Future perspectives of circulating tumor DNA in colorectal cancer.

Tumor biopsy is currently the gold standard for diagnosis and in determining cell signaling pathways involved in the development of treatment resistance. However, there are major challenges with this technique, including the need for serial sampling to monitor treatment resistance, which is invasive and also has the potential for selection bias due to intra-tumoral and inter-tumoral heterogeneity. These challenges highlight the need for more effective methods for obtaining Tumor samples. Liquid biopsy analyzes genetic material or tumor cells shed into the blood from the primary tumor and metastatic sites and consequently provides a comprehensive, real-time picture of the tumor burden in an individual patient. Indeed, liquid biopsy has the potential to revolutionize cancer management. Here, we review recent studies on the potential clinical applications of liquid biopsy using circulating tumor DNA in colorectal cancer, including screening, diagnosis, detection of minimal residual disease after surgery, detection of recurrence, prognosis, predicting treatment response, monitoring tumor burden or response during treatment, and tracking resistance. We also discuss recent data demonstrating the utility of detecting KRAS-mutated circulating tumor DNA, both at diagnosis to determine an appropriate treatment strategy and during anti-epidermal growth factor receptor therapy to predict treatment resistance. The future integration of liquid biopsy into clinical practice is discussed, together with alternative approaches and key questions that need to be answered in future clinical studies before this technology can be implemented and used routinely.

Is there a higher frequency of anal dysplasia and infection by human papillomavirus in Crohn's disease patients?

The aim of this study was to compare the frequency of dysplasia and human papillomavirus (HPV) infection in the anal canal of patients with Crohn's disease (CD) with a control group and assess whether there is a correlation between use of immunosuppressants and anal manifestation of CD. Patients with CD and control individuals were submitted to anal cytology and material collection for polymerase chain reaction (PCR). The cytology was classified as normal, atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or high-grade (HSIL). PCR was considered positive or negative according to virus presence or absence. A total of 117 patients were included (54 in the control group and 63 in the CD group, being 32 without and 31 with immunosuppressants). ASCUS and LSIL were found in 25.9 and 22.2% of control patients and 28.6 and 39.7% of CD patients. HPV was identified in 14.8% of the control group and 27% of the CD group. In CD patients, HPV was found in 37.5 and 16.1% of those without and with immunosuppressants, respectively. Patients with perianal involvement had 15.6% of PCR positivity. There was no statistical difference in dysplasia and infection by HPV between the groups. Use of immunosuppressants did not influence the result, but anal manifestation was inversely proportional to viral detection.

Abdominal tumors in patients with neurofibromatosis type I: Genotype-phenotype relationships.

BACKGROUND: Gastrointestinal stromal tumors have been detected in 25% of the necropsies performed on NF1 patients, but have been reported only in 7% of NF1 patients in the largest series. Such data imply an important gap between the true presence of tumors and those diagnosed. Few genotype-phenotype relationships have been described but to date none referring to abdominal tumors. OBJECTIVES: Evaluate retrospectively the efficacy of a regular and proactive follow-up of NF1 patients to early diagnose abdominal tumors and report their mutations. METHODS: Cohort study performed between 2010 and 2020, with 43 NF1 adult patients followed at our Dermatology department. RESULTS: Eight abdominal tumors were diagnosed in six patients, meaning that 14% of the followed patients developed an abdominal tumor. Five patients (83%) were asymptomatic. Five (83.3%) had a family history of NF1 with abdominal tumors (patients 1,2 and 3,4,5 were relatives). CONCLUSIONS: Although currently gastrointestinal routine screening investigations for asymptomatic patients are not recommended in the guidelines, the family aggregation in our series suggests it should be considered a close follow-up of the relatives of a patient with an NF1-related abdominal tumor. Also, for the first time, two mutations [c.2041C > T (p.Arg681Ter) and c.4537C > T (p.Arg1513*)] have been associated with family aggregation of abdominal tumors in NF1 patients.

[Dermatology service utilization and reasons for consultation by Spanish and immigrant patients in the region served by Hospital Son Llàtzer, Palma de Majorca, Spain]. / Motivos de consulta dermatológicos en la población inmigrante y española del área de salud del Hospital Son Llàtzer (Mallorca).

