Bridging pre-surgical endocrine therapy for breast cancer during the COVID-19 pandemic: outcomes from the B-MaP-C study.

PURPOSE: The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources. METHODS: This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb-July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis. RESULTS: 1094 patients were prescribed BrET, over a median period of 53 days (IQR 32-81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7-8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months' treatment duration; median of 4 mm [IQR - 20, 4]. In a small subset of patients (n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month's duration of BrET. DISCUSSION: This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials.

Diagnostic accuracy of C-reactive protein, procalcitonin and neutrophils for the early detection of anastomotic leakage after colorectal resection: a multicentric, prospective study.

AIM: The aim was to determine the accuracy of C-reactive protein (CRP), procalcitonin and neutrophils in the early detection (fourth postoperative day) of anastomotic leakage (AL) after colorectal surgery. METHODS: We conducted a multicentre, prospective study that included a consecutive series of patients who underwent colorectal resection with anastomosis without ostomy (September 2015 to December 2017). CRP, procalcitonin and neutrophil values on the fourth postoperative day after colorectal resection along with the postoperative outcome (60-day AL, morbidity and mortality) were prospectively included in an online, anonymous database. RESULTS: The analysis ultimately included 2501 cases. The overall morbidity and mortality was 30.1% and 1.6%, respectively, and the AL rate was 8.6%. The area under the receiver operating characteristic curve values (95% CI) for detecting AL were 0.84 (0.81-0.87), 0.75 (0.72-0.79) and 0.70 (0.66-0.74) for CRP, procalcitonin and neutrophils, respectively. The best cut-off level for CRP was 119 mg/l, resulting in 70% sensitivity, 81% specificity and 97% negative predictive value. After laparoscopic resection, the accuracy for CRP and procalcitonin was increased, compared with open resection. The combination of two or three of these biomarkers did not significantly increase their accuracy. CONCLUSION: On the fourth postoperative day, CRP was the most reliable marker for excluding AL. Its high negative predictive value, especially after laparoscopic resection, allows for safe hospital discharge on the fourth postoperative day. The routine use of procalcitonin or neutrophil counts does not seem to increase the diagnostic accuracy.

Mesenteric tumor due to chronic anisakiasis.

Intestinal anisakiasis is a rare parasitic disease and difficult to diagnose due to symptoms are not specific, so it is considered an underdiagnosed disease. The clinical suspicion with a correct diagnosis of anisakiasis allows the establishment of a correct treatment; in most cases, the resolution is possible with conservative treatment, avoiding unnecessary surgery to the preoperative differential diagnosis of acute abdomen. We report the case of apatient who required urgent surgery secondary to an exacerbation of chronic anisakiasis.

[Is the claiming of costs justifiable in Jehovah's witness surgical patients after healthcare that is not part of the public health system?]. / ¿Es justificable el reintegro del gasto en enfermos quirúrgicos testigos de Jehová tras asistencia sanitaria ajena al sistema público de salud?

INTRODUCTION: Jehovah's witnesses refuse blood transfusions. The conflict arises when the patient, entitled to public health treatment, come to surgical centres without blood, to later claim the costs incurred. OBJECTIVES: To analyse the legal claims for the refunding of costs by Jehovah's witnesses treated outside the public health system. To make a cost comparison regarding this, using Diagnosis Related Groups (DRGs) in a similar hypothetical healthcare model and equal to a stay in our hospital. MATERIAL AND METHODS: A retrospective study was made of the High, Constitutional, and Supreme Court rulings. A cost analysis was made using the clinical information obtained in the rulings, to process this in the DRG in our hospital using 3MHealth Information Systems. RESULTS/CONCLUSIONS: The State is not obliged to finance religious aspects or those outside the general interest. The establishment of working protocols would avoid ethical conflicts. There are very difficult to justify differences in the costs demanded, 431,001.66 €, and compared to a model with an equal stay, 397,404.48 €.

Correlation between methylphenidate and ritalinic acid concentrations in oral fluid and plasma.

