Intraoperative left-sided colorectal anastomotic testing in clinical practice: a multi-treatment machine-learning analysis of the iCral3 prospective cohort.

BACKGROUND: Current evidence about intraoperative anastomotic testing after left-sided colorectal resections is still controversial. The aim of this study was to analyze the impact of Indocyanine Green fluorescent angiography (ICG-FA) and air-leak test (ALT) over standard assessment on anastomotic leakage (AL) rates according to surgeon's perception of anastomosis perfusion and/or integrity in clinical practice. METHODS: A database of 2061 patients who underwent left-sided colorectal resections was selected from patients enrolled in a prospective multicenter study. It was retrospectively analyzed through a multi-treatment machine-learning model considering standard visual assessment (NW; No. = 899; 43.6%) as the reference treatment arm, compared to ICG-FA alone (WP; No. = 409; 19.8%), ALT alone (WI; No. = 420; 20.4%) or both (WPI; No. = 333; 16.2%). Twenty-four covariates potentially affecting the outcomes were included and balanced into the model within the subgroups. The primary endpoint was AL, the secondary endpoints were overall morbidity (OM), major morbidity (MM), reoperation for AL, and mortality. All the results were reported as odds ratio (OR) with 95% confidence intervals (95%CI). RESULTS: The WPI subgroup showed significantly higher AL risk (OR 1.91; 95% CI 1.02-3.59; p 0.043), MM risk (OR 2.35; 95% CI 1.39-3.97; p 0.001), and reoperation for AL risk (OR 2.44; 95% CI 1.12-5.31; p 0.025). No other significant differences were recorded. CONCLUSIONS: This study showed that the surgeons' perception of both anastomotic perfusion and integrity (WPI subgroup) was associated to a significantly higher risk of AL and related morbidity, notwithstanding the extensive use of both ICG-FA and ALT testing.

Bowel preparation for elective colorectal resection: multi-treatment machine learning analysis on 6241 cases from a prospective Italian cohort.

BACKGROUND: Current evidence concerning bowel preparation before elective colorectal surgery is still controversial. This study aimed to compare the incidence of anastomotic leakage (AL), surgical site infections (SSIs), and overall morbidity (any adverse event, OM) after elective colorectal surgery using four different types of bowel preparation. METHODS: A prospective database gathered among 78 Italian surgical centers in two prospective studies, including 6241 patients who underwent elective colorectal resection with anastomosis for malignant or benign disease, was re-analyzed through a multi-treatment machine-learning model considering no bowel preparation (NBP; No. = 3742; 60.0%) as the reference treatment arm, compared to oral antibiotics alone (oA; No. = 406; 6.5%), mechanical bowel preparation alone (MBP; No. = 1486; 23.8%), or in combination with oAB (MoABP; No. = 607; 9.7%). Twenty covariates related to biometric data, surgical procedures, perioperative management, and hospital/center data potentially affecting outcomes were included and balanced into the model. The primary endpoints were AL, SSIs, and OM. All the results were reported as odds ratio (OR) with 95% confidence intervals (95% CI). RESULTS: Compared to NBP, MBP showed significantly higher AL risk (OR 1.82; 95% CI 1.23-2.71; p = .003) and OM risk (OR 1.38; 95% CI 1.10-1.72; p = .005), no significant differences for all the endpoints were recorded in the oA group, whereas MoABP showed a significantly reduced SSI risk (OR 0.45; 95% CI 0.25-0.79; p = .008). CONCLUSIONS: MoABP significantly reduced the SSI risk after elective colorectal surgery, therefore representing a valid alternative to NBP.

Oral Antibiotics Alone versus Oral Antibiotics Combined with Mechanical Bowel Preparation for Elective Colorectal Surgery: A Propensity Score-Matching Re-Analysis of the iCral 2 and 3 Prospective Cohorts.

