Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases.

BACKGROUND: There is little evidence on KRAS mutational profiles in colorectal cancer (CRC) peritoneal metastases (PM). This study aims to determine the prevalence of specific KRAS mutations and their prognostic value in a homogeneous cohort of patients with isolated CRC PM treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS: Data were collected from 13 Italian centers, gathered in a collaborative group of the Italian Society of Surgical Oncology. KRAS mutation subtypes have been correlated with clinical and pathological characteristics and survival [overall survival (OS), local (peritoneal) disease-free survival (LDFS) and disease-free survival (DFS)]. RESULTS: KRAS mutations occurred in 172 patients (47.5%) out of the 362 analyzed. Two different prognostic groups of KRAS mutation subtypes were identified: KRASMUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRASMUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRASMUT2 mutations mainly occurred in the P-loop region (P < 0.001) with decreased guanosine triphosphate (GTP) hydrolysis activity (P < 0.001) and were more frequently related to size (P < 0.001) and polarity change (P < 0.001) of the substituted amino acid (AA). When KRASMUT1 and KRASMUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRASMUT1 showed a similar survival rate to KRASWT patients, whereas KRASMUT2 was independently associated with poorer prognosis (hazard ratios: OS 2.1, P < 0.001; DFS 1.9, P < 0.001; LDFS 2.5, P < 0.0001). CONCLUSIONS: In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

Leg Lymphoedema After Inguinal and Ilio-Inguinal Lymphadenectomy for Melanoma: Results from a Prospective, Randomised Trial.

BACKGROUND: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema. METHODS: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex®) > 10 or change of L-Dex® > 10 from baseline. RESULTS: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection. CONCLUSIONS: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study's small sample did not have the statistical evidence to support an overall difference between the surgical groups.

Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Long term oncologic outcomes from the international PSOGI registry.

The laparoscopic approach for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (L-CRS + HIPEC) in highly selected patients was previously reported from the PSOGI registry with a demonstrable reduction in length of stay and post-operative morbidity. This study aims to update this international PSOGI registry with a larger cohort of patients and a longer follow-up period. METHODS: An international registry was designed through a networking database (REDCAP®). All centers performing L-CRS + HIPEC were invited through PSOGI to submit data on their cases. Variables such as demographics, clinical outcomes, and survival were analyzed. RESULTS: A total of 315 L-CRS + HIPEC cases were provided by 14 worldwide centers. A total of 215 patients were included in the L-CRS + HIPEC group. The median peritoneal cancer index (PCI) was 3 (3-5). The median length of stay was 7 days (5-10) and the major morbidity (Clavien-Dindo ≥3) was 6.1% after 30 days. The 5-year disease-free survival (DFS) per tumor origin was: 94% for PMP-LG, 85% for PMP-HG, 100% for benign multicyst peritoneal mesothelioma (MPM), 37.4% for colonic origin, and 54%(at 3 years) for ovarian origin. The 5 years overall survival (OS) per tumor origin was: 100% for PMP-LG, PMP-HG and MPM; 61% for colonic origin, and 74% (at 3 years) for ovarian origin. In addition, a total of 85 patients were analyzed in the laparoscopic risk-reducing HIPEC (L-RR + HIPEC). The median length of stay was 5 days (4-6) and the major morbidity was 6% after 30 days. The 5-year DFS per tumor origin was: 96% for perforated low grade appendiceal mucinous neoplasm (LAMN II) and 68.1% for colon origin. The 5 years OS per tumor origin was: 98% for LAMN II and 83.5% for colonic origin. CONCLUSIONS: Minimally invasive CRS + HIPEC is a safe procedure for selected patients with peritoneal carcinomatosis in specialized centers. It improves perioperative results while providing satisfactory oncologic outcomes. L-RR + HIPEC represents a promising strategy that could be evaluated in patients with high risk of developing peritoneal carcinomatosis into prospective randomized trials.