INTRODUCTION: Spain has come to be one of the main European destinations for immigrants from countries with low per capita incomes. The Balearic Islands have the second largest proportion of immigrants in a Spanish autonomous community. The aim of this study was to describe the dermatology service utilization by immigrant and Spanish populations at Hospital Son Llàtzer in Palma de Majorca, Spain. PATIENTS AND METHODS: A longitudinal, descriptive study was undertaken to analyze first visits to the dermatology department of Hospital Son Llàtzer between July 10, 2007 and July 9, 2008. RESULTS: Of the 6699 first visits, 13. 2% were by non-Spanish patients, originating from 64 different countries, with Argentina, Ecuador, and Columbia the most common. Spanish patients consulted more frequently than non-Spanish patients. Patients from outside the European Union consulted most often for inflammatory conditions, whereas patients from Spain and other countries of the European Union mainly consulted for benign tumors. Consultations were for sexually transmitted disease in 2% of visits. The reason for the visit was classified as cosmetic in 14. 1% of patients. CONCLUSIONS: The dermatology service utilization by the immigrant population was lower than by Spanish patients, although with differences according to the country of origin.

Incidental Skin Cancer Detection in a Hospital Department: A Prospective Study. / Evaluación de la tasa de detección incidental de cáncer cutáneo: estudio prospectivo en un servicio hospitalario.

BACKGROUND AND OBJECTIVES: Skin cancer is a common cause for referral to dermatology, but it may also be an incidental finding during examination of patients referred for other reasons. The objective of the study was to compare the characteristics of skin cancer lesions (squamous skin carcinoma, basal cell carcinoma, melanoma) diagnosed at a dermatology department over 1 year between patients referred for suspected skin cancer and those referred for another reason but in whom skin cancer was detected as an incidental finding. Pearson's χ2 test was used to compare different study variables between the 2 groups. RESULTS: Data were collected from 433 patients with a mean age of 72 years; 233 (51.3%) of the patients were female. The most common skin types were Fitzpatrick types II and III. Basal cell carcinoma was the most frequent cancer in all the analyses and accounted for 68.4% of all cancers diagnosed (296/433). Twenty-six percent of the malignant skin tumors were detected incidentally. Statistical analysis revealed that these tumors tended to be located in nonvisible areas and were smaller and of more recent onset than tumors initially suspected to be malignant. CONCLUSIONS: The high rate of skin cancer diagnosed incidentally by dermatologists highlights the need to carry out thorough examinations of patients in order to facilitate early detection and treatment.

Impact of prior pneumococcal vaccination on clinical outcomes in HIV-infected adult patients hospitalized with invasive pneumococcal disease.

BACKGROUND: Recent studies in hospitalized patients with community-acquired pneumonia have found a lower risk of bacteraemia and better clinical outcomes in patients who had previously received the 23-valent pneumococcal polysaccharide vaccine (PPV) in comparison with unvaccinated individuals. The aim of this study was to assess the influence of prior PPV on clinical outcomes in HIV-infected adult patients hospitalized with invasive pneumococcal disease (IPD). METHODS: This was an observational study of all consecutive HIV-infected adults hospitalized with IPD from January 1996 to October 2007 in three hospitals in Spain. Baseline characteristics and clinical outcome-related variables were compared according to prior PPV vaccination status. RESULTS: A total of 162 episodes of IPD were studied. In 23 of these (14.2%), patients had previously received PPV. In both vaccinated and unvaccinated patients, most of the causal serotypes were included in the 23-valent PPV (76.9% and 84.1%, respectively). Overall, 25 patients (15.4%) died during hospitalization, 21 patients (13%) required admission to an intensive care unit (ICU) and 34 patients (21%) reached the composite outcome of death and/or admission to the ICU. None of the 23 patients who had previously received PPV died or required ICU admission, in comparison with 25 (18%; P=0.026) and 21 (15.1%; P=0.046), respectively, of the unvaccinated patients. The length of hospital stay for vaccinated patients was significantly shorter (8.48 vs. 13.27 days; P=0.011). CONCLUSIONS: Although 23-valent PPV failed to prevent IPD in some HIV-infected patients, vaccination produced beneficial effects on clinical outcomes by decreasing illness severity and mortality related to IPD.

[Subcutaneous gammaglobulin in common variable immunodeficiency. First experience in Spain]. / Gammaglobulina subcutánea en inmunodeficiencia común variable. Primera experiencia en España.