BACKGROUND: We studied the excretion profile of methylphenidate (MPH) and its metabolite ritalinic acid (RA) in oral fluid and plasma, the oral fluid-to-plasma (OF/P) drug ratio, and the variations of oral fluid pH after drug administration. METHODS: We analyzed oral fluid and plasma samples, obtained from 8 healthy volunteers after ingestion of a single dose of 20 mg fast-release or extended-release MPH, for MPH and RA by LC-MS. We estimated the apparent pharmacokinetic parameters of MPH in plasma and oral fluid and calculated the OF/P ratio for each time interval. RESULTS: MPH and RA were detected in oral fluid. Whereas parent drug concentrations in oral fluid were an order of magnitude higher than those in plasma, the opposite was observed for RA. Oral fluid concentrations of MPH ranged between 0.5 and 466.7 microg/L and peaked at 0.5 h after administration of the fast-release formulation; they ranged between 0.7 and 89.5 microg/L and peaked at 2 h after administration of the extended-release formulation. Both formulations presented bimodal time-course curves for the OF/P ratio, ranging between 1.8 and 242.1 for the fast-release formulation and between 2.6 and 27.0 for extended-release. Oral fluid pH did not appear to be modified by the administration of the drug, and its influence on OF/P ratio did not affect the correlation of MPH between the 2 body fluids. CONCLUSIONS: The results obtained support the measurement of MPH in oral fluid as an alternative to plasma if the extended-release formulation is used.

Usefulness of sweat testing for the detection of methylphenidate after fast- and extended-release drug administration: a pilot study.

The pharmacokinetics of methylphenidate (MPH), a prescription amphetamine derivative used in the treatment of attention-deficit hyperactivity disorder, has been amply described in conventional biological matrices. Recently, the excretion of MPH and its principal metabolite, ritalinic acid (RA) in oral fluid and plasma after a single drug administration has been described. The aim of this study was to describe the excretion of MPH and RA in sweat after the administration of a single dose of either fast-release or extended-release MPH. Three male subjects received 2 simultaneous oral doses of 10 mg fast-release MPH, and 1 male subject received one dose of 20 mg extended-release MPH. Sweat patches were applied to the back of each participant and removed at timed intervals. MPH and RA were determined in patches using a previously validated liquid chromatography-electrospray ionization mass spectrometric method. MPH was detected in sweat after the administration of fast- and extended-release formulations. For the fast-release formulation, MPH appeared in the sweat patches 2 hours after administration with a maximum of 15.9 nanogram per patch, reached after 24 hours. Mean total MPH excreted was 0.02 mg (about 0.08% of the administered dose). For the extended-release formulation, MPH appeared in the sweat 5 hours after administration and reached a maximum of 34.3 nanogram per patch after 24 hours. Mean total MPH excreted was 0.04 mg (about 0.18% of the administered dose). RA was not detected in either of the sweat patches probably because of its acidic properties. Measuring MPH in sweat patches can be a viable alternative to urine testing for noninvasive monitoring of use and misuse of the drug.

[Spice drugs: cannabinoids as a new designer drugs]. / Spice drugs: los cannabinoides como nuevas drogas de diseño.

Some smokable herbal mixtures under the brand name Spice drugs have been sold on the Internet and in specialised shops (smart shops) since 2004. The mixtures are advertised as an exotic incense blend which releases a rich aroma and not for human consumption. When smoked, Spice drugs products have been reported by products have been reported by some users to have effects similar to those of cannabis. Spice drugs have received intensive attention in drug forums due to the possibility to obtain a non legal substitute of cannabis. Forensic analyses have found different potent synthetic cannabinoid agonists in some Spice drugs products, as JWH-018, CP 47497, JWH-073 and HU-210. There are few data about its pharmacological properties in animals, but nothing about its toxicity. At present, almost nothing is known about the pharmacology, toxicology and safety profile of such compounds in humans, except the opinions of consumers in internet forums. Neither the herbal ingredients of Spice drugs, nor any of the synthetic cannabinoids found in them, are internationally controlled under the 1961 or 1971 UN drug control conventions. Some European countries have recently taken legal actions to ban or otherwise control Spice drugs products and related compounds. These cannabinoid substances can be considered as new products to be added to the list of 'designer drugs'.