External multicentre validation of pseudomyxoma peritonei PSOGI-Ki67 classification.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignant disease. Adding of the Ki67 proliferation index to the PSOGI PMP classification provided two different subcategories of the extensive HG-PMP group (HG-PMP ≤15% and HG-PMP >15%) with different survival in a previous unicentric study. This study aims to carry out an external and multicentre validation of this new proposed classification. METHOD: It was a prospective analysis of samples from a historical and international cohort of patients. A representative area with higher cellular density was used to determine the Ki67%. The Ki67 proliferation index (%) was determined in all the HG-PMP patients. A Cox proportional hazard models and multivariable COX models were used. The Kaplan-Meier method and the two-tailed log-rank test were used to analyse the effect of different PSOGI-Ki67 categories on OS and DFS. Its predictive accuracy was analysed using Harrel's C-index and the ROC curve. The calibration was performed using the calibration plots matching. RESULTS: After exclusions, 349 patients were available for analysis. The 5-years OS were 86% for LG-PMP, 59% for HG-PMP≤15, 38% for HG-PMP>15 and 42% for SRC-PMP (p = 0.0001). The 5-years DFS were 49% for LG-PMP, 35% for HG-PMP≤15, 16% for HG-PMP>15 and 18% SRC-PMP (p = 0.0001). The discrimination capability of PSOGI-Ki67 was validated. CONCLUSION: the PSOGI-Ki67 classification discriminates and predicts the OS and DFS in patients with PMP dividing the HG-PMP category into two well-defined sub-categories. The Ki67 proliferation index should be incorporated routinely in the pathology report for these patients.

Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for limited peritoneal metastasis. The PSOGI international collaborative registry.

INTRODUCTION: A laparoscopic approach for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (L-CRS+HIPEC) in highly selected patients has been reported in small cohorts with a demonstrable reduction in length of stay and post-operative morbidity. This study aims to analyse individual patient data from these international centres collected through the Peritoneal Surface Oncology Group International (PSOGI) L-CRS+HIPEC registry. METHODS: An international registry was designed through a networking database (REDCAP®). All centres performing L-CRS+HIPEC were invited through PSOGI to submit data on their cases. Patient's characteristics, postoperative outcomes and survival were analysed. RESULTS: Ten international centres contributed a total of 143 L-CRS+HIPEC patients during the study period. The most frequent indication was low grade pseudomyxoma peritonei in 79/143 (55%). Other indications were benign multicyst mesothelioma in 21/143(14%) and peritoneal metastasis from colon carcinoma in 18/143 (12,5%) and ovarian carcinoma in 13/143 (9%). The median PCI was 3 (2-5). The median length of stay was 6 (5-10) days, with 30-day major morbidity rate of 8.3% and 30-day mortality rate of 0.7%. At a median follow-up of 37 (16-64) months 126/143 patients (88.2%) were free of disease. CONCLUSIONS: Analysis of these data demonstrates that L-CRS+HIPEC is a safe and feasible procedure in highly selected patients with limited peritoneal disease when performed at experienced centres. While short to midterm outcomes are encouraging in patients with less invasive histology, longer follow up is required before recommending it for patients with more aggressive cancers with peritoneal dissemination.

Prospective observational study on the complications and tolerability of a peripherally inserted central catheter (PICC) in neuro-oncological patients.

