Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Waiting for the "liquid revolution" in the adjuvant treatment of colon cancer patients: a review of ongoing trials.

Since colon cancer has a high rate of shedding of tumour fragments into the blood, several research efforts are now focused on the investigation of the minimal residual disease through the detection of ctDNA to tailor the adjuvant therapy of colon cancer patients and optimize its cost/effectiveness balance. The negative prognostic impact of detectable ctDNA in patients' blood after radical surgery for colon cancer is well established. Several clinical trials adopting heterogeneous designs and techniques are now ongoing to translate promises into daily practice by answering five general questions: i) is a ctDNA-guided decision making efficacious in the post-operative management of colon cancer patients? ii) are de-escalation strategies possible in ctDNA-negative cases? iii) are escalation strategies useful to improve the prognosis of ctDNA-positive patients? iv) when MRD is identified at the end of the adjuvant chemotherapy, is another post-adjuvant systemic therapy efficacious? v) can we exploit ctDNA technologies in the follow up of colon cancer patients? This review focuses on currently ongoing trials and how their results may affect the ctDNA "liquid revolution" of early colon cancer.

Predicting early recurrence after resection of initially unresectable colorectal liver metastases: the role of baseline and pre-surgery clinical, radiological and molecular factors in a real-life multicentre experience.

BACKGROUND: Advances in surgical techniques and systemic treatments have increased the likelihood of achieving radical surgery and long-term survival in metastatic colorectal cancer (mCRC) patients with initially unresectable colorectal liver metastases (CRLMs). Nonetheless, roughly half of the patients resected after an upfront systemic therapy experience disease relapse within 6 months from surgery, thus leading to the question whether surgery is actually beneficial for these patients. MATERIALS AND METHODS: A real-world dataset of mCRC patients with initially unresectable liver-limited disease treated with conversion chemotherapy followed by radical resection of CRLMs at three high-volume Italian institutions was retrospectively assessed with the aim of investigating the association of baseline and pre-surgical clinical, radiological and molecular factors with the risk of relapse within 6 or 12 months from surgery. RESULTS: Overall, 268 patients were included in the analysis and 207 (77%) experienced recurrence. Ninety-six (46%) of them had disease relapse within 6 months after CRLM resection and in spite of several variables associated with early recurrence at univariate analyses, only primary tumour resection at diagnosis [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.32-0.89, P = 0.02] remained significant in the multivariable model. Among patients with resected primary tumours, pN+ stage was associated with higher risk of disease relapse within 6 months (OR 3.02, 95% CI 1.23-7.41, P = 0.02). One hundred and forty-nine patients (72%) had disease relapse within 12 months after CRLMs resection but none of the analysed variables was independently associated with outcome. CONCLUSIONS: Clinical, radiological and molecular factors assessed before and after conversion chemotherapy do not reliably predict early recurrence after secondary resection of initially unresectable CRLMs. While novel markers are needed to optimize the cost/efficacy balance of surgical procedures, CRLM resection should be offered as soon as metastases become resectable during first-line chemotherapy to all patients eligible for surgery.

Clinical impact of neutropenia and febrile neutropenia in metastatic colorectal cancer patients treated with FOLFOXIRI/bevacizumab: a pooled analysis of TRIBE and TRIBE2 studies by GONO.

BACKGROUND: TRIBE and TRIBE-2 studies demonstrated higher benefit from FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan)/bevacizumab compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX/bevacizumab as an upfront option for metastatic colorectal cancer patients, with more toxicities. We focused on the incidence and longitudinal dynamics of neutropenia and febrile neutropenia (FN) in the two studies, to evaluate their clinical relevance, the magnitude of impact of FOLFOXIRI/bevacizumab, and the role of risk factors in predicting their occurrence. METHODS: The overall incidence of grade 3-4 (G3-4) neutropenia and FN, the time to their onset, the use of granulocyte colony-stimulating factor, and the association with risk factors were evaluated in the overall population and according to treatment arm. FN episodes were assessed by Multinational Association for Supportive Care in Cancer (MASCC) score. RESULTS: Among 1155 patients, 568 (49%) received FOLFOXIRI/bevacizumab. Overall, 410 (35%) experienced G3-4 neutropenia and 70 (6%) FN, 21 (2%) at high risk. FOLFOXIRI/bevacizumab was associated with higher incidence of neutropenia (51% versus 21%, P < 0.001), FN (8% versus 4%, P = 0.02), and high-risk FN [18 (3%) versus 3 (1%), P = 0.015]. No related deaths were observed. The first episode of G3-4 neutropenia and FN occurred mainly in the first 2 months in both arms. Longitudinal analysis showed different patterns of evolution over cycles between the arms (P < 0.001) G3-4 neutropenia being more frequent in the first cycles with FOLFOXIRI/bevacizumab. Older patients (P = 0.01) and females (P < 0.001) had a significantly higher risk of G3-4 neutropenia. No significant interaction effect between arm and analysed risk factors in terms of risk of G3-4 neutropenia or FN was observed. The incidence of FN among older females receiving FOLFOXIRI/bevacizumab was 12%. Neither G3-4 neutropenia nor FN impaired efficacy in terms of overall response rate, progression-free survival, and overall survival. CONCLUSIONS: FOLFOXIRI/bevacizumab has a higher risk of G3-4 neutropenia and FN than doublets/bevacizumab. FN occurred in <10% of patients, mostly as low-risk episodes. A closer monitoring during the first 2 months is recommended; prophylactic use of granulocyte colony-stimulating factor may be considered for older females.