INTRODUCTION AND AIM: Weekly home-based subcutaneous immunoglobulin (SCIg) therapy is an alternative to intravenous immunoglobulin (IVIg) in the treatment of patients with primary antibody deficiencies. The objective of this study was to investigate the efficacy, safety, related quality of life and cost effectiveness of SCIg in our area. MATERIALS AND METHODS: Observational and descriptive study including paediatric patients with common variable immunodeficiency (CVID) receiving SCIg in our hospital (November 2006 to April 2008). Obtained data were compared with those from the last year with IVIg. RESULTS: Eleven patients with CVID were included. Median age was 15 years. The median trough serum IgG level was 622 mg/dl with IVIg. In patients in whom the SCIg dose was maintained or reduced compared to IVIg, the median trough serum IgG level was 850 mg/dl (p < 0.0005). Annual rate of infection was 2.22 per patient-year, without significant differences to IVIg (p = 0.212). There were 58 treatment-related adverse events (AE) reported with SCIg (45 local AE and 13 systemic AE). The most frequent treatment-related adverse event was infusion-site reaction. Switching to home-based subcutaneous IgG treatment led to significant improvements in quality of life and substantial cost savings. CONCLUSIONS: We conclude that subcutaneous administration of 16% SCIg is a safe and cost-effective alternative to IVIg for replacement therapy of primary antibody deficiencies. Median trough serum IgG levels were higher with SCIg. Local AE were common but mild and the incidence decreased over time. Quality of life is significantly improved.

Spanish Consensus Document on the Treatment Algorithm for Rosacea. / Documento de consenso español para el algoritmo de tratamiento de la rosácea.

Recent scientific evidence and the incorporation of new drugs into the therapeutic arsenal against rosacea have made it necessary to review and update treatment criteria and strategies. To this end, a panel of 15 dermatologists, all experts in rosacea, was formed to share experiences and discuss treatment options, response criteria, and changes to treatment. Based on a critical review of the literature and a discussion of the routine practices of Spanish dermatologists, the panel proposed and debated different options, with consideration of the experience of professionals and the preferences of patients or equality criteria. Following validation of the proposals, the final recommendations were formulated and, together with the evidence from the main international guidelines and studies, used to produce this consensus document. The goal of this consensus document is to provide dermatologists with practical recommendations for the management of rosacea.

Author Correction: Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.

[Invasive pneumococcal disease and hemolytic uremic syndrome]. / Enfermedad neumocócica invasiva y síndrome hemolítico urémico.

INTRODUCTION: Streptococcus pneumoniae is an infrequent casual agent of hemolytic uremic syndrome (HUS) with more severity than classic HUS. CASE REPORT: We present two patients with pneumococcal pneumonia and empyema who developed HUS. One patient the renal function returned to normal and the other needed a renal transplantation. CONCLUSION: Pneumococcal invasive disease may be a cause of severe HUS, so a high index of suspicion is mandatory to prompt appropriate diagnosis and management.

[Arterial hypertension and stenosis of the accessory renal artery]. / Hipertensión arterial y estenosis de la arteria renal accesoria.

We present the case of a 45 year old patient with severe hypertension refractory to medical treatment who was diagnosed a significant stenosis of an accessory renal artery whilst the main renal arteries were normal. The arterial dilatation through angioplasty of the accessory artery improved dramatically the control of his hypertension.

Is there a higher frequency of anal dysplasia and infection by human papillomavirus in Crohn's disease patients?

The aim of this study was to compare the frequency of dysplasia and human papillomavirus (HPV) infection in the anal canal of patients with Crohn's disease (CD) with a control group and assess whether there is a correlation between use of immunosuppressants and anal manifestation of CD. Patients with CD and control individuals were submitted to anal cytology and material collection for polymerase chain reaction (PCR). The cytology was classified as normal, atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or high-grade (HSIL). PCR was considered positive or negative according to virus presence or absence. A total of 117 patients were included (54 in the control group and 63 in the CD group, being 32 without and 31 with immunosuppressants). ASCUS and LSIL were found in 25.9 and 22.2% of control patients and 28.6 and 39.7% of CD patients. HPV was identified in 14.8% of the control group and 27% of the CD group. In CD patients, HPV was found in 37.5 and 16.1% of those without and with immunosuppressants, respectively. Patients with perianal involvement had 15.6% of PCR positivity. There was no statistical difference in dysplasia and infection by HPV between the groups. Use of immunosuppressants did not influence the result, but anal manifestation was inversely proportional to viral detection.

[D-lactic acidosis in an 11-year-old patient with short bowel syndrome]. / Acidosis D-láctica en un paciente de 11 años con síndrome de intestino corto.