PURPOSE: The use of central venous catheters with peripheral insertion (PICC) has increased rapidly in recent years, particularly in cancer patients. The benefits provided may occasionally be affected by relevant complications, such as infections and thrombotic events, especially in neuro-oncological patients. To date, the risk of PICC-related complications in this subset of patients is unknown, as is tolerability. As a primary objective, this study aimed to collect complications related to PICCs in primary neuro-oncological patients. As a secondary objective, the study aimed to evaluate PICC tolerability. METHODS: Neuro-oncological patients with PICCs that were placed as part of normal clinical practice at IRCCS Neurologico C. Besta were consecutively enrolled in the study. PICC-related complications were recorded immediately (during the procedure), early (within 1 week after PICC insertion), and late (1-3-5 months after PICC placement). At the same time points, all patients were also evaluated for tolerability through interviews with semi-structured, open-ended questions. RESULTS: Sixty patients were enrolled (41 males and 19 females, with a median age of 56.2 years). Excluding loss to follow-up, 33/49 patients developed at least one complication related to the PICC. Immediate complications mainly included hematoma (8), accidental arterial puncture (4), and primary malpositioning (3). Regarding early and late complications, 3 device-related infections, 8 thrombotic events, and 20 mechanical complications were registered. Semi-structured interviews revealed an overall positive experience with the device. The most negative impact was on hygiene habits, with 34 patients becoming caregiver-dependent. Over time, almost all patients became used to the device and perceived greater security during chemotherapy. A strongly negative issue was the difficulty of relying on competently trained healthcare personnel in outpatient setting. CONCLUSION: The results showed a nonnegligible increased thromboembolic risk in neuro-oncological patients with PICCs, almost double that in historical oncological populations. It is essential to extend the study to a greater number of patients to achieve reliable results and to identify patients at high risk. The device seems to be positively accepted by the majority of patients, without affecting activities of daily living.

The current practice of cytoreductive surgery and HIPEC for colorectal peritoneal metastases: Results of a worldwide web-based survey of the Peritoneal Surface Oncology Group International (PSOGI).

BACKGROUND: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice. METHODS: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and countrywide practice. RESULTS: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies. CONCLUSION: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed.

Measuring the quality of melanoma surgery - Highlighting issues with standardization and quality assurance of care in surgical oncology.

In an attempt to ensure high standards of cancer care, there is increasing interest in determining and monitoring the quality of interventions in surgical oncology. In recent years, this has been particularly the case for melanoma surgery. The vast majority of patients with melanoma undergo surgery. Usually, this is with combinations of wide excision, sentinel lymph node biopsy and lymphadenectomy. The indications for these procedures evolved during a time when no effective systemic adjuvant therapy was available, and whilst the rationale has been sound, the justification for differences in extent and thoroughness has generally been supported by inadequate or low-level evidence. This has led to a substantial variation among melanoma centres or even among surgeons within a centre in how these procedures are done. With recent rapid progress in the efficacy of systemic treatments that are impacting on overall survival, the prospect of long-term survival in these previously high risk patients means that more than ever long-term locoregional control of melanoma is imperative. Furthermore, the understanding of effects of systemic therapy on locoregional disease will only be interpretable if surgeons use standardized, high quality techniques. This article focuses on standardization and evolution of quality indicators for melanoma surgery and how these might have a positive impact on patient care.

Videoscopic ilioinguinal lymphadenectomy for groin lymph node metastases from melanoma.

BACKGROUND: Groin lymph node dissection for melanoma is burdened by high postoperative morbidity. Videoscopic lymphadenectomy may lower the incidence of complications, including infection, dehiscence and lymphoedema. This pilot study aimed to investigate the feasibility and postoperative outcomes of videoscopic ilioinguinal lymphadenectomy in patients with inguinal nodal melanoma metastases. METHODS: Patients with inguinal nodal metastases, with either a positive sentinel lymph node biopsy or clinically positive nodes from melanoma, were enrolled. Inguinal dissection was performed via three ports. Iliac dissection was obtained through a preperitoneal access. Intraoperative and postoperative data were collected. RESULTS: Of 23 patients selected for 24 procedures, four needed conversion to an open procedure. Median duration of surgery was 270 (i.q.r. 245-300) min. Wound-related postoperative complications occurred in four patients, although only one needed further intervention. The median number of excised lymph nodes was 21 (i.q.r. 15-25). After a median follow-up of 18 months, regional lymph node recurrence was observed in two patients. CONCLUSION: Videoscopic ilioinguinal lymphadenectomy for melanoma groin lymph node metastases is technically feasible, safe, and associated with acceptable morbidity and oncological outcome.

Video endoscopic inguinal lymphadenectomy for lymph node metastasis from solid tumors.

