Reshaping preoperative treatment of pancreatic cancer in the era of precision medicine.

This review summarises the recent evidence on preoperative therapeutic strategies in pancreatic cancer and discusses the rationale for an imminent need for a personalised therapeutic approach in non-metastatic disease. The molecular diversity of pancreatic cancer and its influence on prognosis and treatment response, combined with the failure of 'all-comer' treatments to significantly impact on patient outcomes, requires a paradigm shift towards a genomic-driven approach. This is particularly important in the preoperative, potentially curable setting, where a personalised treatment allocation has the substantial potential to reduce pancreatic cancer mortality.

Analysis of Yersinia pseudotuberculosis Isolates Recovered from Deceased Mammals of a German Zoo Animal Collection.

Yersinia pseudotuberculosis is an important pathogen for both humans and animals. It can infect livestock, as well as pets and wild animals. During recent years, a number of reports have described the isolation of Y. pseudotuberculosis from zoo animals, mainly birds and mammals, for which the infection was mostly lethal. Between 2005 and 2019, there were at least 17 cases of deceased mammals, belonging to five different species, which suffered from a Y. pseudotuberculosis infection at the Zoo Wuppertal, Germany. Since only scarce information exists on the properties of Y. pseudotuberculosis from zoo animals, we characterized eight isolates, covering all infected species, in detail. All isolates were members of biotype 1, but belonged to five serotypes, five sequence types (STs), and seven core-genome multilocus sequence types (cgMLSTs). Using pulsed-field gel electrophoresis (PFGE) analysis and whole-genome sequencing (WGS), the seven isolates could be discriminated from each other. They differed significantly regarding their virulence genes and mobile genetic elements. While the virulence plasmid pYV existed in all serotypes (five isolates), a complete high-pathogenicity island (HPI) was detected only in the serotypes O:1a, O:1b, and O:13 (four isolates), but not in O:2a and O:2b. Similarly, the content of other plasmids and prophages varied greatly between the isolates. The data demonstrate that the deceased mammals were infected by seven individual isolates and not by a single type predominating in the zoo animals.

Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

BACKGROUND: Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS: An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION: Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

ANTECEDENTES: Actualmente se desconoce si la quimioterapia adyuvante ofrece un beneficio en la supervivencia de los pacientes que se someten a resección de un adenocarcinoma ampular. El objetivo de este estudio fue comparar la supervivencia mediante la concordancia estimada por emparejamiento por puntaje de propensión, entre pacientes con y sin quimioterapia adyuvante después de la resección de un adenocarcinoma ampular. MÉTODOS: Se realizó un estudio internacional de cohortes multicéntrico, que incluyó a los pacientes que se sometieron a una duodenopancreatectomía por adenocarcinoma ampular (2006-2017) en 13 centros de seis países. Los puntajes de propensión se usaron para emparejar a los pacientes que recibieron quimioterapia adyuvante con los que no; tanto en la cohorte completa como en dos subgrupos (subtipo pancreaticobiliar / mixto e intestinal). La supervivencia se evaluó utilizando el método de Kaplan-Meier y las regresiones de Cox. RESULTADOS: En total, 1.163 pacientes fueron sometidos a una duodenopancreatectomía por adenocarcinoma ampular. Después de excluir a 179 pacientes, la mediana de supervivencia de los 976 pacientes restantes fue de 67 meses (i.c. del 95%, 56-78), de los cuales un total de 520 pacientes (53%) recibieron quimioterapia adyuvante. En una cohorte de emparejamiento por puntaje de propensión (194 versus 194 pacientes), la mediana de supervivencia fue mejor en los pacientes tratados con quimioterapia adyuvante en comparación con aquellos sin quimioterapia adyuvante (no se alcanzó la mediana de supervivencia versus 60 meses, respectivamente; P = 0,051). En el subtipo pancreaticobiliar/mixto se observó un beneficio en la supervivencia; no se alcanzó la mediana de supervivencia en pacientes que recibieron quimioterapia adyuvante versus 32 meses en el grupo sin quimioterapia, P = 0,020. El subtipo intestinal no mostró beneficio en la supervivencia de la quimioterapia adyuvante. CONCLUSIÓN: Los pacientes con adenocarcinoma ampular resecado pueden beneficiarse de la quimioterapia adyuvante basada en gemcitabina, pero este efecto podría reservarse para aquellos pacientes con subtipo de tumor pancreaticobiliar y/o mixto.

Optogenetic surface stimulation of the rat cervical spinal cord.

