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.

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.

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.

[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.

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.

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.