The evidence regarding the role of oral antibiotics alone (oA) or combined with mechanical bowel preparation (MoABP) for elective colorectal surgery remains controversial. A prospective database of 8359 colorectal resections gathered over a 32-month period from 78 Italian surgical units (the iCral 2 and 3 studies), reporting patient-, disease-, and procedure-related variables together with 60-day adverse events, was re-analyzed to identify a subgroup of 1013 cases (12.1%) that received either oA or MoABP. This dataset was analyzed using a 1:1 propensity score-matching model including 20 covariates. Two well-balanced groups of 243 patients each were obtained: group A (oA) and group B (MoABP). The primary endpoints were anastomotic leakage (AL) and surgical site infection (SSI) rates. Group A vs. group B showed a significantly higher AL risk [14 (5.8%) vs. 6 (2.5%) events; OR: 3.77; 95%CI: 1.22-11.67; p = 0.021], while no significant difference was recorded between the two groups regarding SSIs. These results strongly support the use of MoABP for elective colorectal resections.

Abdominal drainage after elective colorectal surgery: propensity score-matched retrospective analysis of an Italian cohort.

BACKGROUND: In Italy, surgeons continue to drain the abdominal cavity in more than 50 per cent of patients after colorectal resection. The aim of this study was to evaluate the impact of abdominal drain placement on early adverse events in patients undergoing elective colorectal surgery. METHODS: A database was retrospectively analysed through a 1:1 propensity score-matching model including 21 covariates. The primary endpoint was the postoperative duration of stay, and the secondary endpoints were surgical site infections, infectious morbidity rate defined as surgical site infections plus pulmonary infections plus urinary infections, anastomotic leakage, overall morbidity rate, major morbidity rate, reoperation and mortality rates. The results of multiple logistic regression analyses were presented as odds ratios (OR) and 95 per cent c.i. RESULTS: A total of 6157 patients were analysed to produce two well-balanced groups of 1802 patients: group (A), no abdominal drain(s) and group (B), abdominal drain(s). Group A versus group B showed a significantly lower risk of postoperative duration of stay >6 days (OR 0.60; 95 per cent c.i. 0.51-0.70; P < 0.001). A mean postoperative duration of stay difference of 0.86 days was detected between groups. No difference was recorded between the two groups for all the other endpoints. CONCLUSION: This study confirms that placement of abdominal drain(s) after elective colorectal surgery is associated with a non-clinically significant longer (0.86 days) postoperative duration of stay but has no impact on any other secondary outcomes, confirming that abdominal drains should not be used routinely in colorectal surgery.

Mechanical bowel preparation in elective colorectal surgery: a propensity score-matched analysis of the Italian colorectal anastomotic leakage (iCral) study group prospective cohorts.

Retrospective evaluation of the effects of mechanical bowel preparation (MBP) on data derived from two prospective open-label observational multicenter studies in Italy regarding elective colorectal surgery. MBP for elective colorectal surgery remains a controversial issue with contrasting recommendations in current guidelines. The Italian ColoRectal Anastomotic Leakage (iCral) study group, therefore, decided to estimate the effects of no MBP (treatment variable) versus MBP for elective colorectal surgery. A total of 8359 patients who underwent colorectal resection with anastomosis were enrolled in two consecutive prospective studies in 78 surgical centers in Italy from January 2019 to September 2021. A retrospective PSMA was performed on 5455 (65.3%) cases after the application of explicit exclusion criteria to eliminate confounders. The primary endpoints were anastomotic leakage (AL) and surgical site infections (SSI) rates; the secondary endpoints included SSI subgroups, overall and major morbidity, reoperation, and mortality rates. Overall length of postoperative hospital stay (LOS) was also considered. Two well-balanced groups of 1125 patients each were generated: group A (No MBP, true population of interest), and group B (MBP, control population), performing a PSMA considering 21 covariates. Group A vs. group B resulted significantly associated with a lower risk of AL [42 (3.5%) vs. 73 (6.0%) events; OR 0.57; 95% CI 0.38-0.84; p = 0.005]. No difference was recorded between the two groups for SSI [73 (6.0%) vs. 85 (7.0%) events; OR 0.88; 95% CI 0.63-1.22; p = 0.441]. Regarding the secondary endpoints, no MBP resulted significantly associated with a lower risk of reoperation and LOS > 6 days. This study confirms that no MBP before elective colorectal surgery is significantly associated with a lower risk of AL, reoperation rate, and LOS < 6 days when compared with MBP.

