Recommendations for the optimal management of peritoneal metastases in patients with colorectal cancer: a TTD and GECOP-SEOQ expert consensus statement.

Peritoneal metastases (PM) occur when cancer cells spread inside the abdominal cavity and entail an advanced stage of colorectal cancer (CRC). Prognosis, which is poor, correlates highly with tumour burden, as measured by the peritoneal cancer index (PCI). Cytoreductive surgery (CRS) in specialized centres should be offered especially to patients with a low to moderate PCI when complete resection is expected. The presence of resectable metastatic disease in other organs is not a contraindication in well-selected patients. Although several retrospective and small prospective studies have suggested a survival benefit of adding hyperthermic intraperitoneal chemotherapy (HIPEC) to CRS, the recently published phase III studies PRODIGE-7 in CRC patients with PM, and COLOPEC and PROPHYLOCHIP in resected CRC with high-risk of PM, failed to show any survival advantage of this strategy using oxaliplatin in a 30-min perfusion. Final results from ongoing randomized phase III trials testing CRS plus HIPEC based on mitomycin C (MMC) are awaited with interest. In this article, a group of experts selected by the Spanish Group for the Treatment of Digestive Tumours (TTD) and the Spanish Group of Peritoneal Oncologic Surgery (GECOP), which is part of the Spanish Society of Surgical Oncology (SEOQ), reviewed the role of HIPEC plus CRS in CRC patients with PM. As a result, a series of recommendations to optimize the management of these patients is proposed.

New DPYD variants causing DPD deficiency in patients treated with fluoropyrimidine.

PURPOSE: Several clinical guidelines recommend genetic screening of DPYD, including coverage of the variants c.1905 + 1G>A(DPYD*2A), c.1679T>G(DPYD*13), c.2846A>T, and c.1129-5923C>G, before initiating treatment with fluoropyrimidines. However, this screening is often inadequate at predicting the occurrence of severe fluoropyrimidine-induced toxicity in patients. METHODS: Using a complementary approach combining whole DPYD exome sequencing and in silico and structural analysis, as well as phenotyping of DPD by measuring uracilemia (U), dihydrouracilemia (UH2), and the UH2/U ratio in plasma, we were able to characterize and interpret DPYD variants in 28 patients with severe fluoropyrimidine-induced toxicity after negative screening. RESULTS: Twenty-five out of 28 patients (90%) had at least 1 variant in the DPYD coding sequence, and 42% of the variants (6/14) were classified as potentially deleterious by at least 2 of the following algorithms: SIFT, Poly-Phen-2, and DPYD varifier. We identified two very rare deleterious mutations, namely, c.2087G>A (p.R696H) and c.2324T>G (p.L775W). We were able to demonstrate partial DPD deficiency, as measured by the UH2/U ratio in a patient carrying the variant p.L775W for the first time. CONCLUSION: Whole exon sequencing of DPYD in patients with suspicion of partial DPD deficiency can help to identify rare or new variants that lead to enzyme inactivation. Combining different techniques can yield abundant information without increasing workload and cost burden, thus making it a useful approach for implementation in patient care.

Current Options for Third-line and Beyond Treatment of Metastatic Colorectal Cancer. Spanish TTD Group Expert Opinion.

Colorectal cancer (CRC) is a public health problem: it is the third most common cancer in men (746,000 new cases/year) and the second in women (614,000 new cases/year), representing the second leading cause of death by cancer worldwide. The survival of patients with metastatic CRC (mCRC) has increased prominently in recent years, reaching a median of 25 to 30 months. A growing number of patients with mCRC are candidates to receive a treatment in third line or beyond, although the optimal drug regimen and sequence are still unknown. In this situation of refractoriness, there are several alternatives: (1) To administer sequentially the 2 oral drugs approved in this indication: trifluridine/tipiracil and regorafenib, which have shown a statistically significant benefit in progression-free survival and overall survival with a different toxicity profile. (2) To administer cetuximab or panitumumab in treatment-naive patients with RAS wild type, which is increasingly rare because these drugs are usually indicated in first- or second-line. (3) To reuse drugs already administered that were discontinued owing to toxicity or progression (oxaliplatin, irinotecan, fluoropyrimidine, antiangiogenics, anti-epidermal growth factor receptor [if RAS wild-type]). High-quality evidence is limited, but this strategy is often used in routine clinical practice in the absence of alternative therapies especially in patients with good performance status. (4) To use specific treatments for very selected populations, such as trastuzumab/lapatinib in mCRC human epidermal growth factor receptor 2-positive, immunotherapy in microsatellite instability, intrahepatic therapies in limited disease or primarily located in the liver, although the main recommendation is to include patients in clinical trials.