A knowledge discovery framework to predict the N2O emissions in the wastewater sector.

Data Analytics is being deployed to predict the dissolved nitrous oxide (N2O) concentration in a full-scale sidestream sequence batch reactor (SBR) treating the anaerobic supernatant. On average, the N2O emissions are equal to 7.6% of the NH4-N load and can contribute up to 97% to the operational carbon footprint of the studied nitritation-denitritation and via-nitrite enhanced biological phosphorus removal process (SCENA). The analysis showed that average aerobic dissolved N2O concentration could significantly vary under similar influent loads, dissolved oxygen (DO), pH and removal efficiencies. A combination of density-based clustering, support vector machine (SVM), and support vector regression (SVR) models were deployed to estimate the dissolved N2O concentration and behaviour in the different phases of the SBR system. The results of the study reveal that the aerobic dissolved N2O concentration is correlated with the drop of average aerobic conductivity rate (spearman correlation coefficient equal to 0.7), the DO (spearman correlation coefficient equal to -0.7) and the changes of conductivity between sequential cycles. Additionally, operational conditions resulting in low aerobic N2O accumulation (<0.6 mg/L) were identified; step-feeding, control of initial NH4+ concentrations and aeration duration can mitigate the N2O peaks observed in the system. The N2O emissions during aeration shows correlation with the stripping of accumulated N2O from the previous anoxic cycle. The analysis shows that N2O is always consumed after the depletion of NO2- during denitritation (after the "nitrite knee"). Based on these findings SVM classifiers were constructed to predict whether dissolved N2O will be consumed during the anoxic and anaerobic phases and SVR models were trained to predict the N2O concentration at the end of the anaerobic phase and the average dissolved N2O concentration during aeration. The proposed approach accurately predicts the N2O emissions as a latent parameter from other low-cost sensors that are traditionally deployed in biological batch processes.

Keratitis secondary to Fusarium spp. in Spain 2012-2014. / Queratitis secundaria a Fusarium spp. en España 2012-2014.

OBJECTIVE: To describe the clinical-epidemiological characteristics of a case series of fungal keratitis associated with Fusarium spp.., in Spain during the years 2012 to 2014. METHODS: A retrospective study of a case series was conducted on a systematic random sample of 10% of patients identified in Health Centres of provincial capitals (n=250). The centres were asked whether they had been presented with cases of Fusarium spp. keratitis characterised by microbiological methods. Of the 23 centres that responded, 14 had detected cases, with 13 of them accepting to participate, and 11 of them completing the study. The latter being sent a previously validated questionnaire. The variables analysed were: age, gender, habitual residence, profession, disease and medical history (previous systemic and ocular diseases, previous eye surgeries), and their outcomes. RESULTS: The response rate was 92%, identifying 23 cases of Fusarium spp.. of which 21 (91.3%) of them lived in urban areas. The professions most affected by the disease included chefs, administrative, and technical, with 13 cases (56.5%). The treatment guidelines established to confirm the infection showed the combined use of topical antibiotics associated with antiviral and/or antifungal agents. The use of contact lenses (86.9%) was the main risk factor. DISCUSSION: This study showed that this is a rare disease in Spain, but that a large percentage of people who present with the disease are resident in urban areas, and they work in closed environments, focusing attention on microtraumas caused by use of contact lenses.

Multidrug resistant Fusarium keratitis.