Three-row versus two-row circular staplers for left-sided colorectal anastomosis: a propensity score-matched analysis of the iCral 2 and 3 prospective cohorts.

BACKGROUND: Since most anastomoses after left-sided colorectal resections are performed with a circular stapler, any technological change in stapling devices may influence the incidence of anastomotic adverse events. The aim of the present study was to analyze the effect of a three-row circular stapler on anastomotic leakage and related morbidity after left-sided colorectal resections. MATERIALS AND METHODS: A circular stapled anastomosis was performed in 4255 (50.9%) out of 8359 patients enrolled in two prospective multicenter studies in Italy, and, after exclusion criteria to reduce heterogeneity, 2799 (65.8%) cases were retrospectively analyzed through a 1:1 propensity score-matching model including 20 covariates relative to patient characteristics, to surgery and to perioperative management. Two well-balanced groups of 425 patients each were obtained: group (A) - true population of interest, anastomosis performed with a three-row circular stapler; group (B) - control population, anastomosis performed with a two-row circular stapler. The target of inferences was the average treatment effect in the treated (ATT). The primary endpoints were overall and major anastomotic leakage and overall anastomotic bleeding; the secondary endpoints were overall and major morbidity and mortality rates. The results of multiple logistic regression analyses for the outcomes, including the 20 covariates selected for matching, were presented as odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Group A versus group B showed a significantly lower risk of overall anastomotic leakage (2.1 vs. 6.1%; OR 0.33; 95% CI 0.15-0.73; P =0.006), major anastomotic leakage (2.1 vs. 5.2%; OR 0.39; 95% CI 0.17-0.87; P =0.022), and major morbidity (3.5 vs. 6.6% events; OR 0.47; 95% CI 0.24-0.91; P =0.026). CONCLUSION: The use of three-row circular staplers independently reduced the risk of anastomotic leakage and related morbidity after left-sided colorectal resection. Twenty-five patients were required to avoid one leakage.

Blood Transfusions and Adverse Events after Colorectal Surgery: A Propensity-Score-Matched Analysis of a Hen-Egg Issue.

Blood transfusions are considered a risk factor for adverse outcomes after colorectal surgery. However, it is still unclear if they are the cause (the hen) or the consequence (the egg) of adverse events. A prospective database of 4529 colorectal resections gathered over a 12-month period in 76 Italian surgical units (the iCral3 study), reporting patient-, disease-, and procedure-related variables, together with 60-day adverse events, was retrospectively analyzed identifying a subgroup of 304 cases (6.7%) that received intra- and/or postoperative blood transfusions (IPBTs). The endpoints considered were overall and major morbidity (OM and MM, respectively), anastomotic leakage (AL), and mortality (M) rates. After the exclusion of 336 patients who underwent neo-adjuvant treatments, 4193 (92.6%) cases were analyzed through a 1:1 propensity score matching model including 22 covariates. Two well-balanced groups of 275 patients each were obtained: group A, presence of IPBT, and group B, absence of IPBT. Group A vs. group B showed a significantly higher risk of overall morbidity (154 (56%) vs. 84 (31%) events; OR 3.07; 95%CI 2.13-4.43; p = 0.001), major morbidity (59 (21%) vs. 13 (4.7%) events; OR 6.06; 95%CI 3.17-11.6; p = 0.001), and anastomotic leakage (31 (11.3%) vs. 8 (2.9%) events; OR 4.72; 95%CI 2.09-10.66; p = 0.0002). No significant difference was recorded between the two groups concerning the risk of mortality. The original subpopulation of 304 patients that received IPBT was further analyzed considering three variables: appropriateness of BT according to liberal transfusion thresholds, BT following any hemorrhagic and/or major adverse event, and major adverse event following BT without any previous hemorrhagic adverse event. Inappropriate BT was administered in more than a quarter of cases, without any significant influence on any endpoint. The majority of BT was administered after a hemorrhagic or a major adverse event, with significantly higher rates of MM and AL. Finally, a major adverse event followed BT in a minority (4.3%) of cases, with significantly higher MM, AL, and M rates. In conclusion, although the majority of IPBT was administered with the consequence of hemorrhage and/or major adverse events (the egg), after adjustment accounting for 22 covariates, IPBT still resulted in a definite source of a higher risk of major morbidity and anastomotic leakage rates after colorectal surgery (the hen), calling urgent attention to the implementation of patient blood management programs.