VITAL phase 2 study: Upfront 5-fluorouracil, mitomycin-C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09-02).

AIM: VITAL, a phase II single-arm study, aimed to evaluate efficacy and safety of panitumumab addition to 5-fluorouracil (5-FU), mitomycin-C (MMC) and radiotherapy (RT) in patients with localized squamous cell carcinoma of the anal canal (SCCAC). METHODS: Adult, treatment-naïve SCCAC patients (Stage T2-T4, any N, M0) and ECOG-PS ≤2, received panitumumab (6 mg/kg, day 1 and Q2W; 8 weeks), 5-FU (1000 mg/m2 /d, days 1-4 and 29-32), MMC (10 mg/m2 , days 1 and 29) and RT 45 Gy (1.8 Gy/fraction) to the primary tumor and mesorectal, iliac and inguinal lymph nodes, plus 10-15 Gy boost dose to the primary tumor and affected lymph nodes. The primary objective was disease free survival rate (DFS) at 3-years (expected 3-year DFS rate: 73.7 ± 12%). RESULTS: Fifty-eight patients (31 women; median age: 59 years; ECOG-PS 0-1:98%; TNM II [29%] (T2 or T3/N0/M0)/IIIA (T1-T3/N1/M0 or T4/N0/M0) [21%]/IIIB (T4/N1/M0 or any T/N2 or N3/M0) [47%]/nonevaluable [4%]) were included. The median follow-up was 45 months. The 3-year DFS rate was 61.1% (95% CI: 47.1, 72.4). The 3-year overall survival rate was 78.4% (95% CI: 65.1, 87.1). Eighteen patients (31.0%) required a colostomy within 2 years posttreatment. Grade 3-4 toxicities were experienced by 53 (91%) patients. Most common grade 3-4 treatment-related events were radiation skin injury (40%) and neutropenia (24%). No toxic deaths occurred. Improved efficacy in colostomy-free survival and complete response rate was observed in human papilloma virus positive patients. CONCLUSIONS: Panitumumab addition to MMC-5FU regimen in SCCAC patients increases toxicity and does not improve patients' outcomes. RT plus MMC-5FU remains the standard of care for localized SCCAC patients.

Twelve years of experience with miglustat in the treatment of type 1 Gaucher disease: The Spanish ZAGAL project.

We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-naïve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p<0.01) were registered. Gastrointestinal disturbances were reported in 25/63 (40%), causing miglustat suspension in 11/63 (17.5%) cases. Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long-term therapy in mild to moderate naïve and ERT stabilized patients. No unexpected safety signals were identified during 12-years follow-up.

The role of antiangiogenic agents in the treatment of patients with advanced colorectal cancer according to K-RAS status.

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Recently, it has been found that about 40 % of patients with CRC have mutations in the K-RAS gene. Several clinical trials have showed that patients with metastatic colorectal cancer (mCRC) who present tumour-promoting mutations in signalling pathways involving the epidermal growth factor receptor (EGFR), which includes activating K-RAS mutations, do not respond to anti-EGFR drugs such as panitumumab and cetuximab. Hence, K-RAS status is now considered an important negative predictive factor for response to anti-EGFR drugs. Moreover, K-RAS status seems to have also a prognostic role in CRC, but this fact is somewhat controversial. Activity of antiangiogenic agents seems not to be influenced by K-RAS gene status. Tumour angiogenesis has attracted interest in attempts to improve the management of mCRC. The vascular endothelial growth factor (VEGF) pathway is fundamental to the regulation of angiogenesis, and research has focused on developing agents that selectively target it. In this way, the anti-VEGF antibody bevacizumab in combination with chemotherapy has provided important clinical benefits in terms of response rate, progression-free survival and overall survival to patients with mCRC. Efficacy data of bevacizumab in K-RAS wild-type patients seem to be comparable with the efficacy data observed with anti-EGFR therapies in a cross-trial comparison. Although there is a lack of prospective and randomized data in this setting, the combination of chemotherapy plus antiangiogenic agents could be considered as an effective alternative for the treatment of mCRC with independence of K-RAS gene status. Here, we review the available data we have in the literature of the use of antiangiogenic strategies in the treatment of mCRC nowadays.