Electrical intraspinal microstimulation (ISMS) at various sites along the cervical spinal cord permits forelimb muscle activation, elicits complex limb movements and may enhance functional recovery after spinal cord injury. Here, we explore optogenetic spinal stimulation (OSS) as a less invasive and cell type-specific alternative to ISMS. To map forelimb muscle activation by OSS in rats, adeno-associated viruses (AAV) carrying the blue-light sensitive ion channels channelrhodopsin-2 (ChR2) and Chronos were injected into the cervical spinal cord at different depths and volumes. Following an AAV incubation period of several weeks, OSS-induced forelimb muscle activation and movements were assessed at 16 sites along the dorsal surface of the cervical spinal cord. Three distinct movement types were observed. We find that AAV injection volume and depth can be titrated to achieve OSS-based activation of several movements. Optical stimulation of the spinal cord is thus a promising method for dissecting the function of spinal circuitry and targeting therapies following injury. NEW & NOTEWORTHY Optogenetics in the spinal cord can be used both for therapeutic treatments and to uncover basic mechanisms of spinal cord physiology. For the first time, we describe the methodology and outcomes of optogenetic surface stimulation of the rat spinal cord. Specifically, we describe the evoked responses of forelimbs and address the effects of different adeno-associated virus injection paradigms. Additionally, we are the first to report on the limitations of light penetration through the rat spinal cord.

Defining the molecular pathology of pancreatic body and tail adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome.

The LIM-homeodomain protein Lmx1b plays a central role in dorso-ventral patterning of the vertebrate limb. Targeted disruption of Lmx1b results in skeletal defects including hypoplastic nails, absent patellae and a unique form of renal dysplasia (see accompanying manuscript by H. Chen et al.; ref. 2). These features are reminiscent of the dominantly inherited skeletal malformation nail patella syndrome (NPS). We show that LMX1B maps to the NPS locus and that three independent NPS patients carry de novo heterozygous mutations in this gene. Functional studies show that one of these mutations disrupts sequence-specific DNA binding, while the other two mutations result in premature termination of translation. These data demonstrate a unique role for LMX1B in renal development and in patterning of the skeletal system, and suggest that alteration of Lmx1b/LMX1B function in mice and humans results in similar phenotypes. Furthermore, we provide evidence for the first described mutations in a LIM-homeodomain protein which account for an inherited form of abnormal skeletal patterning and renal failure.

Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome.

Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture syndrome; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.

Preventive effects of perioperative parecoxib on post-discectomy pain.

BACKGROUND: Cyclooxygenase inhibitor treatment is viewed increasingly critical because of safety considerations, and there are several open questions on their optimal use. METHODS: In a randomized placebo-controlled study in 320 patients undergoing discectomy, we administered parecoxib 40 mg either perioperatively (before operation and after operation), after operation (first dose given in the evening after surgery), or before operation (single parecoxib dose given 45 min before surgery). We measured the main outcome variables: average pain score, morphine consumption, and opioid-related symptom distress at 25, 49, and 73 h after surgery. RESULTS: Perioperative parecoxib significantly (i) improved the pain score compared with both placebo and postoperative parecoxib, (ii) decreased morphine consumption, and (iii) reduced the opioid-related symptom distress score. Neither a single preoperative dose nor postoperative parecoxib (first dose given in the evening after surgery) significantly improved morphine's analgesic effectiveness. CONCLUSIONS: Perioperative parecoxib compared with postoperative parecoxib improves post-discectomy pain and results in a reduction in adverse effects associated with opioid therapy. Postoperative parecoxib, or a single pre-incisional parecoxib dose, does not significantly improve post-discectomy pain or opioid side-effects up to 3 days after surgery.

Identification of LMX1B gene point mutations in italian patients affected with Nail-Patella syndrome.

Nail-Patella syndrome, or osteo-onychodysplasia, is an autosomal dominant disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns and nephropathy. Previous studies have demonstrated linkage of the Nail-Patella locus with polymorphic markers on human chromosome 9q34. Recently, point mutations in the LMX1B gene have been identified in Nail-Patella patients and in families with recurrence of Nail-Patella syndrome and open-angle glaucoma. We describe here the identification of additional point mutations in the LMX1B gene in a set of Italian patients affected with Nail-Patella syndrome: two deletions of 1 and 2 bp causing a frameshift in two sporadic patients and nonsense mutations in two familial and one sporadic cases have been identified. All the mutations affect the homeodomain of the LMX1B protein and could cause the Nail-Patella syndrome through a loss of function as well as a dominant negative effect. Haplotype analysis in the two familial cases carrying the same stop codon mutation suggests the presence of a founder effect. Finally, analysis of cDNA clones obtained from human fetal kidney has revealed the existence of two different transcripts of LMX1B gene likely due to an alternative splicing.

Thoracic zygapophyseal joint pain patterns. A study in normal volunteers.