The consequences of 3,4-methylenedioxymethamphetamine induced CYP2D6 inhibition in humans.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely abused substituted amphetamine. MDMA is predominantly O-demethylenated in humans by cytochrome P450 isoforms 2D6 and 1A2 (CYP2D6 and CYP CYP1A2, respectively). MDMA is also a mechanism-based inhibitor of CYP2D6. A controlled clinical trial was conducted in 15 healthy male subjects whereby a probe drug, dextromethorphan (DEX), was administered after an oral dose of 1.5 mg/kg MDMA. The pharmacokinetics of DEX and its metabolites were used to evaluate changes in CYP2D6 activity. The urinary metabolic ratio of DEX and dextrorphan was used to calculate a recovery half-life of CYP2D6. After MDMA, DEX Cmax and area under the curve increased approximately 10-fold with corresponding decreases in dextrorphan pharmacokinetic parameters. The metabolic ratio increased almost 100-fold from 0.0061 +/- 0.0056 to 0.4322 +/- 0.2848 after MDMA administration, with 67% of the subjects having a value greater than the antimode of 0.3 for assigning the poor metabolizer phenotype. CYP2D6 activity recovered after 10 days with a recovery half-life of 46.6 hours. In addition to the possible long-term serotonergic effects of MDMA, users must be warned of the consequences of such an inhibition.

[Microcytic and hypochromic anemia due to a high-grade undifferentiated, embryonal, pleomorphic sarcoma]. / Anemia microcítica e hipocroma como consecuencia de un sarcoma pleomorfo indiferenciado de alto grado.

Undifferentiated (embryonal) sarcoma (UES) of the liver is a primary malignant tumor, rarely diagnosed in adults. Because of the absence of specific symptoms, rapid tumor growth, and normality of the common tumor markers, this neoplasm has a poor prognosis. Histologically, UES of the liver is characterized by anaplastic cells within myxoid matrix. Histological, immunohistochemical and chromosomic alterations are similar in UES and in mesenchymal hamartoma, suggesting a relation between these entities. The mainstay of treatment is surgery, while adjuvant treatment could increase survival.

[Serum vascular endothelial growth factor levels in patients with colorectal cancer and its prognostic significance]. / Valores séricos de factor de crecimiento del endotelio vascular en pacientes con cáncer colorrectal y su significación pronóstica.

BACKGROUND AND OBJECTIVE: Thirty per cent of patients with histologically node-negative colorectal cancer die from disseminated disease. Actually disease stage is the most useful prognostic parameter although it is not sufficient. Vascular endothelial growth factor (VEGF) is an angiogenic cytokine involved in the progression of tumors. In our study we tried to know the prognostic significance of pre and postoperative serum VEGF levels in patients with colorectal cancer. PATIENTS AND METHOD: Cohort study that included 52 patients with colorectal cancer surgically treated in our Department from 1998 to 2000. Serum VEGF and CEA levels were determined the day before surgery and 30 days after it. RESULTS: Preoperative serum VEGF levels (428.5 [38.5] pg/ml) were higher than in control patients (p=0.008). Serum VEGF levels fallen significantly after surgery (343 [31.2] pg/ml; p=0.001). Pre and postoperative serum VEGF levels in poorly differentiated neoplasms were higher than in well differentiated ones (p=0.009 and p=0.008 respectively). Pre and postoperative serum CEA and VEGF levels were significantly associated with cancer relapse (p=0.037, p=0.017, p=0.048 and p=0.001, respectively). In multivariate analysis only postoperative serum VEGF levels were associated with colorectal cancer relapse (p=0.003; HR=1.007; 95% CI, 1.002-1.012). Pre and postoperative CEA levels (p<0.001 and p=0.001 respectively) and postoperative VEGF levels (p=0.001), were associated with mortality. In multivariate analysis only tumor stage (p=0.01) and postoperative serum VEGF levels (p=0.02) were associated with mortality. Postoperative serum VEGF determination and pre and postoperative CEA levels raise specificity and positive predictive values to 100% in relation to mortality. CONCLUSIONS: Pre and postoperative serum VEGF determination has prognostic significance, regardless of tumor stage, in patients with colorectal cancer. In survival methods, postoperative VEGF levels >343 pg/ml are significantly with tumor relapse and mortality. These results suggest the use of serum VEGF levels as a prognostic and monitoring factor besides CEA.