The short bowel syndrome is the result of a congenital or acquired loss of a large part of the small intestine. The most frequent causes of surgical resection of the intestine in infants are arterial or venous thrombosis, intestinal volvulus, necrotizing enterocolitis, and Crohn's disease. Symptoms include nutrient and electrolyte malabsorption, steatorrhea and diarrhea, which can result in failure to thrive. The consequences of extensive small bowel resections consist of nutritional deficiencies, gastric acid hypersecretion, nephrolithiasis, cholelithiasis and lactic acidosis. Of these, D-lactic acidosis is an infrequent but important complication because of the symptoms that it can produce. D-lactic acid in the human organism is generated by intestinal bacteria, D-lactate ingestion, or endogenous production in the methyl glycoxylase pathway. Neurological symptoms such as somnolence, ataxia or altered behavior in a patient with short bowel syndrome should make us think of D-lactic acidosis caused by bacterial overgrowth. We present the case of an 11-year-old boy with short bowel syndrome secondary to multiple resections during the postnatal period who was admitted to hospital for episodes of confusion and altered behavior. The diagnosis was lactic acidosis. Outcome was favorable due to prompt instauration of treatment.

Lysosomal enzyme activities in the regenerating rat liver.

The activity of four lysosomal enzymes (hyaluronidase, beta-N-acetylglucosaminidase, acid phosphatase, and cathepsin D) was studied in aqueous extracts of the light mitochondrial fraction of regenerating male rat liver. This tissue was chosen as a model for normal cell division in vivo. In the first wave of division, 40 to 50% of the cells divide synchronously. Activities were measured at 0, 9, 18 (end of G1 phase), 24 (S phase), and 30 hr (mitosis) and during regeneration, 4 and 11 days after partial hepatectomy. Activities were related to fresh tissue weight, to cellular DNA, and to protein content of the extracts. At 9 hr, there was an important increase in hyaluronidase and cathespin D activities (these two enzymes act upon macromolecules); beta-N-acetylglucosaminidase and acid phosphatase activities were only slightly increased. At the end of the G1 phase, 40 to 50% of the activity of all four enzymes was lost, which might indicate complete loss of activity in cells undergoing division. This depletion persisted until mitosis was complete. Four days later, there was a slow restoration of enzyme activities; after 11 days, hyaluronidase and cathepsin D exhibited about 80% of their initial activity, whereas beta-N-acetylglucosaminidase and acid phosphatase only regained about 50%. These results show that the lysosomal system perhaps plays some role in cell division.

[Is familial screening useful in selective immunoglobulin A deficiency?]. / ¿Es útil el cribado familiar en el déficit selectivo de inmunoglobulina A?

INTRODUCTION: Selective immunoglobulin A deficiency (SIgAD), the most common primary immunodeficiency, is often asymptomatic. High rates of familial clustering have been described in SIgAD, but the causative genetic defect and mechanism of inheritance are unknown. OBJECTIVES: To determine whether familial SIgAD cases show more severe clinical and immunological characteristics than sporadic ones; to investigate the utility of screening first-degree relatives (FDRs) of these patients, and to determine whether symptoms in affected family members are important enough to justify screening. PATIENTS AND METHODS: Descriptive, cross-sectional study (October 2010-September 2011) of all patients with SIgAD and followed up in our center. Demographic, clinical, and analytical data were reviewed. A familial case was defined as an SIgAD patient with at least one affected FDR. RESULTS: Of the 130 participants, 42 were SIgAD patients and 88 FDR. There were 13 (31%) familial cases and and 14 (16%) affected FDRs. Six family members had to be analyzed in order to detect one affected one. There were no clinical differences between familial and sporadic SIgAD cases. The percentages of intestinal disease (p=001, OR=9.57, 95%CI 2.59-35.3), hospitalizations (p=045, OR=4.01; 95%CI 1.10-14.67], and need for chronic treatment (p=006, OR=5.5; 95%CI 1.57-19.54) were higher in affected FDRs than in unaffected ones. CONCLUSIONS: The symptoms were not more severe in familial than sporadic SIgAD cases. Nonetheless, the elevated prevalence of affected FDRs with significant morbidity may justify routine screening of close family members of these patients.

Radiolocalization of squamous lung carcinoma with 131I-labeled epidermal growth factor.

