Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience.

BACKGROUND: Encorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage. PATIENTS AND METHODS: This real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019. RESULTS: Out of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome. CONCLUSIONS: Our real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.

Neurotoxicity and ototoxicity of cisplatin plus paclitaxel in comparison to cisplatin plus cyclophosphamide in patients with epithelial ovarian cancer.

PURPOSE: To compare the neurotoxicity and ototoxicity of combination cisplatin plus paclitaxel versus cisplatin plus cyclophosphamide using extensive clinical and instrumental evaluation. PATIENTS AND METHODS: Forty-six of 51 consecutive patients affected by-epithelial ovarian cancer seen in our institution between October 1994 and August 1995 entered the study. After randomization, they were assigned to receive cisplatin 75 mg/m2 every 3 weeks associated with cyclophosphamide 750 mg/m2 (CC group, n = 22) or paclitaxel 175 mg/m2 over a 3-hour infusion (CP group, n = 24). Treatment was repeated six times in 43 patients and nine times in 25. Before treatment and after three, six, and nine courses of chemotherapy, patients underwent clinical and instrumental neurologic and otologic examinations. RESULTS: Mild sensory impairment was evident even after only three courses of both treatments and signs and symptoms were more severe at the end of treatment. On clinical grounds only, it was possible to demonstrate after six and nine courses a difference between CC and CP treatment, due to the involvement in some CP patients of pain and thermal sensory modalities. However, the overall severity of the neuropathy was similar. Audiometric parameters demonstrated a more negative outcome after treatment in CC compared with CP patients. However, the different severity of the involvement was closely correlated to this initial difference in audiologic performance. CONCLUSION: Up to nine courses of chemotherapy, the CC and CP schedules are similar in terms of severity of neurotoxicity and ototoxicity when patients are evaluated during and immediately after treatment. With the doses used in our study, these toxicities are not dose-limiting. Our results suggest that most of the toxic effects observed during the treatment were due to cisplatin.

Risk factors for the development of severe cisplatin neurotoxicity.

Cisplatin sensory neuropathy is not equally severe in all patients and may progress even after drug withdrawal. A major goal in cisplatin chemotherapy would be the identification of early predictors of an unfavorable neurological outcome in order to adjust the schedules of administration. The final neurological outcome of 63 women treated with the same schedule of cisplatin (CDDP) was compared with the general demographic and oncological parameters and with the baseline neurological results. No definite association could be drawn between any of the parameters evaluated and peripheral neuropathy. Further studies are needed to investigate the individual factors which are at the basis of the remarkable variability of this severe side effect of CDDP.

Cryoglobulinaemic neuropathy: lack of progression in patients with good haematological control.

Nine consecutive patients with essential mixed cryoglobulinaemia type II (EMCII) were investigated by a follow-up study of 3-6 years (mean 5.3), to verify the long-term outcome of the peripheral nerve involvement in the disease. At the beginning of the study, a peripheral neuropathy, mild or moderate, mainly sensory, was present approximately in 50% of cases. All patients maintained good general conditions, low-staging of EMCII, were well controlled by therapy or did not need any medical treatment. During the neurological follow-up all patients had regular controls, usually at 1-year intervals, and only slight changes were seen with respect to the first evaluation. Therefore, we conclude that peripheral neuropathy during EMCII is less progressive that it can be thought at least in patients with benign course of the disease.

Sural nerve bioptic findings in essential cryoglobulinemic patients with and without peripheral neuropathy.

Peripheral neuropathy often occurs in cryoglobulinemia but the pathogenesis of the peripheral nerve involvement is not completely understood, so that the relation between the reported endoneural changes and neuropathy is not clear. In this study we compared the sural nerve biopsies of 6 cryoglobulinemic patients with or without signs of peripheral neuropathy and all affected by the essential mixed type II form (ECII) and, moreover, of 8 age-matched controls. We found that in all the patients with neuropathy, axonopathy occurred and it was invariably associated with endoneural vessel damage. Moreover, the fiber losses were patchily distributed within the nerve fascicles. On the contrary both nerve fibers and vessels were normal in the patients without clinical and neurophysiological evidence of neuropathy and in controls. Our results support the hypothesis that the endoneural damage observed during ECII is not simply coincidental, but is relevant in the pathogenesis of cryoglobulinemic neuropathy. They also favor the assumption that ischemic damage of the nerve fibers occurs during ECII.

