Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Synthesis of (Hetero)biaryls Through the Use of Diazonium Salts

The (hetero)biaryl structural motif, which is frequently found in natural products and commercially available agrochemicals and pharmaceuticals, exhibits significant bioactivities across a wide range of therapeutic classes, including antihypertensive, antifungal, antitumor, antirheumatic, and anti-inflammatory agents. Additionally, the (hetero)biaryl scaffold is a predominant feature in several functional organic materials such as liquid crystals for LCD screens, organic light-emitting diodes (OLEDs), organic photovoltaics and organic field effect transistor. For this reason, reactions able to join two (hetero)aromatic rings to form unsymmetrical (hetero)biaryls through the formation of a new σ Csp2-Csp2 bond are among the most widely used processes in the pharmaceutical, agrochemical and electronic industry and beyond. As a result, for over a century, organic chemists have sought to develop new and more efficient (hetero)aryl-(hetero)aryl bond-forming methods. In this context arenediazonium salts, since their discovery in 1858 by Peter Griess, have emerged as excellent reagents thanks to their highly versatile nature in organic synthesis, that comes from the unique properties of the diazonium linkage. In fact, their reactivity is expressed through a dinitrogen loss by heterolytic or homolytic dissociation into an aryl carbocation or aryl radical respectively, thus displaying large spectrum of reactivities that span from free-radical to organometallic chemistry. Furthermore, arenediazonium salts attracted and keep attract chemist because they combine several advantages as starting materials in organic synthesis: 1) they are easily prepared in large quantities from corresponding commercially available anilines; 2) their reactions take place at mild conditions; 3) the coupling reactions can proceed with high chemo- and regioselectivity; 4) the leaving group N2 does not interfere with the reaction mixture. The rich legacy of arenediazonium salts in the synthesis of (hetero)biaryls, built around the seminal works of Pschorr, Gomberg and Bachmann more than a century ago, continues to make important contributions at the various evolutionary stages of modern (hetero)biaryl synthesis. Thus, based on in-depth mechanistic analysis and design of novel pathways and reaction conditions, arenediazonium salts have been successfully employed in almost all type of transformation, from organometallic reactions such as Suzuki-Miyaura coupling, Stille coupling, Negishi coupling and Hiyama coupling through applications of transition metal/photoredox catalyst, to transition-metal free thermal, photochemical, and electrochemical radical chain reactions. In this way, the scope and ease of (hetero)biaryl synthesis with arenediazonium salts has enormously expanded and improved over the years through several researches, studies and efforts carried out by chemists all over the world. Recent developments have indeed provided a facile synthetic access to a wide variety of unsymmetrical (hetero)biaryl compounds of pharmaceutical, agrochemical, and optoelectronic importance with green scale-up options, and created opportunities for late-stage modification of important biological molecules such as peptides and nucleosides. Hence, regardless of the long history, arenediazonium salts still attract attention, and new developments have been emerging constantly. This thesis consists of two parts: a desk-based and an experimental one. In the desk-based part, the aim is to collect and summarize all the protocols reported in literature to date for the synthesis of (hetero)biaryl compounds involving aryldiazonium salts, highlighting the advantages and disadvantages of each procedure and reporting the possible applications in the industrial field. About the experimental part (interrupted by CoVid-19 pandemic), in literature there are very few reports regarding the direct and selective C−H direct arylation of azoles with aryldiazonium salts. In particular, in this context there are no studies about the arylation of imidazoles and their derivatives (1-methyl-1H-imidazole, 1,2-dimethyl-1H-imidazole, 1-methyl-1H-benzo[d]-imidazole, etc.). Therefore, intrigued by this unexplored field, and in view of the fact that azoles are ubiquitous features of biologically active natural products, pharmaceuticals and fluorescent dyes and synthetic protocols that enable the direct and selective elaboration of these heteroaromatics are invaluable tools for natural product synthesis and medicinal chemistry, I decided to develop new protocols for the selective and direct C−H arylation of imidazoles (and other azoles) with arenediazonium salts. Since I won the “Erasmus+ Traineeship” scholarship, the experimental part is formed by a study realized at the university of Pisa with prof. Fabio Bellina and one carried out at the university of Göttingen (Germany) under the supervision of prof. Lutz Ackermann. Regarding the first study, the goal was to develop the direct C−H arylation of imidazoles (and other azoles) with aryldiazonium salts in transition-metal free conditions. Through a preliminary study, I developed a (unfinished) catalyst-free procedure for the selective C−H arylation of 1,2-dimethyl-1H-imidazole, 1H-benzo[d]imidazole, 1-methyl-1H-benzo[d]-imidazole and 1H-pyrazole with electron-poor arenediazonium salts in mild conditions with moderate yields (5 examples, 28-58% yield). About the second study, the goal was to develop new protocols for the selective photoredox C−H arylation of imidazoles (and other heteroarenes) with arenediazonium salts through the use of manganese-based photocatalysts. However, unfortunately this study did not furnish the expected results due to its premature termination due to Covid-19 pandemia