Three-dimensional analysis of nasolabial soft tissues while smiling using stereophotogrammetry (3dMDTM) / Análisis tridimensional de los tejidos blandos nasolabiales en sonrisa utilizando estereofotogrametría (3dMDTM)

SUMMARY: The nasolabial region is the central esthetic unit of the face and is considered one of the most important determinants of the facial esthetic. The facial morphometry of soft tissues is a very important tool in facial surgery. Advances have been made recently in the capture and analysis of 3D images, which offer great development potential in the diagnosis and treatment of facial deformities. The aim of this study was to characterize the nasolabial region of patient candidates for orthognathic surgery using 3D facial captures. A study was conducted to characterize the width of the nasal base and the nasolabial angle in adult patients through 3D photographs. 30 subjects were included, taking two 3D photos each, one in a resting position and the other smiling. The three-dimensional capture was done with the 3dMDface System. The measurements were taken with the 3dMD Vultus software. The length of the alar base was an average of 34.3 ± 2.6 mm at rest, and 39.1 ± 2.9 mm smiling. The mean of the nasolabial angle was 104.6 ± 9.6° at rest and 105.4 ± 14.3º smiling. Additionally, the distance of the alar base smiling compared to its distance at rest increased an average of 4.83 mm, whereas the nasolabial angle smiling increased an average of 0.8º compared to at rest. In this study, the nasolabial angle did not present any significant changes so that its assessments in the case of facial modifications can be standard; the width of the nasal base is significantly modified with the smile and thus a more intense study of any type of modification in this area is required.

RESUMEN: La región nasolabial es la unidad estética central de la cara y se considera uno de los determinantes más importantes de la estética facial. La morfometría facial en tejidos bandos, es una herramienta de gran importancia en Cirugía Facial. En el último tiempo, se han realizado avances en captura y análisis de imágenes 3D, las cuales ofrecen un gran potencial de desarrollo en el diagnóstico y tratamiento de las deformidades faciales. El objetivo de éste trabajo fue caracterizar mediante capturas faciales 3D la región nasolabial de pacientes candidatos a cirugía ortognática. Se realizó un estudio para caracterizar a través de fotografías tridimensionales de pacientes adultos el ancho de la base nasal y el ángulo nasolabial. Se incluyeron 30 sujetos, tomando 2 fotografías 3D a cada uno, una en posición de reposo y otra en sonrisa. Se realizó la captura tridimensional con la camara facial 3dMDface System. Las mediciones fueron realizadas con el software 3dMD Vultus. La longitud de base alar en reposo, fue en promedio de 34,3 ± 2,6 mm, y de 39,1 ± 2,9 mm, en sonrisa. Por otra parte, la media del ángulo nasolabial en reposo fue de 104,6 ± 9,6° y en sonrisa, de 105,4 ± 14,3º. Por otro lado, la distancia de la base alar en sonrisa respecto a su distancia en reposo, aumentó un promedio de 4,83 mm, mientras que el ángulo nasolabial en sonrisa, aumentó en promedio 0,8º respecto a la posición de reposo. En esta investigación, el ángulo nasolabial no presentó cambios significativos de forma que su valoración frente a modificaciones faciales puede ser estándar; el ancho de base nasal se modifica significativamente con la sonrisa de forma que su estudio debe ser más agudo frente a cualquier tipo de modificación en esta zona.

Changes in CYP1A2 activity in humans after 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) administration using caffeine as a probe drug.

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is a ring-substituted amphetamine widely used for recreational purposes. MDMA is predominantly O-demethylenated in humans by cytochrome P450 (CYP) 2D6, and is also a potent mechanism-based inhibitor of the enzyme. After assessing the inhibition and recovery of CYP2D6 in a previous study, the aim of this work was to study in humans the activity of CYP1A2 in vivo after CYP2D6 had been inhibited by MDMA, using caffeine as a probe drug. Twelve male and nine female recreational MDMA users were included. In session 1, 100 mg of caffeine was given at 0 h. In session 2, a 1.5 mg/kg MDMA dose (range 75-100 mg) was given at 0 h followed by a 100 mg dose of caffeine 4 h later. Aliquots of plasma were assayed for caffeine (137X) and paraxanthine (17X) and statistically significant differences were assessed with a one-way ANOVA. There were significant gender differences at basal condition, which persisted after MDMA administration. CYP1A2 activity was higher in both genders after drug administration, with an increase in 40% in females and 20% in males. Results show an increase in CYP1A2 activity when CYP2D6 is inhibited by MDMA in both genders, being more pronounced in females.

