Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Second-line treatment strategies for RAS wild-type colorectal cancer: A systematic review and Network Meta-analysis (NMA).

BACKGROUND: The optimal strategy for second-line (IIL) treatment in KRAS wt metastatic colorectal cancer (mCRC) is not determined yet. METHODS: A random-effect NMA of phase II/III RCTs was conducted to evaluate IIL treatment for all-RAS wt mCRC, comparing anti-EGFR or anti-VEGF, and chemotherapy (CT). RESULTS: Overall, 11 RCTs (3613 patients) were included. In KRAS wt patients, PFS was improved with anti-VEGF (HR 0.43) and anti-EGFR (HR 0.63) vs CT. However, anti-VEGF based therapy had the highest likelihood of being ranked as the best treatment in terms of PFS (SUCRA 99.3%) and OS (SUCRA 99.4%). Bevacizumab-based treatment is most likely to be the best treatment in terms of PFS (SUCRA 89.1%) and OS (SUCRA 86.7%). CONCLUSIONS: Second line treatment with anti-VEGF and anti-EGFR improved PFS in mCRC patients, however, anti-VEGF based therapy, particularly CT plus bevacizumab, is the best treatment according to SUCRA in terms of PFS and OS.

T-DM1 versus pertuzumab, trastuzumab and a taxane as first-line therapy of early-relapsed HER2-positive metastatic breast cancer: an Italian multicenter observational study.

BACKGROUND: The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. PATIENTS AND METHODS: We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian 'real-world' setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. RESULTS: Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095). CONCLUSIONS: Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.

Do platinum salts fit all triple negative breast cancers?

Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options and poor prognosis once metastatic. Pre-clinical and clinical data suggest that TNBC could be more sensitive to platinum-based chemotherapy, especially among BRCA1/2-mutated patients. In recent years, several randomised trials have been conducted to evaluate platinum efficacy in both early-stage and advanced TNBC, with conflicting results especially for long-term outcomes. Experimental studies are now focusing on identifying biomarkers of response to help selecting patients who may benefit most from platinum-based therapies, including BRCA1/2 mutational status and genomic instability signatures (such as HRD-LOH or HRD-LST scores). A standard therapy for TNBC is still missing and platinum-based regimens represent an emerging therapeutic option for selected patients with a defect in the homologous recombination repair system. The identification of these patients through validated biomarker assays will be crucial to optimize the use of currently approved agents in TNBC.

Modified percutaneous ethanol injection of parathyroid adenoma in primary hyperparathyroidism.

Surgery is the treatment of choice for symptomatic primary hyperparathyroidism; unlikely few patients do not meet established surgical criteria or have comorbid conditions that prohibit surgery. In these subjects, medical therapy alone offers little hope for a sustained long normocalcemic period. However percutaneous ethanol injection (PEI) may represent an alternative therapeutic procedure. It is currently in use for the treatment of secondary or tertiary hyperparathyroidism, however, few studies or case reports suggest it for the treatment of primary hyperparathyroidism. Moreover, little information is available about the long-term follow-up, where incomplete necrosis or the spreading of ethanol in the surrounding tissues is often reported. We believe that many of the side effects could be correlated to procedure itself. Taking these experiences into account, we have reasoned that in order to limit these side effects, we had to modify the standard PEI procedure. We reported this preliminary experience describing our modified PEI procedure.

Osteitis fibrosa cystica, coeliac disease and Turner syndrome. A case report.

Today, osteitis fibrosa cystica is seldom present in primary hyperparathyroidism while it is mainly observed in uraemic osteodystrophy. We describe the case of a 54-year-old woman who was found to have huge bone cysts due to osteitis fibrosa cystica in the long bones. A parathyroid adenoma was identified and removed. Coeliac disease and Turner syndrome were diagnosed. Metabolic bone disease due to secondary hyperparathyroidism is common in coeliac disease; however, osteitis fibrosa cystica has not yet been described.

[Prevalence and aggressiveness of thyroid carcinoma with diameter less than one centimetre in iodine deficiency areas]. / Prevalenza ed aggressività del carcinoma tiroideo nei noduli con diametro inferiore al centimetro in aree iodio carenti.

BACKGROUND: The introduction of highly sensitive imaging techniques has made it possible to detect many non-palpable thyroid nodules with size less than 1 centimetre. The prevalence of these lesions appears to be high in the general population and increases in iodine deficiency areas. Fine needle aspiration biopsy (FNAB) is considered the most reliable test for the diagnosis of thyroid nodules. METHODS: From January 1991 to December 2000, 6627 nodules were referred for FNAB to our department. In 4871 (73.5%) euthyroid patients the mean daily urinary excretion of iodine was 73+/-18 micromg/day. RESULTS: In 2401 nodules (36.2%) the diameter was less than one centimetre. Histologic confirmation of malignancy was available in 187 (89.9%) of 208 operated nodules with diameter more than 1 cm and in 64 (78%) of 82 with diameter less than 1 cm. Logistic regression analysis indicated that a solid hypoechoic feature was a useful criterion to predict malignancy (p<0.001), as well as the presence of calcification (p<0.5) and blurred margins (p<0.5). Lymph node metastases were present in 24.3% of carcinomas with diameter more than 1 cm but, surprisingly, also in 20.3% of those with diameter less than 1 cm. No correlation was seen between diameter of carcinoma nodules and presence of lymph node metastasis. CONCLUSIONS: These data suggest that the potential malignancy of thyroid nodules is not only correlated to the diameter but to other parameters such as the biological difference of thyroid cancer that could be hypothesized in an iodine deficiency area. In conclusion, FNAB is recommended for nodules with diameter less than 1 centimetre when sonographic findings suggest malignancy such as a hypoechoic pattern, an irregular margin or internal microcalcification.