Ligandless Palladium-Catalyzed Direct C-5 Arylation of Azoles Promoted by Benzoic Acid in Anisole

The palladium-catalyzed direct arylation of azoles with (hetero)aryl halides is nowadays one of the most versatile and efficient procedures for the selective synthesis of heterobiaryls. Although this procedure is, due to its characteristics, also of great interest in the industrial field, the wide use of a reaction medium such as DMF or DMA, two polar aprotic solvents coded as dangerous according to environmental, health, safety (EHS) parameters, strongly limits its actual use. In contrast, the use of aromatic solvents as the reaction medium for direct arylations, although some of them show good EHS values, is poorly reported, probably due to their low solvent power against reagents and their potential involvement in undesired side reactions. In this paper we report an unprecedented selective C-5 arylation procedure involving anisole as an EHS green reaction solvent. In addition, the beneficial role of benzoic acid as an additive was also highlighted, a role that had never been previously described

Predicting Functional Recovery and Quality of Life in Older Patients Undergoing Colorectal Cancer Surgery: Real-World Data From the International GOSAFE Study

PURPOSE The GOSAFE study evaluates risk factors for failing to achieve good quality of life (QoL) and functional recovery (FR) in older patients undergoing surgery for colon and rectal cancer.METHODS Patients age 70 years and older undergoing major elective colorectal surgery were prospectively enrolled. Frailty assessment was performed and outcomes, including QoL (EQ-5D-3L) recorded (3/6 months postoperatively). Postoperative FR was defined as a combination of Activity of Daily Living >= 5 + Timed Up & Go test <20 seconds + MiniCog >2.RESULTS Prospective complete data were available for 625/646 consecutive patients (96.9%; 435 colon and 190 rectal cancer), 52.6% men, and median age was 79.0 years (IQR, 74.6-82.9 years). Surgery was minimally invasive in 73% of patients (321/435 colon; 135/190 rectum). At 3-6 months, 68.9%-70.3% patients experienced equal/better QoL (72.8%-72.9% colon, 60.1%-63.9% rectal cancer). At logistic regression analysis, preoperative Flemish Triage Risk Screening Tool >= 2 (3-month odds ratio [OR], 1.68; 95% CI, 1.04 to 2.73; P = .034, 6-month OR, 1.71; 95% CI, 1.06 to 2.75; P = .027) and postoperative complications (3-month OR, 2.03; 95% CI, 1.20 to 3.42; P = .008, 6-month OR, 2.56; 95% CI, 1.15 to 5.68; P = .02) are associated with decreased QoL after colectomy. Eastern Collaborative Oncology Group performance status (ECOG PS) >= 2 is a strong predictor of postoperative QoL decline in the rectal cancer subgroup (OR, 3.81; 95% CI, 1.45 to 9.92; P = .006). FR was reported by 254/323 (78.6%) patients with colon and 94/133 (70.6%) with rectal cancer. Charlson Age Comorbidity Index >= 7 (OR, 2.59; 95% CI, 1.26 to 5.32; P = .009), ECOG >= 2 (OR, 3.12; 95% CI, 1.36 to 7.20; P = .007 colon; OR, 4.61; 95% CI, 1.45 to 14.63; P = .009 rectal surgery), severe complications (OR, 17.33; 95% CI, 7.30 to 40.8; P < .001), fTRST >= 2 (OR, 2.71; 95% CI, 1.40 to 5.25; P = .003), and palliative surgery (OR, 4.11; 95% CI, 1.29 to 13.07; P = .017) are risk factors for not achieving FR.CONCLUSION The majority of older patients experience good QoL and stay independent after colorectal cancer surgery. Predictors for failing to achieve these essential outcomes are now defined to guide patients' and families' preoperative counseling

Quality of life in older adults after major cancer surgery: the GOSAFE international study