STUDY DESIGN: Nine asymptomatic volunteers underwent 40 provocative intra-articular injections of the thoracic zygapophyseal joints. OBJECTIVE: The purpose of the study was to isolate and stimulate the thoracic zygapophyseal joints via fluoroscopically guided intra-articular injections to determine whether they are potential pain generators. SUMMARY OF BACKGROUND DATA: Experimentally, the cervical and lumbar zygapophyseal joints have been shown to produce pain, and tentative referral patterns have been established. Referral patterns based on stimulation of the thoracic zygapophyseal joints have not been previously reported. METHODS: Four subjects underwent right-sided T3-T4, T5-T6, T7-T8, and T9-T10 joint injections, and four subjects underwent left-sided T4-T5, T6-T7, T8-T9, and T10-T11 joint injections. One subject underwent both the right- and left-sided joint injections. The zygapophyseal joints were injected with contrast medium only, and the quality, intensity, and distribution of evoked pain was recorded. RESULTS: In this asymptomatic population, 72.5% of joints injected produced a sensation/pain that was different from the sensation of needle advancement through the soft tissues. In 27.5% of joints injected, there was no evoked pain despite adequate capsular distension. Evoked referral patterns were consistent in all subjects. Significant overlap occurred in the referral patterns, with most thoracic regions sharing 3-5 different joint referral zones. CONCLUSIONS: This study provides preliminary confirmation that the thoracic zygapophyseal joints can cause both local and referred pain. A referral pain diagram has been constructed.

Lumbar zygapophysial (facet) joint injections.

The lumbar zygapophysial joints are a potential cause of back and lower extremity pain. Absolute diagnosis of lumbar zygapophysial joint-mediated pain is based on selective analgesic injections of these joints or their nerve supply. The therapeutic role of zygapophysial joint injections is controversial. This contemporary concepts paper reviews the anatomy, mechanics, pathology, and diagnosis of this condition. A critical review of previous studies assessing the role of diagnostic and potentially therapeutic zygapophysial joint injection procedures is presented. The need for future studies is addressed, and current recommendations for the role of zygapophysial joint injection procedures based on this critical scientific review are provided.

Management of low back pain. Current assessment and formulation of a blueprint for the health care delivery system of the future.

This article outlines the authors' recommendations for future health care delivery to patients with low back pain and presents one potential blueprint for a modified delivery system. A group of multidisciplinary physicians and support staff that functions as a unified team with common goals is best positioned to overcome the challenges of providing quality care in a managed care environment. The burden on those who manage patients with spine disorders is to define and prove that high quality medical care results in genuine cost savings and better value for the health care customer.

Inter- and intra-tester reliability of clinical measurement to determine medio-lateral patellar position using a pachymeter or visual assessment.

The aim was to investigate inter-tester and intra-tester reliability and parallel reliability between a visual assessment method and a method using a pachymeter for locating the mid-point of the patella in determining the medial/lateral patella orientation. Fifteen asymptomatic subjects were assessed and the mid-point of the patella was determined by both methods on two separate occasions two weeks apart. Inter-tester reliability was obtained by ANOVA and by intraclass correlation coefficient (ICC); intra-tester reliability was obtained by a paired t-test and ICC; and parallel reliability was obtained by Pearson's Correlation and ICC, for the measurement on the first and second evaluations. There was acceptable inter-tester agreement (p=0.490) and reliability for the visual inspection (ICC=0.747) and for the pachymeter (ICC=0.716) at the second evaluation. The inter-tester reliability in the first evaluation was unacceptable (visual ICC=0.604; pachymeter ICC=0.612). Although there was statistical similarity between measurements for the first and second evaluations for all testers, intra-tester reliability was not acceptable for both methods: visual (examiner 1 ICC=0.175; examiner 2 ICC=0.189; examiner 3 ICC=0.155) and pachymeter (examiner 1 ICC=0.214; examiner 2 ICC=0.246; examiner 3 ICC=0.069). Parallel reliability gave a perfect correlation at the first evaluation (r=0.828; p<0.001) and at the second (r=0.756; p<0.001) and reliability was between acceptable and very good (ICC=[0.748-0.813]). Both visual and pachymeter methods provide reliable and similar medial/lateral patella orientation and are reliable between different examiners, but the results between the two assessments at 2 weeks' interval demonstrated an unacceptable reliability.

Planning primary prevention strategy. A survey of the effects of business location on Indian reservation life.

It was hypothesized that the introductions of a new business or industry into a high-poverty-level Indian reservation community would produce conditions that could have both positive and negative effects on mental health. A questionnaire surveying the impact of business location on reservation life was sent to all field offices of the Bureau of Indian Affairs. Survey results supported the expectation that business development may affect community life in a variety of ways. Respondents cited approximately twice as many positive effects as negative ones. Furthermore, it was found that relatively few Indians were actually employed and consequently exposed to either type of effect. Implications of the survey for planning primary prevention strategies which would minimize the pathogenic influences of business development are discussed.

Low back pain and the zygapophysial (facet) joints.

A basic science and clinical review of low back pain due to the lumbar zygapophysial (facet) joints was performed based on a literature search of scientific journals and textbooks. Recent studies estimate that 15% to 40% of chronic low back pain is due to the zygapophysial joints. The histological basis for zygapophysial joint pain has been scientifically established, but the precise clinical etiology remains undetermined. There are no unique identifying features in the history, physical examination, and radiological imaging of patients with pain of lumbar zygapophysial joint origin. Spine physicians diagnose zygapophysial joint pain based on analgesic response to anesthetic injections into the zygapophysial joints or at their nerve supply. Studies on treatment of isolated zygapophysial joint pain are limited. This review summarizes current understanding of lumbar zygapophysial joint disorders while highlighting the need for additional research.