Protoporphyrinaemia and decreased activities of 5-aminolevulinic acid dehydrase and uroporphyrinogen I synthetase in erythrocytes of a Vitamin B6-deficient epileptic boy given valproic acid and carbamazepine

Carbamazepine (CBMZP) has been implicated as an inhibitor of the activities of 5-aminolaevulinic acid dehydratase (ALA-D) and uroporphyrinogen I synthetase (URO-S). In an epileptic boy undergoing long-term treatment with valproic acid (VPA), 1.3 g/d, CBMZP, 0.9 g/d and folic acid, 7.5 mg/d, decreased activities of ALA-D and URO-S coincided with increased levels of erythrocyte protoporphyrin (EP) in the absence of Pb poisoning, iron depletion and erythropoietic protoporphyria. A progressive fall in plasma pyridoxal 5'-phosphate (B6-P) to 7.7 nmol/L (lower reference limit, 14.6 nmol/L) prompted implementation of pyridoxine HCl (B6-HCl), 87.5 mg/d followed by administration of both B6-HCl and preformed B6-P (50 mg/d each). This permitted the eventual withdrawal of VPA and a net reduction of CBMZP to 450 mg/d. During these manipulations, ALA-D and URO-S activities, EP and urinary porphyrins and their precursors were measured serially. An assay system utilizing red cell ALA-D for generation of porphobilinogen (PBG) from added ALA at pH 7.4 was used for determination of ALA-D and URO-S activities in separate aliquots of the same assay mixture both in the absence and presence of Zn and dithiothreitol (DTT). One unit (U) for ALA-D = 1 nmol PBG/L RBC/s; for URO-S = 1 nmol porphyrin/L/s; minimum normal level for ALA-D = 135 U; for URO-S = 6 U. B6-HCl alone entailed increases in ALA-D and URO-S prior to any reduction of CBMZP. After administration of both B6-HCl and B6-P and withdrawal of VPA, the overall increase in ALA-D was from 54.59 to 197.2 U (-Zn; -DTT) and from 50.76 to 217.3 U (+Zn; +DTT). The overall increase in URO-S was from 2.67 to 8.90 U (-Zn; -DTT) and from 3.02 to 8.66 U (+Zn; +DTT). During stepwise reduction of VPA, EP remained elevated to values as high as 2.48 mumol/L (upper reference limit, 1.33 mumol/L). Only after permanent withdrawal of VPA did concentrations of EP fall to normal levels. Values for porphyrins and their precursors in urine were normal throughout. Since both VPA and B6-P are strongly protein-bound, it is suggested that VPA displaced B6-P from protective protein binding sites and that the resulting deficit in B6-P (rather than CBMZP) reduced ALA-D and URO-S activities via primary reduction of ALA-synthetase activity. Increases in EP emerge as a hitherto unappreciated effect of VPA warranting further investigation.     

Does pre-operative multifidus morphology on MRI predict clinical outcomes in adults following surgical treatment for degenerative lumbar spine disease? A systematic review

Low back pain (LBP) resulting from degenerative lumbar spine disease is a leading contributor to global disability. Changes in the morphology of the lumbar multifidus muscle on magnetic-resonance imaging (MRI) are associated with worse LBP and disability, but the association between multifidus morphology and post-operative outcomes is not known. The purpose of this systematic review is to examine the relationship between pre-operative multifidus morphology and post-operative changes in pain and disability. We performed a systematic search using the Cochrane Library, EMBASE, MEDLINE, CINAHL and Scopus databases covering the period from January 1946 to January 2018. The literature was searched and assessed by independent reviewers according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. All relevant papers were assessed for risk of bias according to the Quality in Prognosis Studies tool. The initial search yielded 436 studies, of which 6 studies were included in the analysis. Four studies were at a low risk of bias. These studies included a total of 873 patients undergoing spinal surgery. An association between low fat infiltration and greater improvement in LBP and disability following surgery was identified. There was insufficient evidence to identify a relationship between cross-sectional area (CSA) and LBP or disability. This systematic review found evidence for an association between low multifidus fat infiltration on MRI at baseline and greater reductions in measures of LBP and disability following surgical treatment. There is also limited evidence for an association between larger pre-operative multifidus CSA and improvements in disability, but not pain. The findings of this review should be interpreted with caution due to the small quantity of the available literature.     

Feasibility of Laparoscopic Re-resection for Patients with Recurrent Hepatocellular Carcinoma

Background

Repeated resection via an open approach is an effective treatment for post-operative recurrent hepatocellular carcinoma (HCC). However, there are limited data on the application of laparoscopic approach for recurrent HCC in patients with prior liver resections. The aim of this study was to review our experience of laparoscopic re-resection in patients with postoperative tumor recurrence.