Circulating tumour cell gene expression and chemosensitivity analyses: predictive accuracy for response to multidisciplinary treatment of patients with unresectable refractory recurrent rectal cancer or unresectable refractory colorectal cancer liver metastases.

BACKGROUND: Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs). METHODS: In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected. RESULTS: Our analyses resulted in evaluations of 94.12% (95% CI 0.71-0.99) for sensitivity, 5.26% (95% CI 0.01-0.26) for specificity, a predictive value of 47.06% (95% CI 0.29-0.65) for a positive response, a predictive value of 50% (95% CI 0.01-0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30-0.64). CONCLUSIONS: This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials.

A Prospective Study of Intraarterial Infusion Chemotherapy in Advanced Wild-Type BRAF Melanoma Patients.

BACKGROUND: Treatment strategies for advanced cutaneous melanoma (CM) patients, resistant or not treatable with novel target and immunotherapeutic drugs, remain a significant challenge, particularly for patients with unresectable stage IIIC/D disease localized to inferior limbs and pelvis, for whom specific outcomes are rarely considered. MATERIALS AND METHODS: This is a prospective study of multidisciplinary treatments, including locoregional melphalan chemotherapy, in 62 BRAF wild-type CM patients with locoregional metastases in the inferior limbs and pelvis, including inguinal regions. Patients were either in progression following or ineligible for, or not treatable with novel immunotherapy. For exclusively inferior limb-localised disease, patients received locoregional melphalan chemotherapy performed by hyperthermic isolated limb perfusion (n = 19) or isolated limb infusion (n = 19), and for synchronous lesions localised to inferior limbs and pelvis, received hypoxic pelvic and limb perfusion (n = 24). Additional multidisciplinary therapy included local, locoregional and systemic treatments and the primary endpoint was tumour response. RESULTS: The objective response rate following first cycle of locoregional chemotherapy was 37.1% at 3 mo and median progression-free survival was 4-mo, with 12.9% procedure-related complications, 30.6% low-grade haematological toxicity and 11.3% severe limb toxic tissue reactions. Multivariate logistic regression showed that the odds of response were significantly higher for patients ≤ 75 y of age and for patients with locoregional metastases exclusively located in the inferior limbs. CONCLUSION: In this subgroup of CM patients with BRAF wild-type status, locoregional metastases localized to inferior limbs and pelvis, in progression following or ineligible for immunotherapy, melphalan locoregional chemotherapy demonstrated a safe and effective profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01920516; date of trial registration: August 6, 2013.

Breakthrough Cancer Pain Clinical Features and Differential Opioids Response: A Machine Learning Approach in Patients With Cancer From the IOPS-MS Study.