AIM: Inguinal lymphadenectomy (IL) is the standard treatment for inguinal lymph node (LN) metastases from genitourinary neoplasm and other cutaneous malignancies. Video endoscopic inguinal lymphadenectomy (VEIL) is emerging as a new modality for treating inguinal LN metastasis, with the aim of reducing post-operative complications. However, the safety and effectiveness of this new approach is still unclear. METHOD: A systematic literature review was performed. Patient characteristics, selection criteria, intra-operative data, number of excised LNs and post-operative outcomes were extracted and described for each study. RESULTS: Ten series that encompassed data of 236 procedures performed in 168 patients were reviewed. The conversion to traditional IL rates ranged between 0 and 7.7%. Median/mean operation time varied between 60 and 245 min. Wound-related complications and lymphatic collection/seroma ranged between 0 and 13.3% and 4 and 38.4%, respectively. The median/mean number of excised inguinal LNs ranged between 7 and 16. Although only four studies reported a follow-up time longer then 2 years, local recurrence rate was up to 6.6%. CONCLUSIONS: VEIL is safe and feasible for experienced surgeons with advanced laparoscopic skills and familiarity with groin anatomy. The post-operative morbidity appears lower compared to the open procedure, mainly for wound/skin related complications. The number of harvested LN and the regional recurrence rate is comparable to that of conventional groin dissection. Before VEIL technique can be considered suitable for routine clinical practice, comparable oncological outcomes and lower post-operative morbidity should be assessed in a randomized controlled trial.

Defining and developing expertise in tracheal intubation using a GlideScope(®) for anaesthetists with expertise in Macintosh direct laryngoscopy: an in-vivo longitudinal study.

Although videolaryngoscopy can provide excellent views of the laryngeal structures as both the primary method of tracheal intubation and as a rescue technique for difficult direct laryngoscopy, the existing literature is inadequate to define expertise or even competence. We observed the performance of nine trainees during 890 intubations, with an additional 72 intubations performed by expert anaesthetists used as a control group. Univariate and multivariate mixed-effects logistic regression models were applied to detect potential predictors of successful intubation and define the number of intubations necessary for a trainee to achieve expertise (> 90% probability of optimal performance). Optimal performance was predicted by single laryngoscope insertion (p < 0.001) and a Cormack and Lehane grade-1 view (p < 0.001), and not by normal lifting force applied to the device (p = 0.15), with expertise reached after 76 attempts. These results indicate that expertise in videolaryngoscopy requires prolonged training and practice.

Standardization and quality control of surgical treatment of cutaneous melanoma: looking for consensus of the Italian melanoma intergroup.

BACKGROUND: Quality of surgical care can be an important contributor to differences in survival among patients, and this suggests considerable potential for quality improvement in surgery of melanoma. Although clinical practice guidelines (CPG) for melanoma have been produced by various organizations, none address in detail some aspects of care related to surgery, and this brings about a quite heterogeneous surgical approach. Thus, Quality Assurance (QA) programs in melanoma surgery are essential. METHODS: Using the RAND/UCLA Appropriateness Method, an Italian panel of expert surgeons and pathologists belonging to the Italian Melanoma Intergroup (IMI) were invited to vote on statements regarding surgical treatment of melanoma and potential quality indicators for QA. All statements/indicators were scored for appropriateness and judged as valid in cases of 90% agreement. RESULTS: Consensus was obtained on 15 statements regarding indications for and extent of surgery (wide excision, sentinel node biopsy and lymphadenectomy) and on 7 QA indicators suitable to measure surgical performance for internal audit. CONCLUSIONS: The obtained consensus represents the basis to start a standardized QA program in Italy. The benchmark values of each indicator will be completed and updated according to the forthcoming results of the Clinical National Melanoma Registry (CNMR). Promoting a QA program at each IMI institution should increase the standard of care for melanoma patients in Italy.

Upper limb muscular activity and perceived workload during laryngoscopy: comparison of Glidescope(R) and Macintosh laryngoscopy in manikin: an observational study.