CASE REPORT: We report a case of keratitis in a female contact lens wearer, who developed a deep corneal abscess. The culture of a corneal biopsy scraping was positive for multiresistant Fusarium solani. The patient has a complicated clinical course and failed to respond to local and systemic antifungal treatment, requiring eye enucleation. CONCLUSION: Fusarium keratitis may progress to severe endophthalmitis. Clinical suspicion is paramount in order to start antifungal therapy without delay. Therapy is complex due to the high resistance of this organism to usual antifungal drugs.

[Improving the visualization of non-absorbable T-Flux(®) implants in deep sclerectomy. Colouring technique]. / Mejorando la visualización del implante no absorbible T-Flux(®) para esclerectomía profunda. Técnica de tinción.

PURPOSE: To describe a staining technique that will enhance the visualization of non-absorbable T-Flux implants. METHODS: The technique was applied to non-absorbable T-Flux implants. The implants were submerged for 5 to 10 minutes in a sodium fluorescein solution, and dried with a sponge when removed from the solution. DISCUSSION: This is a very simple and easy procedure that uses a common fluorescein solution to enhance the contrast between the surgical field and a transparent implant used in deep sclerectomy. This colour technique will decrease the risk of loss of the implant in the surgical field.

Colorectal cancer screening in LHU4 Chiavarese, Italy: ethical, methodological and outcome evaluations at the end of the first round.

UNLABELLED: INTRODUCTION. The screening programmes are very challenging from the ethical perspective, and their impact in terms of morbidity and mortality make secondary colorectal cancer prevention a valuable public health intervention. METHODS: The target population people aged 50-69 years receive an invitation card with a test-tube for the fecal occult blood test (FOBT) and an immunochemical test is used for fecal occult blood. Subjects positive to FOBT are invited to perform a gastroenterologic examination and a full colonoscopy. RESULTS: In the firt round of screening, 100% of the target population has been invited with an adhesion rate of 41.3%. A total of 1739 FOBT-positive subjects have been invited to the second level of the screening. 1429 of them have performed the gastroenterologic examination (83.9%). To date 956 full colonoscopies have been completed and the rate of subjects affected by carcinoma, malignant polyp and advanced adenoma has been equal to 23.5%. DISCUSSION: Thanks to the reminders already sent, an increasing compliance has been registered with an increased rate of subjects with a low schooling that have performed a FOBT test. With the aim to optimize all the operative aspects of the screening programme it is already ongoing a set of meetings between health workers of Local Health Unit 4 and General Practioners.

[Retinal nerve fiber layer thickness analysis in children from 6 to 9 years of age]. / Análisis del espesor de la capa de fibras nerviosas en niños de 6 a 9 años.

PURPOSE: To establish a database of scanning laser polarimetry (GDx) parameters for children between 6 and 9 years of age and compare the results at each age. METHODS: The retinal nerve layer thickness of 116 children from one school was evaluated with GDx and the results were analyzed for each age and for the entire group to determinate the normal range for that population. RESULTS: In the global analysis of the software-derived GDx parameters, we obtained a TSNIT average of 59.43 (IC95% 58.41-60.45), a superior average of 71.35 (IC95% 69.99-72.70), an inferior average of 70.08 (IC95% 68.71-71.45), and a TSNIT Std. Deviation of 25.11 (IC95% 24.36-25.86). The results from the analysis for age were similar to the global results. CONCLUSIONS: Given the low level of cooperation required, GDx can be used without problem to study the retinal nerve fiber layer in 6-9-year-old children. GDx could provide objective information about the state of development of the retinal nerve fiber layer during this period of life.

[Simultaneous botulism in two brothers addicted to cocaine]. / Botulismo simultáneo en dos hermanos cocainómanos.

INTRODUCTION: Botulism is currently an uncommon disease in which the botulinum toxin causes a progressive muscular paralysis that can lead to the death due to a failure of respiratory muscles. CLINICAL CASE: Two brothers, both addicted to cocaine, came to the casualty department because of a decrease of near visual acuity and bilateral mydriasis. Two days later, they developed eyelid ptosis, asymmetric dysfunction of the extraocular muscles and vomiting. DISCUSSION: The presence of a paralysis of accommodation, with bilateral mydriasis that reacts to pilocarpine, makes it necessary to consider botulism as a possible cause.

[Modification of the conjuntival flora with cleaning palpebral solutions]. / Modificación de la flora conjuntival por el empleo de soluciones de higiene palpebral.