Abstract Background Accurate quality of life (QoL) data and functional results after cancer surgery are lacking for older patients. The international, multicenter Geriatric Oncology Surgical Assessment and Functional rEcovery after Surgery (GOSAFE) Study compares QoL before and after surgery and identifies predictors of decline in QoL. Methods GOSAFE prospectively collected data before and after major elective cancer surgery on older adults (≥70 years). Frailty assessment was performed and postoperative outcomes recorded (30, 90, and 180 days postoperatively) together with QoL data by means of the three-level version of the EuroQol five-dimensional questionnaire (EQ-5D-3L), including 2 components: an index (range = 0-1) generated by 5 domains (mobility, self-care, ability to perform the usual activities, pain or discomfort, anxiety or depression) and a visual analog scale. Results Data from 26 centers were collected (February 2017-March 2019). Complete data were available for 942/1005 consecutive patients (94.0%): 492 male (52.2%), median age 78 years (range = 70-95 years), and primary tumor was colorectal in 67.8%. A total 61.2% of all surgeries were via a minimally invasive approach. The 30-, 90-, and 180-day mortality was 3.7%, 6.3%, and 9%, respectively. At 30 and 180 days, postoperative morbidity was 39.2% and 52.4%, respectively, and Clavien-Dindo III-IV complications were 13.5% and 18.7%, respectively. The mean EQ-5D-3L index was similar before vs 3 months but improved at 6 months (0.79 vs 0.82; P < .001). Domains showing improvement were pain and anxiety or depression. A Flemish Triage Risk Screening Tool score greater than or equal to 2 (odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.13 to 2.21, P = .007), palliative surgery (OR = 2.14, 95% CI = 1.01 to 4.52, P = .046), postoperative complications (OR = 1.95, 95% CI = 1.19 to 3.18, P = .007) correlated with worsening QoL. Conclusions GOSAFE shows that older adults’ preoperative QoL is preserved 3 months after cancer surgery, independent of their age. Frailty screening tools, patient-reported outcomes, and goals-of-care discussions can guide decisions to pursue surgery and direct patients’ expectations

A prospective cohort analysis of the prevalence and predictive factors of delayed discharge after laparoscopic cholecystectomy in Italy: the DeDiLaCo Study

Background: The concept of early discharge ≤24 hours after Laparoscopic Cholecystectomy (LC) is still doubted in Italy. This prospective multicentre study aims to analyze the prevalence of patients undergoing elective LC who experienced a delayed discharge >24 hours in an extensive Italian national database and identify potential limiting factors of early discharge after LC. Methods: This is a prospective observational multicentre study performed from January 1, 2021 to December 31, 2021 by 90 Italian surgical units. Results: A total of 4664 patients were included in the study. Clinical reasons were found only for 850 patients (37.7%) discharged >24 hours after LC. After excluding patients with nonclinical reasons for delayed discharge >24 hours, 2 groups based on the length of hospitalization were created: the Early group (≤24 h; 2414 patients, 73.9%) and the Delayed group (>24 h; 850 patients, 26.1%). At the multivariate analysis, ASA III class ( P <0.0001), Charlson's Comorbidity Index (P=0.001), history of choledocholithiasis (P=0.03), presence of peritoneal adhesions (P<0.0001), operative time >60 min (P<0.0001), drain placement (P<0.0001), pain ( P =0.001), postoperative vomiting (P=0.001) and complications (P<0.0001) were independent predictors of delayed discharge >24 hours. Conclusions: The majority of delayed discharges >24 hours after LC in our study were unrelated to the surgery itself. ASA class >II, advanced comorbidity, the presence of peritoneal adhesions, prolonged operative time, and placement of abdominal drainage were intraoperative variables independently associated with failure of early discharge

Effect of centre volume on pathological outcomes and postoperative complications after surgery for colorectal cancer: results of a multicentre national study

Background: The association between volume, complications and pathological outcomes is still under debate regarding colorectal cancer surgery. The aim of the study was to assess the association between centre volume and severe complications, mortality, less-than-radical oncologic surgery, and indications for neoadjuvant therapy.Methods: Retrospective analysis of 16,883 colorectal cancer cases from 80 centres (2018-2021). Outcomes: 30-day mortality; Clavien-Dindo grade >2 complications; removal of >= 12 lymph nodes; non-radical resection; neoadjuvant therapy. Quartiles of hospital volumes were classified as LOW, MEDIUM, HIGH, and VERY HIGH. Independent predictors, both overall and for rectal cancer, were evaluated using logistic regression including age, gender, AJCC stage and cancer site.Results: LOW-volume centres reported a higher rate of severe postoperative complications (OR 1.50, 95% c.i. 1.15-1.096, P = 0.003). The rate of >= 12 lymph nodes removed in LOW-volume (OR 0.68, 95% c.i. 0.56-0.85, P = 12 lymph nodes removed was lower in LOW-volume than in VERY HIGH-volume centres (OR 0.57, 95% c.i. 0.41-0.80, P = 0.001). A lower rate of neoadjuvant chemoradiation was associated with HIGH (OR 0.66, 95% c.i. 0.56-0.77, P < 0.001), MEDIUM (OR 0.75, 95% c.i. 0.60-0.92, P = 0.006), and LOW (OR 0.70, 95% c.i. 0.52-0.94, P = 0.019) volume centres (vs. VERY HIGH).Conclusion: Colorectal cancer surgery in low-volume centres is at higher risk of suboptimal management, poor postoperative outcomes, and less-than-adequate oncologic resections. Centralisation of rectal cancer cases should be taken into consideration to optimise the outcomes