PURPOSE: A large proportion of patients with cancer suffer from breakthrough cancer pain (BTcP). Several unmet clinical needs concerning BTcP treatment, such as optimal opioid dosages, are being investigated. In this analysis the hypothesis, we explore with an unsupervised learning algorithm whether distinct subtypes of BTcP exist and whether they can provide new insights into clinical practice. METHODS: Partitioning around a k-medoids algorithm on a large data set of patients with BTcP, previously collected by the Italian Oncologic Pain Survey group, was used to identify possible subgroups of BTcP. Resulting clusters were analyzed in terms of BTcP therapy satisfaction, clinical features, and use of basal pain and rapid-onset opioids. Opioid dosages were converted to a unique scale and the BTcP opioids-to-basal pain opioids ratio was calculated for each patient. We used polynomial logistic regression to catch nonlinear relationships between therapy satisfaction and opioid use. RESULTS: Our algorithm identified 12 distinct BTcP clusters. Optimal BTcP opioids-to-basal pain opioids ratios differed across the clusters, ranging from 15% to 50%. The majority of clusters were linked to a peculiar association of certain drugs with therapy satisfaction or dissatisfaction. A free online tool was created for new patients' cluster computation to validate these clusters in future studies and provide handy indications for personalized BTcP therapy. CONCLUSION: This work proposes a classification for BTcP and identifies subgroups of patients with unique efficacy of different pain medications. This work supports the theory that the optimal dose of BTcP opioids depends on the dose of basal opioids and identifies novel values that are possibly useful for future trials. These results will allow us to target BTcP therapy on the basis of patient characteristics and to define a precision medicine strategy also for supportive care.

Immune response activation following hyperthermic intraperitoneal chemotherapy for peritoneal metastases: A pilot study.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases (PM) is considered to be feasible, safe and to improve survival. AIM: To investigate whether an immune response is activated following HIPEC for PM. METHODS: Six patients were enrolled in this study. Peripheral blood samples were obtained from each patient prior to (day 0) and post-procedure (day 30), and used to evaluate the number of CD3+ total, CD3+/CD4+ T-Helper, CD3+/CD8+ cytotoxic T, CD3+/CD56+ natural killer and CD19+ B lymphocyte numbers, and CD4+: CD8+ T lymphocyte ratios. RESULTS: The total numbers of CD3+, CD3+/CD4+ T-Helper, CD3+/CD8+ cytotoxic T, CD3+/CD56+ natural killer and CD19+ B lymphocytes, and CD4+: CD8+ lymphocyte ratios were increased in all but one patient 30 d following the cytoreductive surgery-HIPEC procedure, and these increases were significant (P ≤ 0.05) for CD3+/CD4+ T Helper and CD3+/CD8+ cytotoxic T lymphocyte numbers. CONCLUSION: This report provides the first evidence that HIPEC exhibits immunomodulating activity in PM patients, resulting in generalized activation of the adaptive immune response. Moreover, the majority of lymphocyte populations increased following HIPEC and continued to be elevated several weeks following the procedure, consistent with a potential authentic immunomodulating effect rather than a normal inflammatory response, to be fully characterised in future studies.

A Pilot Study of the Predictive Potential of Chemosensitivity and Gene Expression Assays Using Circulating Tumour Cells from Patients with Recurrent Ovarian Cancer.

Circulating tumour cells (CTCs) from liquid biopsies are under current investigation in several cancers, including epithelial ovarian cancer (EOC) but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic EOC CTCs, from 10 patients, nine with stage IIIC and one with stage IV disease, in progression after systemic chemotherapy, submitted for hypoxic isolated abdominal perfusion (HAP), are both feasible and useful in predicting response to therapy. Viable metastatic EOC CTCs (>5 cells/mL for all 10 blood samples), enriched by transient culture and identified by reverse transcription polymerase chain reaction (RT-PCR) and indirect immunofluorescence (IF), were subjected to flow cytometry-based Annexin V-PE assays for chemosensitivity to several chemotherapeutic agents and by RT-PCR for tumour gene expression profiling. Using a cut-off value of >80% cell death, CTC chemosensitivity tests were predictive of patient RECIST 1.1 responses to HAP therapy associated with 100% sensitivity, 50% specificity, 33% positive predictive, 100% negative predictive and 60% accuracy values. We propose that the methodology employed in this study is feasible and has the potential to predict response to therapy, setting the stage for a larger study.

Breakthrough Pain in Patients with Lung Cancer. A Secondary Analysis of IOPS MS Study.