OBJECTIVE: The aim of the present study is to evaluate the effectiveness of a solution of palpebral hygiene during the preoperative stage of cataract surgery. MATERIALS AND METHODS: We studied 286 patients divided in 5 groups. One control group that did not use the product, and the remaining 4, that used the product during 3, 4, 5 and 6 days. The design of the study was prospective, randomize and masked. We took a sample of the conjunctival fundus in the morning of the day of the surgery, before commencing treatment with eye drops. This sample was sown according to microbiological techniques and analyzed by the microbiology department. RESULTS: The best time for using palpebral hygiene solutions prior to cataract surgery is four to five days. If it is used at less than three days, it does not decrease the rate of positive cultures and if the solution is applied more than six days, microorganisms that are not part of the common conjunctival flora may appear. CONCLUSIONS: Palpebral hygiene products should not be used more than five consecutive days previous to surgery.

Combined laparoendoscopic approach for biliary lithiasis treatment.

BACKGROUND/AIMS: The treatment of common bile duct stones diagnosed during videolaparoscopic cholecystectomy is still under debate. In cases of suspected common bile duct stones, a double approach with endoscopic retrograde cholangiopancreatography either prior to, or following videolaparoscopic cholecystectomy is the current routine in many centers. An intraoperative endoscopic retrograde cholangiopancreatography with endoscopic papillosphincterotomy and stone extraction has recently been proposed. METHODOLOGY: We compared the approaches for suspected common bile duct stones in 21 cases of combined intervention endoscopic retrograde cholangiopancreatography during videolaparoscopic cholecystectomy to 17 cases of sequential intervention (endoscopic retrograde cholangiopancreatography prior to videolaparoscopic cholecystectomy). Complications and postoperative monitoring are discussed and reported on the basis of hospital stay. RESULTS: Although the efficacy and the complications are similar, patients treated with the sequential approach stayed in the hospital longer because of the double monitoring period during both after endoscopic retrograde cholangiopancreatography and after videolaparoscopic cholecystectomy. CONCLUSIONS: A combined approach to suspected common bile duct stones during videolaparoscopic cholecystectomy could be an effective and a financially worthwhile treatment.

Interferon retreatment in chronic hepatitis C: which patients to choose, and what schedule to use.

UNLABELLED: OBJECTIVE; To evaluate the results of a large cohort of non-responder or relapsing responder patients with chronic hepatitis C retreated with various schedules of interferon (IFN). METHODS: Our study included 276 patients (158 non-responders and 118 relapsing responders) who underwent IFN retreatments. Among the non-responder group, 158 patients underwent further courses of IFN. In particular, 108 patients underwent one course of IFN retreatment, 40 patients underwent two courses, eight patients underwent three courses, and two patients underwent four courses. Regarding the relapsing responder group, the 118 patients were retreated with the same dosage for varying periods. In particular, 50 patients were treated for 6 months, 43 patients for 12 months, and 25 for 24 months. Patients in the subgroups of IFN retreatment were homogeneous as far as age and gender distribution, as well as virological and histological characteristics, are concerned. Qualitative and quantitative HCV-RNA was evaluated at baseline, at the end of treatment and at the last check-up of follow-up. HCV genotype was determined on baseline serum samples. Alanine transaminase (ALT) levels were tested monthly. RESULTS: Long-term biochemical (normal ALT levels) and virological (HCV-RNA negative) response was obtained in 2.6% of non-responder retreated patients, and in 33.9% of relapsing responder retreated patients. Evaluation of response on the basis of the duration of treatment showed that 48%, 19% and 16% of relapsing responder patients retreated for 24, 12 and 6 months, respectively, obtained long-term biochemical and virological response. CONCLUSION: Non-responder patient retreatment is inefficient especially in cirrhotic and/or genotype 1 b patients. IFN retreatment is warranted in relapsing responder patients. In particular, 24-month therapy induces significant long-term biochemical and virological response.

Lymphoblastoid interferon therapy in chronic hepatitis C: biochemical, virological and histological evaluation of two different doses.