Etiology of hepatocellular carcinoma in Italian patients with and without cirrhosis.

We performed a case-control study to assess the role of hepatitis B virus (HBV), hepatitis C virus (HCV), GB virus C/hepatitis G virus (HGV), TT virus, alcohol intake, and tobacco smoking as risk factors for hepatocellular carcinoma (HCC) in the presence or absence of cirrhosis. We prospectively recruited 174 patients with a first diagnosis of HCC admitted to the main hospitals in Brescia, North Italy. On the basis of histological, clinical, and radiological criteria, the presence of cirrhosis was established in 142 cases, excluded in 21 cases, and remained undefined in 11 cases. Among the HCC cases without cirrhosis, a histological picture of normal liver was found in a single patient, chronic viral hepatitis was found in 11 patients, alcoholic hepatitis was found in 5 patients, nonspecific reactive hepatitis was found in 3 patients, and hemochromatosis was found in 1 patient. As controls, we also included 610 subjects unaffected by hepatic diseases and admitted to the same hospitals as cases. The odds ratios for having HCC according to positivity for HCV RNA, HBsAg and/or HBV DNA, and alcohol intake > 80 g/day (95% confidence interval) were as follows, in the presence and absence of cirrhosis, respectively: (a) 33.5 (17.7-63.4) and 19.7 (6-64.8) for HCV RNA; (b) 17.6 (9.0-34.4) and 20.3 (5.7-72.6) for HBsAg; and (c) 5.5 (3.1-9.7) and 4.6 (1.5-13.8) for alcohol intake. No association was found with HGV or TT virus infections or tobacco. This study has shown that most HCC cases arising in the area are due to HBV, HCV, or alcohol intake, in both the presence and absence of cirrhosis.

Recurrent Salmonella sepsis and aortitis in a patient with hepatocellular carcinoma.

A 62 years old man was admitted to hospital because of fever; a small superficial hepatic nodule was showed by ultrasonography. Blood cultures grew Salmonella enteritidis. Cefotaxime was administered for ten days. Fever promptly disappeared but one week later recurred with abdominal and back pain. Cultures grew again Salmonella enteritidis. Biopsy of the hepatic nodule showed hepatocarcinoma. Computed abdominal tomography showed a paraaortic mass. Angiography demonstrated hematoma communicating with the aortic lumen. The patient underwent revascularization of the involved aortic tract and resection of the hepatic nodule. Histology showed suppurative aortic endarteritis and a well-differentiated hepatocellular carcinoma with a large area of suppurative necrosis. The recovery of Salmonella species as of any uncommon bacteria from blood should warrant a through research of underlying disease, especially cancer.

Ultrasound guided percutaneous fine-needle biopsy in a case of eosinophilic gastroenteritis.

Eosinophilic gastroenteritis is a rare disease; clinical features depend on which intestinal layer is involved. In our report a 70-year-old woman presented with intestinal subocclusion and ascites. Endoscopic biopsies of gastric mucosa were negative. Ultrasound guided percutaneous fine-needle biopsy showed muscle infiltration by eosinophils of muscle layer of the stomach and jejunum. Muscular and serosal disease are usually diagnosed only by laparotomy or laparoscopy.

Bacteriological and clinical evaluation of cefotetan in the treatment of severe infections in hospitalized patients.

The authors studied 302 hospitalized patients, 164 males and 138 females aged 15-88 years (average 66 years), with severe infections. Cefotetan was administered to 278 of them at the dose of 1 or 2 g, b.i.d. or a single daily dose i.m. Other patients [24] were treated with a continuous intravenous infusion of cefotetan (3 g daily in 5% dextrose). Of these patients 121 were treated for urinary tract infections (UTI); 114 for respiratory tract infections (RTI); 41 for liver biliary duct infections (BDI); 17 for skin or skin structure infections (SKI); 6 for fever of unknown origin and 3 for sepsis. The following Gram-positive organisms [156] were isolated: Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus group D; and the following Gram-negative organisms [122]: Escherichia coli, Proteus vulgaris, Proteus mirabilis, Serratia spp., Klebsiella spp., Haemophilus influenzae and Pseudomonas aeruginosa. The overall eradication rate for Gram-positive organisms was 74% and for Gram-negative organisms it was 88%. The clinical response was satisfactory in 87.7% of patients (specifically, cefotetan was effective in 90% of UTI, 84.2% of RTI, 97.5% of BDI and 82.3% of SKI). The drug was well tolerated and side-effects (such as skin rash, diarrhoea, purpura and pain at the site of injection) occurred in only 4% of patients treated with cefotetan. In conclusion, cefotetan appears to be safe and highly effective for the treatment of severe infections in hospitalized patients.