AIM: To characterize breakthrough cancer pain (BTcP) in patients with lung cancer. METHODS: This was a secondary analysis of multicenter study of patients with BTcP. Background pain intensity and opioid dose were recorded. The number of BTcP episodes, their intensity, predictability, onset, duration and interference with daily activities were collected. Opioids used for BTcP, the mean time to meaningful pain relief after taking medication, satisfaction and adverse effects were assessed. RESULTS: 1087 patients with lung cancer were examined. In comparison with other tumors, patients with lung cancer showed: higher background pain intensity (p = 0.006), lower opioid doses (p = 0.005), higher intensity of BTcP (p = 0.005), movement (79.5%) and cough (8.2%), as principal triggers for predictable BTcP (p < 0.009), larger BTcP interference with daily activity (p = 0.0001), higher use of adjuvants (p = 0.0001). No relevant differences in the other parameters examined were found. CONCLUSION: Patients with lung cancer have their own peculiarities, including higher basal and BTcP pain intensity and the use of more adjuvant drugs for background pain. The most frequent triggers for predictable BTcP are movement and cough. Future studies should be performed to analyze the prevalence of BTcP in patients with different lung cancers as well as the optimal management strategy for background pain and BTcP.

Circulating tumour cell liquid biopsy in selecting therapy for recurrent cutaneous melanoma with locoregional pelvic metastases: a pilot study.

OBJECTIVES: Circulating tumour cells (CTCs) from liquid biopsies provide an exceptional opportunity to obtain real-time tumour information and are under current investigation in several cancers, including cutaneous melanoma, but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic melanoma (MM) CTCs, from 7 patients with stage IIIC, BRAF wild-type metastatic melanomas, localized exclusively to the pelvic region, un-eligible for immunotherapy and treated with melphalan hypoxic pelvic perfusion (HPP), is both feasible and useful in predicting response to therapy. Viable MM CTCs (> 5 cells/ml for all 7 blood samples), enriched by transient culture, were characterised in flow cytometry-based Annexin V-PE assays for chemosensitivity to several drugs. RESULTS: Using melphalan as a standard, chemosensitivity cut-off values of > 60% cell death, were predictive of patient RECIST 1.1 response to melphalan HPP therapy, associated with calculated 100% sensitivity, 66.67% specificity, 33.33% positive predictive, 100% negative predictive, and 71.43% accuracy values. We propose that the methodology in this study is both feasible and has potential value in predicting response to therapy, setting the stage for a larger study. Trial registration Clinical Trials.gov Identifier NCT01920516; date of trial registration: August 6, 2013.

Real-life multidisciplinary treatment for unresectable colorectal cancer liver metastases including hepatic artery infusion with chemo-filtration and liquid biopsy precision oncotherapy: observational cohort study.

BACKGROUND: Hepatic artery infusion (HAI) and drug selection by liquid biopsy precision oncotherapy are under investigation for the multidisciplinary treatment of unresectable colorectal liver metastases (CRCLM) in progression after systemic therapy. Here, we compare the safety and efficacy of third-line HAI followed by target therapy with drug regimes selected by liquid biopsy precision oncotherapy to third-line systemic therapy with drug regimes selected partly by tissue biopsy precision oncotherapy, in a retrospective real-life study of 106 unresectable CRCLM patients. METHODS: Drug regimens for HAI/target therapy were selected by assessing the sensitivity of purified circulating tumor cell (CTCs) to 5-fluorouracil, carboplatin, cisplatin, oxaliplatin, irinotecan, doxorubicin, mitomycin, raltitrexed, and melphalan in-vitro and by real-time qRT-PCR gene expression assays, and for the Systemic therapy cohort were selected by age, comorbidity, performance status, and absence of RAS mutations. Therapeutic responses, adverse events, and quality of life were evaluated by RECIST 1.1, CTCAE 4.03, and ECOG criteria, respectively, and chemo-filtration performed following HAI to reduce systemic toxic effects. RESULTS: HAI/target therapy with drugs selected by liquid biopsy precision oncotherapy (44 patients), resulted in 2.27% CRs, 38.63% PRs, 56.81% SD,s and 2.27% PDs; ECOG 2 to 1 improvement, but no infusion-related technical or vascular complications, or deaths. Systemic therapy (62 patients) resulted in 1.6% CRs, 17.74% PRs, 37.09% SDs, and 45.16% PDs; more grade 1-2 adverse events and 4.84% ECOG 1 to 2 worsening. The median 5 month PFS in the HAI/target therapy cohort was significantly longer than 3 months in the systemic cohort (P < 0.007) and the median 14 month survival in the HAI/target therapy cohort was longer than 8.5 months in the systemic therapy cohort but not statistically significant. Multivariate analysis identified ECOG grade 2 as the most unfavourable survival prognostic factor in both cohorts. CONCLUSIONS: HAI plus chemo-filtration followed by target therapy, with drug regimens selected by liquid biopsy precision oncotherapy, is a safe and efficacious alternative therapeutic strategy for unresectable CRCLM in progression after two lines of systemic therapy and should be considered for a multicentre prospective phase III study, to fully confirm this potential.

