Circulating L-arginine predicts the survival of cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the systemic approach to cancer treatment. Most patients receiving ICIs, however, do not derive benefits. Therefore, it is crucial to identify reliable predictive biomarkers of response to ICIs. One important pathway in regulating immune cell reactivity is L-arginine (ARG) metabolism, essential to T-cell activation. We therefore aimed to evaluate the association between baseline plasma ARG levels and the clinical benefit of ICIs. PATIENTS AND METHODS: The correlation between ARG levels and clinical ICI activity was assessed by analyzing plasma samples obtained before treatment onset in two independent cohorts of patients with advanced cancer included in two institutional molecular profiling programs (BIP, NCT02534649, n = 77; PREMIS, NCT03984318, n = 296) and from patients in a phase 1 first-in-human study of budigalimab monotherapy (NCT03000257). Additionally, the correlation between ARG levels and ICI efficacy in preclinical settings was evaluated using a syngeneic mouse model of colorectal cancer responsive to ICIs. Using matched peripheral blood mononuclear cell (PBMC) plasma samples, we analyzed the correlation between ARG levels and PBMC features through multiplexed flow cytometry analysis. RESULTS: In both discovery and validation cohorts, low ARG levels at baseline (<42 µM) were significantly and independently associated with a worse clinical benefit rate, progression-free survival, and overall survival. Moreover, at the preclinical level, the tumor rejection rate was significantly higher in mice with high baseline ARG levels than in those with low ARG levels (85.7% versus 23.8%; P = 0.004). Finally, PBMC immunophenotyping showed that low ARG levels were significantly associated with increased programmed death-ligand 1 expression in several immune cell subsets from the myeloid lineage. CONCLUSIONS: We demonstrate that baseline ARG levels predict ICI response. Plasma ARG quantification may therefore represent an attractive biomarker to tailor novel therapeutic regimens targeting the ARG pathway in combination with ICIs.

Management of urinary tract infections, decubitus ulcer and pneumonia in the aging person

Infections in the older person are common and a significant cause of morbidity and mortality. Infections of the urinary tract, skin and soft tissue infections including decubitus ulcers, antibiotics associated diarrhea and lower respiratory tract infections are particularly important in the elderly because of their frequency. While most initial antibiotic therapy is empiric, its important before treatment to try to document the etiology for better use of antibiotics. Infections of the urinary tract are frequently and potentially serious in the elderly, they must be separated from asymptomatic bacteriuria that requires no therapy. Upper and lower urinary tract infections are frequently caused by aerobic gram negative bacilli and or enterococci. Most authors prefer the use of fluoroquinolones to manage such infections. The elderly with decubitus ulcer presents a problem in management, since these are frequent polymicrobic infections in which anaerobes play an important role. The initial therapy usually involves the combination of a fluoroquinolone plus an antianaerobic agent like clindamycin. C. difficile diarrhea as frequent in nursing home residents as well as the older person with prior antibiotics. The treatment should be with metronidazole and avoid the use of vancomycin. Pneumonias in the elderly can be acquired in the community, the nursing home or during a hospitalization. The etiologic agents that predominate change from S. pneumoniae and atypicals in those from the community to an increase in gram negative pneumonia. The initial treatment as started by most authors as well as guidelines include the use of a new fluoroquinolone like gatifloxacin alone or in combination with a beta-lactamic agent like ceftriaxone. For those infections acquired in the hospital therapy with third or fourth generation cephalosporins, carbapenems, beta-lactams with betalactamase inhibitors alone or in combination with an aminoglucoside and or vancomycin if MRSA is suspected is accepted therapy

[Screening for mild cognitive impairment: usefulness of the 7-Minute Screen Test]. / Detección de deterioro cognitivo leve en asistencia primaria. Utilidad del Test de los Siete Minutos.

INTRODUCTION: The <<7- Minute Screen>> is a neurocognitive screening test for the detection of Alzheimer's disease (AD) patients in primary care settings. It consists of 4 brief subtests (orientation, memory, visuoconstruction and verbal fluency) and provides a broader neuropsychological profile than other widely used screening tests, The aim of the present study was to study the usefulness of this screening test for the detection of Mild Cognitive Impairment (MCI). METHODS: Thirty-two patients with probable AD (NINCDS-ADRDA criteria), 25 patients with MCI, and 35 healthy control subjects, matched for age and education, underwent a comprehensive neuropsychological battery and the Rio-de-la-Plata version of the 7-Minute Screen. RESULTS. This test showed 93 % sensitivity and 97% specificity in detecting mild-moderate Alzheimer's disease MMSE<24), but it exhibited a substantially decreased sensitivity (28 %) in its ability to detect MCI in AD (MMSE >2 4 ). CONCLUSION: The screening batteries do not replace a m o re compre h e n s i ve neuro psychological assessment. Th ey are useful in detecting patients with mild dementia, but caution must be the rule when considering a diagnosis of MCI.

[High-dose-rate brachytherapy in esophageal carcinoma: the Italian experience]. / Brachiterapia con alto rateo di dose del carcinoma esofageo: esperienza italiana.

The results are reported of HDR intracavitary brachytherapy in 134 esophageal carcinoma patients (110 men and 24 women) treated in 10 Italian centers. Forty-one patients received radical treatment and brachytherapy was often combined with external irradiation and/or chemotherapy. Clinical response rates follow: 56% complete remissions, 34% partial remissions, 10% no response/disease progression and not assessed. Ninety-three patients underwent palliative treatment: dysphagia was reduced in 80% of them and pain was reduced in 71% of them. Treatment-induced esophageal damage consisted in G3-G4 esophagitis (5% of patients), strictures (10%) and fistulas (3%). Complication rates were correlated with fraction dose (9.5% complications for fraction doses < 500 cGy, 20% with doses ranging 500-800 cGy and 38% with fraction doses > 800 cGy). Moreover, the esophagus was more severely injured when small tubes were used (24% with tubes phi < 2 mm, 19% with tubes phi 2-6 mm and 5% with tubes phi > 6 mm). When external irradiation was combined with brachytherapy, dysphagia was more relieved than with brachytherapy alone (89% vs. 71%), with no increase in complication rates. Also the chemotherapy-brachytherapy combination improved swallowing more than brachytherapy alone (88% vs. 79%) and once again complication rates did not increase. To conclude, in the radical treatment of esophageal carcinoma, HDR brachytherapy permits higher radiation doses to be delivered, with fair complication rates. As for palliative treatment, HDR brachytherapy is safe, has low morbidity and provides adequate relief of dysphagia in 80% of patients. We suggest the use of tubes phi > 6 mm and fraction doses ranging 5-6 Gy.

[Multitest evaluation of the immune status of patients with bronchogenic carcinoma before and after radiotherapy]. / Valutazione con multitest dello stato immunitario nei pazienti con carcinoma broncogeno prima e dopo la radioterapia.

Sixty-two patients with lung cancer underwent the multitest before and after radiotherapy so as to assess the initial immune state and modifications induced by radiation therapy. In cancer patients, a significantly smaller number of positive skin reactions were encountered than in the controls. No statistically significant differences emerged between patients grouped on the basis of histotype, clinical stage and performance or otherwise of surgery. In living patients, higher values were observed than in patients who died. After radiotherapy, multitest values underwent a very slight decrease.