Materials and methods

A total of 11 patients received laparoscopic re-resections for postoperative tumor recurrence in our center. Data were reviewed for demographics, tumor characteristics, and perioperative outcomes. Case-match analysis with the open approach was performed in a 1:2 ratio.

Results

Six patients had their first liver resection carried out via the open approach and the remaining five patients received the laparoscopic approach. The recurrent tumor size was 20 mm (12–50 mm) and ten patients had a solitary recurrence. Two patients had laparoscopic left lateral sectionectomy and the remaining nine patients had sub-segmentectomies. There was no significant difference in patient characteristics, preoperative liver function, and tumor features between the laparoscopic and open groups. Perioperative blood loss was significantly reduced in the laparoscopic group (100 vs. 314 mL; p = 0.014) but the morbidity rate (18.2 vs. 4.5 %; p = 0.199) and length of hospitalization were comparable (6 vs. 5 days; p = 0.831). The 3-year overall survival rates for the laparoscopic and open groups were 60.0 and 89.3 %, respectively (p = 0.279).

Conclusion

Our study showed that laparoscopic re-resection for recurrent HCC was feasible with satisfactory postoperative and oncological outcomes, even in patients with previous major liver resections.     

Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets

Background

The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.

Methods

Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.

Results

The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.

Conclusions

Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.     

Examining physiotherapist use of structured aerobic exercise testing to decrease barriers to aerobic exercise

Objective: To determine the frequency of physiotherapist-administered aerobic exercise testing/training, the proportion of physiotherapists who administer this testing/training, and the barriers that currently exist across different practice environments. A secondary objective is to identify the learning needs of physiotherapists for the development of an education curriculum in aerobic exercise testing and training with electrocardiograph (ECG) administration and interpretation. Design: National, cross-sectional survey. Participants: Registered physiotherapists practicing in Canada. Results: Out of 137 participants, most (75%) physiotherapists prescribed aerobic exercise on a regular basis (weekly); however, 65% had never conducted an aerobic exercise test. There were no significant differences in frequency of aerobic exercise testing across different practice environments or across years of physiotherapy experience. Physiotherapists perceived the main barriers to aerobic exercise testing as being a lack of equipment/space (78%), time (65%), and knowledge (56%). Although most (82%) were uncomfortable administering 12-lead ECG-monitored aerobic exercise tests, 60% stated they would be interested in learning more about ECG interpretation. Conclusion: This study found that physiotherapists are regularly implementing aerobic exercise. This exercise was infrequently guided by formal aerobic exercise testing, which could increase access to safe and effective exercise within the optimal aerobic training zone. As well, this could facilitate training in patients with cardiovascular diagnoses that require additional testing for medical clearance. Increased ECG training and access to equipment for physiotherapists may augment pre-screening aerobic exercise testing. This training should include learning the key arrhythmias for aerobic exercise test termination as defined by the American College of Sports Medicine.     

Long-term follow up of gastric low-grade mucosa-associated lymphoid tissue lymphoma by endosonography emphasizing the application of a miniature ultrasound probe

BACKGROUND AND AIMS: Endoscopic ultrasonography (EUS) is a useful tool for the evaluation of gastric wall infiltration including gastric lymphoma. The aims of this study were to characterize gastric low-grade mucosa-associated lymphoid tissue (MALT) lymphoma according to EUS findings and to evaluate the role of a miniature ultrasound probe in the long-term follow up. METHODS: From January 1994 to March 2002, 20 patients were proven to have gastric low-grade MALT lymphoma. Endoscopic ultrasonography was performed with a conventional echoprobe and/or a miniature ultrasound probe for initial staging and a miniature ultrasound probe was performed during follow up. All patients positive for Helicobacter pylori received a 2-week course of omeprazole, amoxicillin and clarithromycin. RESULTS: Helicobacter pylori infection was found in 17 (85%) patients. In all patients, H. pylori was eradicated after treatment. Initial EUS showed significantly greater wall thickness (6.1 +/- 3.0 mm) in MALT lymphoma patients when compared with control (2.8 +/- 0.3 mm). The infiltrative patterns included wall thickening (3.5-14.1 mm) in 18 patients: stage E-I1 in 16 (mucosa and/or submucosa), stage E-I2 in one and stage E-II in one. Complete regression of MALT lymphoma following treatment for H. pylori was noted in 14 patients, with a mean duration of 11.3 +/- 9.1 months. Follow-up miniature ultrasound probe sonography showed comparative reduction in wall thickness (P < 0.05). CONCLUSIONS: Endoscopic ultrasonography plays a valuable role in the initial staging and long-term follow up of gastric low-grade MALT lymphoma. The application of a miniature ultrasound probe enables adequate evaluation in the majority of these patients, with additional benefits.