Outcomes of Patients With Local Regrowth After Nonoperative Management of Rectal Cancer After Neoadjuvant Chemoradiotherapy.

BACKGROUND: Clinical complete responders after chemoradiation for rectal cancer are increasingly being managed by a watch-and-wait strategy. Nonetheless, a significant proportion will experience a local regrowth, and the long-term oncological outcomes of these patients is not totally known. OBJECTIVE: The purpose of this study was to analyze the outcomes of patients who submitted to a watch-and-wait strategy and developed a local regrowth, and to compare these results with sustained complete clinical responders. DESIGN: This was a retrospective study. SETTING: Single institution, tertiary cancer center involved in alternatives to organ preservation. PATIENTS: Patients with a biopsy-proven rectal adenocarcinoma (stage II/III or low lying cT2N0M0 at risk for an abdominoperineal resection) treated with chemoradiation who were found at restage to have a clinical complete response. INTERVENTIONS: Rectal cancer patients treated with chemoradiation who underwent a watch-and-wait strategy (without a full thickness local excision) and developed a local regrowth were compared to the remaining patients of the watch-and-wait strategy. MAIN OUTCOME MEASURES: Overall survival between groups, incidence of regrowth' and results of salvage surgery. RESULTS: There were 67 patients. Local regrowth occurred in 20 (29.9%) patients treated with a watch-and-wait strategy. Mean follow-up was 62.7 months. Regrowth occurred at mean 14.2 months after chemoradiation, half of them within the first 12 months. Patients presented with comparable initial staging, lateral pelvic lymph-node metastasis, and extramural venous invasion. The regrowth group had a statistically nonsignificant higher incidence of mesorectal fascia involvement (35.0% vs 13.3%, p = 0.089). All regrowths underwent salvage surgery, mostly (75%) a sphincter-sparing procedure. 5-year overall survival was 71.1% in patients with regrowth and 91.1% in patients with a sustained complete clinical response (p = 0.027). LIMITATIONS: This study was limited by its retrospective evaluation of patient selection for a watch-and-wait strategy and outcomes, as well as its small sample size. CONCLUSIONS: Local regrowth is a frequent event when following a watch-and-wait policy (29.9%); however, patients could undergo salvage surgical treatment with adequate pelvic control. In this series, overall survival showed a statistically significant difference from patients managed with a watch-and-wait strategy who experienced a local regrowth compared to those who did not. See Video Abstract at http://links.lww.com/DCR/B773.RESULTADOS DE LOS PACIENTES CON REBROTE LOCAL, DESPUÉS DEL MANEJO NO QUIRÚRGICO DEL CÁNCER DE RECTO, DESPUÉS DE LA QUIMIORRADIOTERAPIA NEOADYUVANTEANTECEDENTES:Los respondedores clínicos completos, después de la quimiorradiación para el cáncer de recto, se tratan cada vez más mediante una estrategia de observación y espera. No obstante, una proporción significativa experimentará un rebrote local y los resultados oncológicos a largo plazo de estos pacientes, no se conocen por completo.OBJETIVO:El propósito de este estudio, fue analizar los resultados de los pacientes sometidos a una estrategia de observación y espera, que desarrollaron un rebrote local, y comparar estos resultados con respondedores clínicos completos sostenidos.DISEÑO:Este fue un estudio retrospectivo.ENTORNO CLINICO.Institución única, centro oncológico terciario involucrado en alternativas a la preservación de órganos.PACIENTES:Pacientes con un adenocarcinoma de recto comprobado por biopsia (estadio II / III o posición baja cT2N0M0, en riesgo de resección abdominoperineal), tratados con quimiorradiación, y que durante un reestadiaje, presentaron una respuesta clínica completa.INTERVENCIONES:Los pacientes con cáncer de recto tratados con quimiorradiación, sometidos a una estrategia de observación y espera (sin una escisión local de espesor total) y que desarrollaron un rebrote local, se compararon con los pacientes restantes de la estrategia de observación y espera.PRINCIPALES MEDIDAS DE VALORACION:Supervivencia global entre los grupos, incidencia de rebrote y resultados de la cirugía de rescate.RESULTADOS:Fueron 67 pacientes. El rebrote local ocurrió en 20 (29,9%) pacientes tratados con una estrategia de observación y espera. El seguimiento medio fue de 62,7 meses. El rebrote se produjo a la media de 14,2 meses después de la quimiorradiación, la mitad de ellos dentro de los primeros 12 meses. Los pacientes se presentaron con una estadificación inicial comparable, metástasis en los ganglios linfáticos pélvicos laterales e invasión venosa extramural. El grupo de rebrote tuvo una mayor incidencia estadísticamente no significativa de afectación de la fascia mesorrectal (35,0 vs 13,3%, p = 0,089). Todos los rebrotes se sometieron a cirugía de rescate, en su mayoría (75%) con procedimiento de preservación del esfínter. La supervivencia global a 5 años fue del 71,1% en pacientes con rebrote y del 91,1% en pacientes con una respuesta clínica completa sostenida (p = 0,027).LIMITACIONES:Evaluación retrospectiva de la selección de pacientes para una estrategia y resultados de observar y esperar, tamaño de muestra pequeño.CONCLUSIONES:El rebrote local es un evento frecuente después de la política de observación y espera (29,9%), sin embargo los pacientes podrían someterse a un tratamiento quirúrgico de rescate con un adecuado control pélvico. En esta serie, la supervivencia global mostró una diferencia estadísticamente significativa de los pacientes manejados con una estrategia de observación y espera que experimentaron un rebrote local, en comparación con los que no lo hicieron. Consulte Video Resumen en http://links.lww.com/DCR/B773. (Traducción-Dr. Fidel Ruiz Healy).