A survey of the necessity of the hospitalization day in an Italian teaching hospital.

To assess the extent of inappropriate hospital use in an adult in-patients population we used a modified version of the Appropriateness Evaluation Protocol (A.E.P.) to evaluate retrospectively a cross-section of 273 patient-days in a large teaching hospital in the Greater Milan area. Overall, 41% were judged to represent inappropriate hospital use on the basis of the protocol's criteria. The rate of inappropriate hospital use was significantly associated with admitting specialty, ranging from 12% for surgery, to 20% for cardiology and to about 60% in psychiatric, geriatrics and neurology departments (p less than 0.01). Hospital days of patients with longer stays were more frequently inappropriate: a statistically significant trend of inappropriateness emerged ranging from 30% among patients with total length of stay (LOS) of 1-10 days to 60% among those with LOS greater than 30 days (p less than 0.01). This study confirms that there is a substantial rate of unnecessary use of hospitals but that such inappropriateness does not seem in most cases to be easily modifiable through "simple" organizational changes.

A clinico-pathological and follow up study of 10 cases of essential type II cryoglobulinaemic neuropathy.

Ten patients with essential cryoglobulinaemia type II were examined for peripheral nerve damage. In six cases distal symmetrical nerve involvement was present, while in three other cases abnormalities restricted to single nerves were found. Electrophysiological and morphological data were consistent with axonal damage, the larger myelinated fibres being most affected. Although active signs of vasculitis and immunoperoxidase staining for immunoglobulins were not present, endoneurial vessels were widely damaged, with abnormally thick endothelial cells and redundant basal membranes. These findings, together with a patchy distribution of myelinated fibre loss, suggest ischaemia as a cause of peripheral neuropathy during essential cryoglobulinaemia type II. A follow up examination, performed one year after haematologial remission, revealed that no further peripheral nerve damage had occurred.

Anticonvulsant drugs and bone metabolism.

The influence of chronic antiepileptic treatment on bone metabolism has been investigated in 52 adult epileptics, who had normal dietary intake, sunlight exposure and daily living activities. None of the patients had symptoms or signs suggestive of osteomalacia. Serum phosphate levels were significantly decreased and serum alkaline phosphatase levels were significantly increased in the patients compared with matched controls. Calcitonin values and bone mineral content, measured by single photon absorptiometry, were significantly lower among anticonvulsant users. Calcium metabolism impairment grossly correlated to the number of drugs concurrently used by the patient but not to the types, to the relative plasma concentrations or to the overall duration of the treatment. Our findings indicate that in ambulatory patients with adequate diet and outdoor activities in Italy present with clinically irrelevant impairment of bone metabolism.

Application of substoichiometric radioisotopic dilution to extraction of trace-level cadmium.

A substoichiometric isotopic dilution method was coupled to the standard addition technique for the determination of trace-level cadmium. 109Cd carrier-free as a radiotracer and extraction with dithizone in chloroform were used. A preconcentration procedure, which also cuts down the main interferences, for tap and natural waters was suggested. The sensitivity and accuracy of the method are discussed.

Trithiozine polyneuropathy: clinical, neurophysiological and histopathological study of three cases.

3 peptic ulcer patients, treated for a few weeks with Trithiozine, developed polyneuropathy. The histopathological patterns in the 2 patients in whom sural nerve biopsy was done presented wallerian degeneration of the axons of the myelinated fibers, especially those of larger caliber. The evidence for a iatrogenic toxic etiology is discussed.