Breakthrough Cancer Pain in Patients Receiving Low Doses of Opioids for Background Pain.

BACKGROUND: This study aimed to assess the characteristics of breakthrough cancer pain (BTcP) in patients receiving low doses of opioids for background pain in comparison with patients receiving at least 60 mg of oral morphine equivalents (OME). MATERIALS AND METHODS: Patients with advanced cancer receiving less than 60 mg/day of OME with episodes of BTcP were included in the analysis (group L). Data were compared with patients receiving doses of opioids ≥60 mg of OME (group H). Pain intensity, current analgesic therapy, number of BTcP episodes, intensity of BTcP, its predictability and triggers, onset duration, interference with daily activities, BTcP medications, and time to meaningful pain relief were collected. Adverse effects imputable to a BTcP medication were recorded. RESULTS: A total of 1,418 and 2,474 patients were included in groups L and H, respectively. A lower number of BTcP episodes (p = .005), a lower BTcP intensity (p = .0001), a faster BTcP onset (p = .024), and a longer time to meaningful pain relief after taking a BTcP medication (p = .009) were found in group L as compared with group H. In group L, BTcP interference on daily activity was less than in group H (p = .009). Patients in group L were less likely to be prescribed an opioid as BTcP medication in comparison with patients in group H (p = .0001). Opioid doses used for BTcP were significantly higher in group H. Patients in group L were more likely to be less satisfied (p = .003) than patients in group H. No adverse effects of severe intensity were reported in both groups. CONCLUSION: Patients receiving lower doses of opioids exhibit some differences in BTcP presentation: fewer episodes with lower intensity and a faster onset, a longer time to meaningful pain relief, and less satisfaction with BTcP medication. A relevant percentage of patients was receiving fentanyl preparations normally reserved for patients receiving higher doses of opioids. IMPLICATIONS FOR PRACTICE: Breakthrough pain is present in patients receiving low doses of opioids. It has its own peculiarities: less frequent, lower intensity, faster onset, longer time to meaningful pain relief, and less satisfaction with medication. Many patients were prescribed fentanyl preparations, which are normally reserved for patients receiving higher doses of opioids.

Precision oncotherapy based on liquid biopsies in multidisciplinary treatment of unresectable recurrent rectal cancer: a retrospective cohort study.

BACKGROUND: Third line innovative systemic treatments and loco-regional chemotherapy by hypoxic pelvic perfusion (HPP) have both been proposed for the treatment of unresectable not responsive recurrent rectal cancer (URRC). In the present study, we have compared the safety and efficacy of HPP/target therapy, using drug regimens selected by liquid biopsy precision oncotherapy, to third-line systemic therapy based on tissue specimens precision oncotherapy. METHODS: HPP/target therapy regimens were selected based on precision oncotherapy, including assays for chemosensitivity and viability, and qRT-PCR for tumor-related gene expression. In the control group, systemic third-line and further lines of therapy were defined according to clinical and biological parameters. RESULTS: From 2007 to 2019, 62 URRC patients were enrolled, comprised of 43 patients in the HPP/target-therapy group and 19 patients in the systemic therapy control group. No HPP related complications were reported and the most common adverse events were skin and bone marrow toxicity. In the HPP/target-therapy group, the ORR was 41.8% whereas in the systemic therapy control group was 15.8%. DCR of the HPP/target-therapy group was significantly improved over the systemic therapy group (P = 0.001), associated with a PFS of 8 vs 4 months (P = 0.009), and OS of 20 vs 8 months (P = 0.046). CONCLUSIONS: The present data indicate that in URCC patients, the integration of HPP/target-therapy and precision oncotherapy based upon liquid biopsy is as effective and efficacious as third-line treatment in local disease control and, therefore, deserves to be further assessed and compared to conventional systemic treatments in future prospective randomized trials.

Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial.

BACKGROUND: The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis). METHODS AND FINDINGS: This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (ß: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (ß: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (ß: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (ß: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs. CONCLUSIONS: In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. TRIAL REGISTRATION: The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.

Multidisciplinary palliative treatment including isolated thoracic perfusion for progressive malignant pleural mesothelioma: a retrospective observational study.

PURPOSE: To investigate the relative importance of isolated thoracic perfusion (ITP) in the multidisciplinary palliative treatment of progressive malignant pleural mesothelioma (MPM) patients. METHODS: Fifty-two MPM patients with progressive disease after systemic chemotherapy with cisplatin and pemetrexed were submitted to 112 ITP using mitomycin C (25 mg/m2) and cisplatin (70 mg/m2) between 2000 and 2017. Isolation of the chest was achieved by insertion of stop-flow balloon catheters via femoral or iliac access. Primary endpoints were adverse events, tumor response rate, progression-free survival (PFS) and overall survival (OS) from initial ITP. RESULTS: Median interval-time from MPM diagnosis was 9 months. There were no perfusion-related postoperative deaths. The main procedure-related complication was persistent leakage of lymphatic fluid from the incision in less than 10% of ITP. No severe perfusion-related toxicity was reported, with grade 3 haematological toxicity and platinum-induced neurotoxicity in less than 8% of the patients. Following initial ITP, overall tumor response rate was 25%, median PFS was 7 months (IQR 5-10.5), and median OS was 16 months (IQR 12.5-21). After the last ITP, 14 patients received further therapies, including targeted therapy with cetuximab or bevacizumab. Non-epithelioid histology, stage III, and ECOG performance status 3 pre-ITP were prognostic factors with a significant influence on OS. Median OS, calculated from the diagnosis of MPM, was 26.5 months (IQR 22.5-28). CONCLUSIONS: ITP is safe, tolerable, and useful but its inclusion in the multidisciplinary palliative treatment of progressive MPM patients should be investigated in a larger multicentre controlled study.

Breakthrough pain in patients with head & neck cancer. A secondary analysis of IOPS MS study.

AIM: To characterize breakthrough pain (BTcP) in patients with Head and neck (H&N) cancer. METHODS: This was a secondary analysis of multicenter study of BTcP. Background pain intensity and opioid dose were recorded. The number of BTcP episodes, their intensity, predictability, onset, duration and interference with daily activities were collected. Opioids used for BTcP, and the mean time to meaningful pain relief after taking medication, were assessed. The presence of mucositis was also assessed. RESULTS: 205 patients with H&N cancer were examined. The mean number of BTcP episodes was 2.8/day, which was higher than in general population. The mean intensity of BTcP was 7.4. BTcP was more predictable in H&N cancer than in other tumors. The main trigger of predictable BTcP was the ingestion of food (76.5%). BTcP onset was fast in 148 patients (72.2%). The mean time to meaningful pain relief after taking a BTcP medication was 15.3 min and BTcP interference with daily activity was relevant in most patients (89.2%). Transdermal drugs and nasal fentanyl preparations were more frequently used for background pain and BTcP, respectively. A consistent number of patients with H&N cancer (38.5%) exhibited different levels of oral mucositis. CONCLUSION: BTcP in patients with H&N cancer is characterized by a larger number of episodes/day and the predictability, particularly with ingestion of food. The use of drugs for background analgesia and BTcP were conditioned by the possible interference with swallowing or local mucosal damage.