The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.

Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.

Combination of Irinotecan, Oxaliplatin and 5-Fluorouracil as a Rechallenge Regimen for Heavily Pretreated Metastatic Colorectal Cancer Patients.

PURPOSE: Our objective was to evaluate the benefit of re-exposing patients with refractory metastatic colorectal cancer (mCRC) to a combination of oxaliplatin, irinotecan and 5-fluorouracil treatment. METHODS: We retrospectively analysed patients with mCRC who received a combination of oxaliplatin, irinotecan and fluorouracil as a rechallenge regimen after progressing on the same drugs. Both FOLFOXIRI and FOLFIRINOX were used. Toxicity was evaluated for each treatment cycle, and survival analysis was performed using the Kaplan-Meier method. RESULTS: A total of 21 patients who were treated between January 2011 and December 2013 were selected for this study. Most of the patients (95.2%) had an ECOG status of 0-1. The median age at diagnosis was 52.1 years (range 36-77 years), and 14 (66.6%) patients had wild-type KRAS. Thirteen patients received FOLFIRINOX, and eight received FOLFOXIRI. Most patients had previously received at least three regimens, with 80% receiving anti-VEGF and 66% anti-EGFR antibodies. The response rate was 38%, and 24% patients had stable disease. The median time to disease progression was 4.0 months (range 1.0-9.1 months), and the median overall survival duration was 8.6 months (range 6.3-11.5 months). Most patients required dose adjustment and treatment delays. One patient experienced grade 5 neutropenic sepsis. CONCLUSIONS: Both FOLFIRINOX and FOLFOXIRI are active and potentially feasible rechallenge treatment options for heavily pretreated patients with good performance status. With dose reduction and close monitoring for toxicity, the risk of serious adverse events can be minimised.

Twenty-four-hour intraocular pressure and ocular perfusion pressure characteristics in newly diagnosed patients with normal tension glaucoma.

PurposeTo determine the mean 24-h intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) characteristics of newly diagnosed, previously untreated, Caucasian, normal tension glaucoma (NTG) patients and to identify relationships between these features and visual field (VF) loss at diagnosis.MethodsConsecutive newly diagnosed NTG patients underwent 24-h habitual IOP and blood pressure (BP) monitoring. Parameters from pooled measurements obtained in the sitting (0800-2200 hours) and supine (1200-0600 hours) positions were compared and associations were sought with VF mean deviation (MD) and pattern standard deviation (PSD).ResultsSixty-two Caucasian NTG patients (24 men and 38 women) successfully completed circadian IOP and BP monitoring. In habitual position, 8 subjects (12.9%) exhibited a diurnal acrophase, 42 subjects (67.7%) demonstrated a nocturnal acrophase, one subject (1.6%) showed a flat rhythm and 11 patients (17.7%) revealed a biphasic/polyphasic rhythm. Nighttime MOPP values (supine position) were significantly greater than diurnal values (sitting position); (P<0.001). No association could be demonstrated between glaucomatous damage, as indicated by VF parameters, and either mean habitual 24-h IOP (P=0.20 and P=0.12 for MD and PSD, respectively), or habitual 24-h MOPP (P=0.96 and 0.29, for MD and PSD, respectively).ConclusionsIn this cohort of Caucasian NTG patients, most patients exhibited a nocturnal IOP acrophase when evaluated in a habitual position. No association was found between 24-h IOP or MOPP and VF damage.