Overexpression of epidermal growth factor receptor (EGFr) in squamous carcinomas has been demonstrated extensively. Preliminary clinical studies have shown that radiolabeled anti-EGFr monoclonal antibodies can localize to these tumors. The aims of this study were to determine the tolerance, pharmacokinetics, and radiolocalization properties of 131I-labeled EGF in patients (n = 9) with advanced squamous lung cancer. Patients' vital signs and symptoms were monitored regularly for 3 days. Daily scintigrams and biological samples for pharmacokinetic analysis were obtained for 3-4 days. 99mTc-labeled human serum albumin was administered to patients with positive tumor scans. Six patients had positive tumor scans, and five of them had received >/=1.0 mg EGF. In all of these cases, tumors were visualized the same day of the infusion, although best tumor-background contrast was obtained at 50-74 h. There were no false-positive images. Whole-body radioactivity retention rose significantly with increasing EGF doses; most labeled EGF was eliminated by urinary excretion. Tumor:normal tissue uptake ratios increased during the course of the study. All patients presented self-limited, dose-related gastrointestinal adverse effects. In conclusion, recombinant 131I-labeled EGF administered i.v. can localize to squamous lung cancer efficiently, can be administered safely to patients, and has more advantageous pharmacokinetic properties than monoclonal antibodies. Further studies are warranted to determine more accurately the potential of EGF and EGF-related peptides in the imaging and/or therapy of EGFr-overexpressing human cancers.

Nonregenerative stimulation of hepatocyte proliferation in the rat: variable effects in relation to spontaneous liver growth; a possible link with metabolic induction.

Three procedures were used to stimulate hepatocyte proliferation in the rat without reducing liver mass, resulting in a supplementary growth which differs from the regenerative growth observed after loss of liver mass by hepatectomy or toxic necrosis. They were: (a) the ingestion of cyproterone, a cytochrome P450 inducing drug (b) the injection of an irritant which provokes glycogenesis and synthesis of acute-phase proteins (c) the injection of albumin-bound bilirubin leading to elimination of glucuronated bilirubin in bile. This ensuing supplementary growth was studied in the rat under several conditions of hepatic proliferation: 1. In normal adult rats, in which hepatocyte proliferation is very low, the effect on proliferation was either weak or undetectable. 2. In suckling rats, with a rapid body and liver growth, all the stimulants provoked a synchronized wave of proliferation with a steep increase of the percentage of S-phase hepatocytes from 4.5% in controls to 15-30% in treated rats. This increase was followed by a compensatory period of low proliferation during which a treatment with a second stimulant was much less effective. 3. In 2/3 hepatectomized adult rats, the proliferation induced by cyproterone was higher than the spontaneous regenerative proliferation alone and additional to it during all of the regenerative process. The proliferation induced by acute inflammation was competitive with the synchronous spontaneous proliferation during the early period of synchronized proliferation following surgery, suggesting that both are similar acute responses. Differently, during the late period of lower and unsynchronized regenerative proliferation, the proliferation provoked by acute inflammation was additional to the spontaneous one. A stimulation of proliferation by injection of the albumin-bilirubin complex was observed during the late period after 2/3 hepatectomy. The highest level of stimulation occurred when the liver growth and the hepatocyte proliferation were already high. This suggests that these stimulants are not complete mitogenic stimuli and need cofactors which are present during the spontaneous growth or, alternatively, that the effect of stimulants is opposed by an inhibitory mechanism present in the adult rat.

A phase II trial of the combination of gemcitabine, ifosfamide and cisplatin in the treatment of advanced non-small cell lung cancer.

OBJECTIVE: This phase II trial was designed to assess the efficacy and toxicity profile of the combination of gemcitabine, ifosfamide and cisplatin (GIP) in the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients included in the study were those with surgically unresectable or metastatic NSCLC, with bidimensionally measurable disease, a Karnofsky performance status > 60, and who had not received previous chemotherapy. Treatment consisted of 1000 mg/m(2) gemcitabine on days 1 and 8, 3 g/m(2) ifosfamide on day 1, and 50 mg/m(2) cisplatin on day 1, administered in 21-day cycles. A maximum of six cycles were administered. RESULTS: Between March 1996 and December 1997, 60 patients were included in the study (37 stage III and 23 stage IV), of which 59 were evaluated for response. An objective response was obtained in 43% of patients (3% complete and 40% partial responses), whereas 22% had stable disease. The median survival time for the whole group was 52 weeks (65 weeks in patients with stage III, and 35 weeks in stage IV). The most frequent toxicity was haematological, 56% of patients presented grade 3 or 4 myelotoxicity in one of the cycles, although only seven episodes of febrile neutropenia were recorded in the 255 cycles administered. CONCLUSIONS: The GIP regimen attains response rates similar to those obtained with the gemcitabine plus cisplatin combination used in advanced NSCLC, and had an acceptable toxicity profile.