Therapeutic strategies for Gaucher disease: miglustat (NB-DNJ) as a pharmacological chaperone for glucocerebrosidase and the different thermostability of velaglucerase alfa and imiglucerase.

Gaucher disease (GD) is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal glucocerebrosidase (GlcCerase) activity, due to conformationally or functionally defective variants, resulting in progressive deposition of glycosylceramide in macrophages. The glucose analogue, N-butyldeoxynojirimycin (NB-DNJ, miglustat), is an inhibitor of the ceramide-specific glycosyltransferase, which catalyzes the first step of glycosphingolipid biosynthesis and is currently approved for the oral treatment of type 1 GD. In a previous work, we found a GlcCerase activity increase in cell cultures in the presence of NB-DNJ, which could imply that this compound is not only a substrate reducer but also a pharmacological chaperone or inhibitor for GlcCerase degradation. In this work we compare imiglucerase (the enzyme currently used for replacement therapy) and velaglucerase alfa (a novel therapeutic enzyme form) in terms of conformational stability and enzymatic activity, as well as the effect of NB-DNJ on them. The interaction between these enzymes and NB-DNJ was studied by isothermal titration calorimetry. Our results reveal that, although velaglucerase alfa and imiglucerase exhibit very similar activity profiles, velaglucerase alfa shows higher in vitro thermal stability and is less prone to aggregation/precipitation, which could be advantageous for storage and clinical administration. In addition, we show that at neutral pH NB-DNJ binds to and enhances the stability of both enzymes, while at mildly acidic lysosomal conditions it does not bind to them. These results support the potential role of NB-DNJ as a pharmacological chaperone, susceptible of being part of pharmaceutical formulation or combination therapy for GD in the future.

Real-world clinical experience with long-term miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project.

There are few published data from real-world clinical experience with miglustat (Zavesca), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease. We report data from a prospective, open-label investigational study that evaluated substrate reduction therapy with miglustat 100 mg t.i.d. as a maintenance therapy in patients with Type 1 Gaucher disease who had been switched from previous enzyme replacement therapy. Long-term data on changes in organ size, blood counts, disease severity bio-markers, bone marrow infiltration, overall clinical status and safety/tolerability were analyzed from 28 patients with Type 1 Gaucher disease who were attending routine clinic visits. Assessments were performed at six, 12, 24, 36 and 48 months of therapy. Disease severity biomarkers improved up to 48 months after initiation of miglustat, while other disease parameters remained stable. Miglustat showed an acceptable profile of safety and tolerability throughout treatment. In conclusion, miglustat is an effective therapy for the long-term maintenance of patients with Type 1 Gaucher disease previously stabilized with enzyme replacement therapy.

Neurologic improvement in a type 3 Gaucher disease patient treated with imiglucerase/miglustat combination.

PURPOSE: Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a deficiency of glucocerebrosidase. The neurologic manifestations of GD patients have to date been refractory to any treatment approach. We present a report of a neuronopathic GD patient whose myoclonic epilepsy improved after combination therapy with imiglucerase and miglustat. METHODS: In an adult type 3 GD patient who, despite good visceral and analytic response to ERT, developed progressive neurologic deterioration with marked myoclonic epilepsy and dystonia, we added miglustat to the enzyme-replacement therapy. RESULTS: After 2 years of combined miglustat (200 mg, 3 t.i.d.) and imiglucerase (60 IU/kg every 2 weeks), generalized tonic-clonic seizures decreased, speech improved, and the general neurologic clinical picture improved markedly. The EEG showed a reduction in focal and generalized paroxysmal discharges. No significant adverse effects were observed. CONCLUSIONS: Combined imiglucerase and miglustat therapy may be beneficial for some neuronopathic forms of GD.

Short-term effect of miglustat in every day clinical use in treatment-naïve or previously treated patients with type 1 Gaucher's disease.