Test-retest variability of intraocular pressure and ocular pulse amplitude for dynamic contour tonometry: a multicentre study.

AIMS: To assess the test-retest variability of intraocular pressure (IOP) and ocular pulse amplitude (OPA) measurements utilising dynamic contour tonometry (DCT) and to evaluate possible influential factors. METHODS: The study included 350 consecutive subjects (175 glaucoma, 175 control; one eye per subject) from seven European centres. IOP was measured once with a Goldmann applanation tonometer (GAT) and twice by DCT (DCT1, DCT2) in a randomised sequence. OPA was also recorded for both DCT measurements. Differences (DCT1-DCT2; OPA1-OPA2; GAT-DCT1; GAT-DCT2) were assessed using the t test. The intraclass coefficient of correlation (ICC) and coefficient of variation (CoV) for DCT and OPA were calculated. RESULTS: DCT1 was 0.6+/-1.6 mm Hg higher than DCT2 (p<0.001); OPA1 was 0.1+/-0.7 mm Hg higher than OPA2 (p=0.02). Results were not influenced by randomisation test order. In both glaucoma and normal subjects, DCT and OPA showed ICC>0.90 and >0.76, and CoV=4.8-5.0% and 10.3-10.5%, respectively. DCT1 and 2 were 2.4+/-2.6 and 1.8+/-2.6 mm Hg higher respectively than GAT (p<0.001). DISCUSSION: DCT test-retest variability was almost perfect for IOP and good for OPA. Tonometry measurements with DCT tended to be overestimated compared with GAT.

Efficacy of the fixed combinations of bimatoprost or latanoprost plus timolol in patients uncontrolled with prostaglandin monotherapy: a multicenter, randomized, investigator-masked, clinical study.

PURPOSE: To compare the efficacy and tolerability of a once-daily evening dose of bimatoprost/timolol fixed combination (BTFC) with that of a once-daily evening dose of latanoprost/timolol fixed combination (LTFC) in patients not controlled with prostaglandins analogues monotherapy. METHODS: A total of 82 patients on prostaglandin analogues monotherapy were enrolled in this prospective, multicenter, investigator masked, clinical study and were randomized to either BTFC (n=47) or LTFC (n=35) topical therapy once at night for 12 weeks. The primary endpoint of the study was to compare the mean daily intraocular pressure (IOP) reduction from baseline between the two treatment arms. Secondary endpoints included the mean daily IOP at 1 and 3 months compared to baseline and the percentage of patients showing a mean IOP reduction from baseline greater than or equal to 15% or 20%. RESULTS: Mean IOP at baseline was 22.7+/-2.0 and 22.1+/-2.6 mmHg in the BTFC and LTFC groups, respectively (p=0.23). Both treatments were effective in reducing the IOP from baseline. The mean IOP reduction was significantly greater in the BTFC group than in the LTFC group (-21.4% vs -13.7%, p<0.001). A higher percentage of patients in the BTFC group showed a mean IOP reduction from baseline >or=15% (72.3% vs 40.0%) and >or=20% (61.7% vs 17.1%) compared to patients in the LTFC group. CONCLUSIONS: Both BTFC and LTFC were more effective versus the monotherapy with prostaglandin analogues. BTFC demonstrated higher performance than LTFC in terms of relative IOP reduction.

The role of Humphrey Matrix testing in the early diagnosis of retinopathy in type 1 diabetes.