Sixty patients of both sexes with biopsy-proven chronic hepatitis C were randomized to receive lymphoblastoid interferon 3 MU or 6 MU three times weekly for 6 months. A follow-up period of 3 months at the end of the therapy was scheduled. Thirty-two patients (53.3%) normalized alanine aminotransferase at the end of the therapy. Of these, 17 received 3 MU (56.7%) and 15 (50%) received 6 MU. Eighteen of the 32 patients (56.2%) relapsed in the follow-up period after treatment. No significant difference in relapse rate was observed between the two groups. The overall percentage of the non-responder patients was 36.6%. The treatment was discontinued because of non-compliance and/or side effects in six patients (10%): three in the 3-MU group and three in the 6-MU group. An improvement in liver histology was observed in about a quarter of chronic active hepatitis patients whose overall diagnosis changed to chronic persistent hepatitis. Knodell's score system showed a significant improvement (p < 0.05) with regard to peripheral necrosis, fibrosis and total score. HCV-RNA was positive at the beginning in all patients and it became undetectable in almost all responder patients. In some cases there was no correlation between viraemia and biochemical signs of liver disease. Our study shows that 6 MU does not increase the response rate compared to 3 MU. Moreover, the lower dose is able to improve the liver histology and to abolish the HCV viraemia in responder patients.

Effect of sulglycotide in the prevention of duodenal ulcer relapse.

OBJECTIVE: To evaluate the effectiveness of sulglycotide, a gastroprotective drug, as maintenance treatment for patients with duodenal ulcer. DESIGN: A randomized double-blind study. METHODS: A total of 119 patients with recently healed duodenal ulcers were randomly allocated, in a double-blind fashion, to receive sulglycotide 200 mg twice daily (60 patients) or placebo (59 patients) for 1 year. Patients underwent clinical assessment every third month and endoscopy at 6 and 12 months, or earlier if relapse was suspected. RESULTS: The cumulative endoscopic relapse rates, compared using the log rank test, were 37 and 52% after 6 and 12 months, respectively, in the sulglycotide group and 62 and 71% (P = 0.03), respectively, in the placebo group. CONCLUSIONS: Sulglycotide is moderately effective as a maintenance treatment for duodenal ulcer disease.

Endocrine evaluation in patients treated with interferon-alpha for chronic hepatitis C.

The aim of our study was to evaluate the hormonal profile in a group of 31 subjects who underwent recombinant interferon-alpha therapy for chronic active hepatitis C. Hormonal determinations were performed before treatment began and at the end of the 3rd and 6th months of therapy. Free-T4 concentrations, though remaining in the normal range, showed a significant reduction (p < 0.05) after 3 and 6 months of therapy compared with pretreatment levels. A lesser decrease in free-T3 levels was also seen. TSH basal values did not show any variation, while an increased secretory response to TRH stimulation was observed at the end of the 6th month. Thyroglobulin and calcitonin levels remained normal, while an increase in antithyroglobulin and antithyreoperoxidase antibody levels was observed in 4 patients (12.9%). No modifications in the other pituitary hormones or in adrenal and sex steroid concentrations were noticed. A significant increase in IGF-I concentrations (p < 0.05) was observed during treatment, and an inverse correlation was seen between IGF-I and alanine aminotransferase levels (p < 0.01). This study supports the view that interferon treatment can influence thyroid function. The increase in IGF-I concentration observed during therapy may reflect an improvement in patients with hepatic disease, but a direct stimulatory effect of interferon on IGF-I secretion cannot be excluded.

Recombinant interferon alfa-2b treatment in chronic non-A, non-B/type C hepatitis.

In a study of 60 patients with non-A, non-B/type C (NANB/C) chronic hepatitis alanine aminotransferase (ALT) activities returned to normal after treatment with interferon alfa-2b (3 million units for six months) in 70.7% and 29.3% did not respond. The response was maintained during four to six months, follow up in 41.4% of patients. Liver biopsy specimen showed histological improvement in all patients surveyed. Treatment was well tolerated with only mild side effects.

[The behaviour of gamma-glutamyltranspeptidase in the diagnosis of secondary hepatic malignancy: its relationship to other serum enzymes (author's transl)]. / Il comportamento della gamma-glutamiltranspeptidasi (GGTP) nella diagnosi delle neoplasie epatiche secondarie: correlazione con altre attività enzimatiche sieriche.

In order to determine the value of serum Gamma-glutamyltranspeptidase in the diagnosis of secondary hepatic malignancy, the variations of the serum measurement of different hepatic enzymes have been studied in 160 patients, 80 of which have hepatic metastases gamma GT showed an increase in 95% of the patients with metastases even if there has been a high percentage of false-positive results in the control patients and in those who were carriers of cancer without hepatic metastases. The Authors, after having briefly discussed the meaning of the false positivity rate, conclude that such an enzyme proves once to be a simple and sensitive test of secondary hepatic malignancy and that further studies will help to make it more specific.