In a prospective, open-label study, 25 patients with mild-to-moderate type 1 Gaucher's disease (GD1) were treated with miglustat (Zavesca), an oral glucosylceramide synthase inhibitor, over 12 months. Of the 25 patients, 10 were therapy-naïve and 15 had previously received enzyme replacement therapy (ERT). Clinical status, blood parameters, biomarkers, and organomegaly were assessed at baseline at 6 months and at 12 months. At 6 months the previously untreated patients showed a mean increase in hemoglobin of 0.77 g/dL, platelet counts improved or remaining stable, chitotriosidase and CCL18 decreased. These results were similar to those observed in 40 Spanish GD1 patients on ERT. Bone marrow infiltration cleared at 12 months. In the previously treated group, clinical and hematologic parameters and biomarkers were maintained/ improved at 12 months. Miglustat was well tolerated. The efficacy of miglustat treatment after 6 months was comparable to that of ERT.

Tratamiento paliativo del cáncer colorrectal / Palliative treatment of colorectal cancer

El tratamiento de los pacientes con cáncer colorrectal (CCR) metastásico ha cambiado drásticamente en los últimos años. Hasta la década de los noventa la única opción terapéutica era el 5-FU en sus diferentes esquemas de administración, como son la modulación con leucovorín o la infusión continua. Los nuevos fármacos como el CPT-11, oxaliplatino, raltitrexed y fluoropirimidinas orales poseen una marcada actividad y han permitido mejorar los resultados del CCR. Las combinaciones de 5-FU/leucovorín con irinotecán o con oxaliplatino en primera línea han incrementado la supervivencia y la tasa de respuestas, lo que ha permitido el desarrollo de la neoadyuvancia en pacientes con metástasis hepáticas y contribuido a aumentar la tasa de resecciones curativas. Las fluoropirimidinas orales (UFT y capecitabina) poseen una actividad comparable al 5-FU en bolo en primera línea y puede que lleguen a sustituirlo en las combinaciones aportando menor toxicidad y la comodidad de la vía oral. Los nuevos agentes que actúan sobre dianas moleculares muestran una actividad prometedora y llegarán a formar parte de los esquemas terapéuticos futuros del CCR metastásico. (AU)

Cetoacidosis diabética grave: tratamiento / Severe diabetic ketoacidosis: treatment

El tratamiento de la cetoacidosis diabética grave incluye: hidratación, insulina, reposición de electrólitos y soluciones alcalinizantes. La hidratación se inicia con solución salina isotónica, 1.000 ml por hora en las primeras tres horas, disminuyendo luego el ritmo de infusión, según respuesta clínica; cuando la glicemia desciende a 250 mg/dl se continúa con solución glucosada al 5% hasta completar las primeras 24 horas. La insulinoterapia se realiza con dosis bajas de insulina cristalina, existiendo tres sistemas para su administración: infusión endovenosa continua con bomba, bolos endovenosos horarios e inyecciones vía intramuscular horaria, cuyos resultados son igualmente efectivos y seguros. Nosotros empleamos el esquema intramuscular horario por su mayor facilidad de manejo; se recomienda una dosis inicial de 5 U. e.v. y 5 U. i.m., seguida de 5 U. i.m. por hora, hasta lograr glicemia cercana a 250 mg/dl, en que se prosigue con 5-10 U. subcutánea cada 6 horas, segun controles de glicemias. La reposición de electrólitos se refiere fundamentalmente a la administración de potasio, en dosis de 30 a 40 mEq por cada 1.000 ml de infusión a partor del segundo litro de hidratación, completando 100 a 140 mEq en las primeras 24 horas. El uso de soluciones alcalinizantes actualmente se reserva sólo para los casos con pH inferior a 7,1 o HCO3- bajo 10 mEq/1, recomendándose una dosis de 50 a 100 mM de bicarbonato de sodio a pasar en 30 a 60 minutos. La transición al tratamiento habitual incluye la alimentación oral que se reinicia cuando el sujeto está consciente y sin vómitos, en forma de régimen líquido fraccionado; la insulina cristalina se mantiene por 48 horas, 5-15 U. subcutánea cada 6 a 8 hrs., pasando luego a insulina de acción intermedia en la dosis previa al episodio agudo o 1/2 a 2/3 de la dosis total de I. cristalina usada el día anterior; el potasio por vía oral se prolongará durante 5 a 7 días...