AIM: The aim of the study was to investigate the role of Humphrey Matrix threshold testing in the detection of early functional retinal impairment in subjects with type 1 diabetes mellitus (DM1) without any signs of retinal vasculopathy, and to investigate the relationship between both functional and structural retinal parameters and metabolic control. METHODS: Thirty eyes of 30 subjects with DM1, with no sign of retinal vasculopathy, and 30 eyes of 30 age- and sex-matched healthy subjects were enrolled in this cross-sectional clinical study. Functional testing included Humphrey Matrix perimetry and white-on-white Humphrey visual field perimetry (HFA), while retinal nerve fibre layer (RNFL) thickness was measured by scanning laser polarimetry with variable corneal birefringence compensator (GDx VCC). RESULTS: Matrix mean deviation (MD) was found to be significantly reduced in subjects with DM1 compared with controls (-1.10 (SD 2.98; 95% CI -2.21 to 0.01) vs 1.37 (SD 2.11; 95% CI 0.58 to 2.16), p = 0.0005). HFA MD and pattern standard deviation (PSD) were significantly worse in subjects with DM1 compared with controls (p = 0.010 and p = 0.013 respectively). Among structural parameters, average peripapillary RNFL thickness was reduced in DM1 subjects (p = 0.006). Matrix MD and HFA MD and PSD, and average peripapillary and superior RNFL, were significantly reduced in subjects with DM1 with HbA(1c) > or = 7% compared with controls. CONCLUSIONS: Functional and structural retinal testing by Humphrey Matrix and GDx VCC could be useful for the identification of early retinal impairment in people with DM1 with no sign of retinal vasculopathy.

Reliability of the IOLMaster in axial length evaluation in silicone oil-filled eyes.

PURPOSE: To assess the reliability of IOLMaster in axial length (AL) measurement in phakic silicone oil-filled vs pseudophakic saline-filled eyes. METHODS: Ten eyes of 10 patients, vitrectomized with silicone oil tamponade and scleral buckled with significant lens opacity were enrolled. Optical biometry with IOLMaster (Carl Zeiss Meditec AG, Germany) was performed 1 day before and 1 week after silicone oil removal and phacoemulsification with artificial intraocular lens (IOL) implantation in order to assess changes in AL measurements. RESULTS: Mean AL was 26.16+/-1.23 mm (range 24.64-28.8 mm) and 26.27+/-1.46 mm (range 25.26-29.6 mm), respectively, the day before and 1 week after silicone oil removal and cataract surgery, and the difference was not statistically significant (P=0.2). CONCLUSIONS: Presence vs absence of silicone oil tamponade as well as phakic vs pseudophakic status in buckled and vitrectomized eyes did not influence the AL measurement by means of no-contact optical biometry, suggesting that such eyes might be candidate for silicone oil removal and cataract surgery at one time.

Corneal birefringence changes after laser assisted in situ keratomileusis and their influence on retinal nerve fibre layer thickness measurement by means of scanning laser polarimetry.

AIM: To evaluate changes in corneal polarisation properties and their influence on peripapillary retinal nerve fibre layer (RNFL) thickness measurements after laser assisted in situ keratomileusis (LASIK) by means of scanning laser polarimetry (SLP) with variable corneal polarisation compensator (VCC) in normal white subjects. METHODS: SLP was performed by means of GDx VCC on 32 eyes of 32 normal subjects who underwent LASIK for ametropia correction. Corneal polarisation axis and magnitude and RNFL thickness were measured before and 8 days after LASIK. RNFL thickness data and corneal polarimetric data of one randomly selected eye per subject were analysed by the Wilcoxon signed ranks test. Correlations between corneal ablation depth, corneal polarimetric changes, and RNFL thickness changes were investigated using Spearman's rho test. RESULTS: The corneal polarisation axis significantly shifted from 15.1 degrees (17.0 degrees ) to 6.9 degrees (12.9 degrees ) (p = 0.00006) after LASIK and this change showed a strong correlation with corneal ablation depth (rho = -0.7, p = 0.00002). Among GDx parameters, TSNIT, SUP, and SD showed significant changes after LASIK and for SUP and SD these changes were well correlated with the shift in corneal polarisation axis (rho = 0.54, p = 0.03 and rho = 0.45, p = 0.01, respectively). SUP and SD changes were neutralised after compensating for corneal polarimetric changes but not TSNIT changes. NFI, a discriminating parameter, was found to be affected after LASIK only after compensating for corneal polarimetric changes. CONCLUSIONS: LASIK induces a shift in corneal polarisation axis which is responsible for inaccuracies in RNFL thickness measurements. A customised compensation for corneal polarimetric changes after LASIK allows normalisation of some of the thickness parameters except for TSNIT and NFI.

Pilot study to evaluate the efficacy and safety of pneumatic trabeculoplasty in glaucoma and ocular hypertension.