Sex differences in 3,4-methylenedioxymethamphetamine (MDMA; ecstasy)-induced cytochrome P450 2D6 inhibition in humans.

BACKGROUND AND OBJECTIVE: 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is a ring-substituted amphetamine widely used for recreational purposes. MDMA is predominantly O-demethylenated in humans by cytochrome P450 (CYP) 2D6 and is also a potent mechanism-based inhibitor of the enzyme. This study assessed the inhibition and recovery half-life of CYP2D6 and CYP3A4 activity in female subjects by administering the probe drug dextromethorphan before and repeatedly after MDMA administration. These data were compared with the data obtained from a previous study in male subjects. STUDY DESIGN: Twelve healthy female subjects who were CYP2D6 extensive metabolizers participated as outpatients in two experimental sessions. Session 1 was conducted over 2 days and session 2 over 10 days, with a minimum of 3 days between sessions. In session 1, subjects received a single oral dose of dextromethorphan 30 mg. In session 2, a 1.5 mg/kg MDMA dose was given at 0 hours, followed at 4 hours by repeated 30 mg doses of dextromethorphan over the next 10 days. METHODS: Plasma concentration-time profiles and urinary recoveries of dextromethorphan and its metabolites dextrorphan (DOR), 3-methoxymorphinan (MM) and hydroxymorphinan-3-ol (HM) were measured. RESULTS: MDMA given prior to dextromethorphan resulted in a 10-fold increase in the dextromethorphan maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC), with corresponding decreases in DOR and HM pharmacokinetic parameters. The mean ± SD C(max) of MDMA was 188.8 ± 16.7 ng/mL, with a time to reach C(max) (t(max)) of 2.0 ± 0.4 hours and an AUC from 0 to 25 hours of 2645.2 ± 170.9 mg · h/mL. The urinary recovery of the dextromethorphan dose as dextromethorphan and its main metabolites was 25.4 ± 8.9% with no MDMA pretreatment versus 6.6 ± 1.1% after 1.5 mg/kg of MDMA (p = 0.0001). The metabolic ratio (MR) increased almost 60-fold from 0.018 ± 0.028 to 0.998 ± 0.932 after MDMA administration, with 100% of the subjects having a value greater than the antimode of 0.3 that signified the poor-metabolizer phenotype. Data analysis of results obtained in the present study compared with those from a previous study in male subjects showed significant differences in the dextromethorphan/DOR MR in the 0- to 8-hour (session 1) and 4- to 12-hour (session 2, post MDMA) collection periods (p = 0.032 and p = 0.01, respectively). CYP2D6 activity recovered after 10 days to 90% of baseline activity, with a recovery half-life of 36.6 ± 22.9 hours. Male subjects showed a shorter recovery half-life (27.6 ± 25.1 hours). The measurement of CYP3A4 activity indicated a non-significant increase in C(max) and AUC values of MM after drug intake, but urinary data reflected significant differences in dextromethorphan/MM MR in both sexes, although the difference was more pronounced in women. Dextromethorphan/MM MR increased almost 3-fold from baseline. DISCUSSION AND CONCLUSION: In women the pretreatment with MDMA resulted in a decrease in dextromethorphan clearance. CYP2D6 activity recovered after 10 days to 90% of baseline activity. Regarding CYP3A4 activity, there is an apparent decrease in its activity after MDMA use. In women, MDMA use has been associated with psychiatric symptoms and psychological problems that may require psychopharmacological treatment with antidepressant drugs, some of which are known CYP2D6 substrates. MDMA-induced mechanism-based inhibition of CYP2D6 is of relevance, and physicians should be advised to prescribe medications whose metabolic disposition is not regulated by CYP2D6.