was successfully managed by endoscopic ultrasound guided transgastric stent placement. CASE REPORT: A 28-year-old female jockey presented with abdominal pain after being kicked by a horse. Computerised tomography and magnetic resonance imaging revealed pancreatitis which resolved with conservative treatment. She proceeded to develop a pancreatic pseudocyst demonstrated on a magnetic resonance cholangiopancreatogram. This was managed by transgastric placement of two double pigtail stents into the pseudocyst by endoscopic ultrasound guidance. Rapid recovery followed with the patient remaining well on follow up. CONCLUSIONS: EUS guided transgastric stent placement for drainage of pancreatic pseudocysts is recommended particularly if they are in close proximity to the stomach.

Multidisciplinary management of surgical disorders of the pancreas in childhood.

OBJECTIVES: To describe the frequency and range of pancreatic disorders in children requiring surgical intervention and to highlight the importance of multidisciplinary management. METHODS: An audit of all children under 17 years of age referred with surgical disorders of the pancreas or pancreatitis to a regional pediatric gastroenterology unit in the United Kingdom during a 10-year period. A retrospective chart review of clinical features, pathology and outcome was undertaken. RESULTS: Surgical intervention was required for the following pancreatic disorders: persistent hyperinsulinemic hypoglycemia of infancy (n = 4), pancreatic tumors (n = 5), pancreaticobiliary malunion (n = 12), pancreatic trauma (n = 6) and pancreatitis (n = 10). The indications for surgery in acute pancreatitis were a persistent pseudocyst (n = 1) and treatment of an underlying cause of pancreatitis (n = 4); in chronic pancreatitis, surgery was used to treat symptomatic pancreatic duct strictures (n = 4). One child died of a progressive lymphoma but all others who underwent surgery are alive and well. All 33 children with acute pancreatitis, including four with pancreatic necrosis, survived. CONCLUSIONS: Surgery for pancreatic disorders in children is rarely required but may be necessary a) for definitive management of primary pancreatic pathology, b) to treat sequelae of acute or chronic pancreatitis and c) to treat an underlying cause of pancreatitis. There is a broad spectrum of potential pathologies. These patients are best managed by a multidisciplinary team approach.

Bile duct strictures after hepatobiliary surgery: assessment with MR cholangiography.

PURPOSE: To establish the accuracy of magnetic resonance (MR) cholangiography for diagnosis of postsurgical bile duct strictures. MATERIALS AND METHODS: Sixty-seven patients suspected of having bile duct strictures after liver transplantation (n = 54), cholecystectomy (n = 8), hepatic resection (n = 4), or pancreaticoduodenectomy (n = 1) underwent MR cholangiography. Thick-slab single-shot fast spin-echo (repetition time msec/echo time msec, 4,500/940) imaging was performed in the coronal through sagittal planes with rotation in 10 degrees increments, and contiguous thin-section images were obtained in the transverse and the optimal coronal oblique planes by using half-Fourier rapid acquisition with relaxation enhancement (1,900/96). Three blinded observers independently reviewed the MR images and recorded diagnostic features including presence of biliary stricture by using a five-point confidence scale. Receiver operating characteristic analysis was used to measure the accuracy of MR cholangiography. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Final diagnosis was established at surgery (n = 29) and direct cholangiography (23 of 29) or at direct cholangiography, liver biopsy, and/or serial liver function tests (n = 38). RESULTS: Thirty-three of 67 patients had strictures confirmed with the reference standard. MR cholangiography enabled correct diagnosis and depicted the site of strictures in all cases. Findings of stricture at MR cholangiography were false-positive in five patients with moderate duct dilatation and caliber change at the level of the anastomosis. Mean accuracy, sensitivity, specificity, PPV, and NPV were 94%, 97%, 74%, 86%, and 96%, respectively. CONCLUSION: MR cholangiography is as sensitive as direct cholangiography for the assessment of bile duct strictures after hepatobiliary surgery but may lead to overestimation of the importance of duct dilatation and caliber change.

Esophageal stenting.

Malignant obstruction of the esophagus is a debilitating condition, with dysphagia as its main symptom. Many patients present with advanced disease and palliative treatment is the only possibility. Since their widespread introduction 10 years ago, self-expanding metal stents have become accepted as an extremely effective method of palliating malignant dysphagia. Early reports suggesting very low complications have been superseded by results from randomized trials. It is now evident that the complication rate is significant and the need for reintervention can be as high as 50%. Modifications in stent design should reduce this reintervention rate. There are a large number of stent designs now available and it is essential that the interventional radiologist understand the particular strengths and weaknesses of each design, so that the correct choice of stent can be made for a particular patient. The most recent designs include antireflux stents and removable stents. Both represent significant advances and should reduce stent-related complications.

Heterotopic gastric mucosa in a duplicate gallbladder.

A 7-year-old girl presented with recurrent acute pancreatitis. Detailed investigations, including endoscopic retrograde cholangiography, suggested a poorly defined biliary tract abnormality. At laparotomy, this was discovered to be a duplicate gallbladder each with a separate cystic duct but contained within a single serosal envelope. Both gallbladders were removed, and histologic examination found the inferior organ to be lined by heterotopic fundic-type gastric mucosa. Despite the absence of any remaining structural biliary abnormality and no evidence of residual ectopic gastric mucosa, the patient experienced a few further episodes of self-limiting mild acute pancreatitis during the following 3 years. The presence of heterotopic gastric mucosa in a duplicate gallbladder has not been described previously.