PURPOSE: Following laser-assisted in situ keratomileusis (LASIK), intraocular pressure (IOP) is measurably lower in a significant number of cases. It has been proposed that the decrease in IOP may be a real event. Prior trials have evaluated pneumatic trabeculoplasty (PNT) in combination with concomitant glaucoma medications. The aim of this study was to determine the efficacy and the safety of PNT alone to lower IOP in patients with primary open angle glaucoma (POAG) or ocular hypertension (OH). METHODS AND RESULTS: A total of 37 subjects with POAG or OH were enrolled in a prospective, open-label, fellow-eye, multicenter trial to determine the IOP lowering effects of PNT. All subjects underwent ophthalmologic examinations and IOP measurements and were washed out from all glaucoma medications prior to the start of the study. The trial was intrapatient controlled for the first 30 days, with one eye receiving PNT at days 0 and 7 and the fellow eye serving as the control. The second eye was treated with PNT at day 30. The patients were followed for 120 days, with the first eye receiving an additional PNT treatment at days 90 and 97. Two analyses-an intent to treat analysis in which the last IOP measurement for patients dropped from the study was carried forward and an analysis including only those patients who completed the trial-were performed. Of the 37 patients enrolled, 27 (73%) completed the study. For the intent to treat analysis the baseline mean IOP was 24.7+/-1.9 mmHg for eye 1 and 23.6+/-2.3 mmHg for eye 2 and the difference was statistically significant (p<0.05). Using this analysis the differences between eye 1 mean IOP at days 1, 7, 14, and 60 and the baseline mean IOP were statistically significant (p<0.05). The differences between eye 2 mean IOP and the baseline mean IOP were statistically significant (p<0.05) at all time points except day 14 and day 30. The greater mean IOP reductions from the baseline mean IOP for eye 1 were at study day 1 (-16,1%), day 14 (-9%), and day 60 (-8.9%). For eye 2 they were at day 60 (-8.7%) and at day 120 (-9.1%). For the analysis that included only those subjects who completed the trial the decrease in eye 1 mean IOP from baseline was statistically significant (p<0.05) at all time points. The decrease in eye 2 mean IOP from baseline was statistically significant at all time points except day 30. Using this analysis the greater mean IOP reductions from the baseline mean IOP for eye 1 were at study day 1 (-19%), day 14 (-15.7%), day 37 (-16.3%), day 60 (-20.0%), day 90 (-18.1%), day 97 (-16.8%), and day 120 (-15.8%). For eye 2 greater mean IOP reductions from baseline mean IOP were seen on day 37 (-13.0%), day 60 (-16.7%), day 90 (-15.5%), day 97 (-14.5%), and day 120 (-7.2%). No statistically significant differences were found in mean IOP reduction between the two eyes treated. A total of 34 patients (92%) showed adverse effects: conjunctival hyperemia in 26 (70.3%) and conjunctival hemorrhage in 14 (37.8%). CONCLUSIONS: This pilot study of PNT showed a potentially good IOP lowering effect on glaucoma and hypertensive patients. Additional studies would help to better define the types of patients who respond to PNT and to identify risk factors that may lead to treatment failure.

Impaired neural conduction in crossed visual pathways in patients with ocular hypertension.

PURPOSE: To evaluate the neural conduction along crossed and uncrossed visual pathways in patients with ocular hypertension (OHT). METHODS: Fifteen patients (mean age 59.1+/-6.8 years) with OHT (IOP>22 mmHg, Humphrey 24-2 with mean deviation [MD]>-2 dB) were enrolled. They were compared to 15 age-matched controls. In OHT patients and control subjects, visual evoked potentials (VEPs) were recorded using full-field checkerboard patterns (the check subtended 15' of visual arc; contrast 80%) reversed at 2 Hz. VEP responses were simultaneously recorded in the homolateral visual cortex (HC) and in the contralateral visual cortex (CC), with respect to the stimulated eye. RESULTS: In OHT patients, VEP P100 implicit times observed in HC and CC were both significantly delayed (analysis of variance, p<0.01) when compared to those of controls, and, in particular, longer in CC than in HC. The interhemispheric differences (ID: P100 implicit time in HC - P100 implicit time in CC) were significantly higher in OHT patients than controls (-3.16+/-1.80 msec and 1.16+/-1.04 msec, respectively, p=0.001). In OHT patients we observed an MD hemifield difference (difference between nasal and temporal MD values) higher than in controls (-0.82+/-0.80 dB and 0.04+/-1.03 dB, respectively, p<0.01) and significantly correlated with the ID (r: 0.836, p<0.001). CONCLUSIONS: The observed asymmetry in the bioelectrical cortical responses and in the visual hemifield parameters suggests that crossed visual pathways could be impaired earlier than uncrossed visual pathways in OHT patients.