BACKGROUND: The interaction between operators and their working environment during laryngoscopy is poorly understood. Numerous studies have focused on the forces applied to the patient's airway during laryngoscopy, but only a few authors have addressed operator muscle activity and workload. We tested whether different devices (Glidescope(®) and Macintosh) use different muscles and how these differences affect the perceived workload. METHODS: Ten staff anaesthetists performed three intubations with each device on a manikin. Surface electromyography was recorded for eight single muscles of the left upper limb. The NASA Task Load Index (TLX) was administered after each experimental session to evaluate perceived workload. RESULTS: A consistent reduction in muscular activation occurred with Glidescope(®) compared with Macintosh for all muscles tested (mean effect size d=3.28), and significant differences for the upper trapezius (P=0.002), anterior deltoid (P=0.001), posterior deltoid (P=0.000), and brachioradialis (P=0.001) were observed. The overall NASA-TLX workload score was significantly lower for Glidescope(®) than for Macintosh (P=0.006), and the factors of physical demand (P=0.008) and effort (P=0.006) decreased significantly. CONCLUSIONS: Greater muscular activity and workload were observed with the Macintosh laryngoscope. Augmented vision and related postural adjustments related to using the Glidescope(®) may reduce activation of the operator's muscles and task workload.

Factors affecting false-negative rates on ex vivo sentinel lymph node mapping in colorectal cancer.

PURPOSE: Despite the increasing use of sentinel lymph node (SLN) mapping after colorectal cancer resection, reported node identification and false-negative rates vary considerably. The main aim of this prospective study was to quantify the false-negative rates on SLN mapping after resection and to evaluate factors influencing them. METHODS: Sixty-nine patients with biopsy-proven cancer of the colon and rectum underwent SLN mapping according to a protocol involving the ex vivo submucosal and peritumoral injection of 2-4 ml of Patent Blue V dye. All lymph nodes visualized were marked as SLN and totally embedded, then two 4 microm sections were cut for hematoxylin and eosin staining, and cytokeratin (AE1/AE3) immunostaining. A standard examination of the whole specimen and of the regional non-sentinel lymph nodes was also performed. RESULTS: SLNs were identified in 97.3% of the evaluable cases. A mean of 5.0 SLNs were removed per patient (SD+/-4.2). Nine false negatives were identified. Rectal cancer, tumor size>60mm, number of metastatic non-sentinel lymph nodes, and mucinous tumors were associated with false-negative SLNs. At multivariate analysis, a rectal location and mucinous differentiation were independently associated with false-negative SLNs. CONCLUSIONS: Ex vivo SLN mapping after colorectal cancer surgery is technically feasible with a high identification rate. Tumor size and stage, rectal involvement and a mucinous histology seem to interfere with the reliability of SLN staging. It is mandatory to standardize the procedure and selection criteria in order to deal with the question of the reliability of SLN mapping in colorectal cancer.

Anastomotic leaks after anterior resection for mid and low rectal cancer: survey of the Italian Society of Colorectal Surgery.

BACKGROUND: The aim of the survey was to assess the incidence of anastomotic leaks (AL) and to identify risk factors predicting incidence and gravity of AL after low anterior resection (LAR) for rectal cancer performed by colorectal surgeons of the Italian Society of Colorectal Surgery (SICCR). METHODS: Information about patients with rectal cancers less than 12 cm from the anal verge who underwent LAR during 2005 was collected retrospectively. AL was classified as grade I to IV according to gravity. Fifteen clinical variables were examined by univariate and multivariate analyses. Further analysis was conducted on patients with AL to identify factors correlated with gravity. RESULTS: There were 520 patients representing 64% of LAR for rectal cancer performed by SICCR members. The overall rate of AL was 15.2%. Mortality was 2.7% including 0.6% from AL. The incidence of AL was correlated with higher age (p<0.05), lower (<20 per year) centre case volume (p<0.05), obesity (p<0.05), malnutrition (p<0.01) and intraoperative contamination (p<0.05), and was lower in patients with a colonic J-pouch reservoir (p<0.05). In the multivariate analysis age, malnutrition and intraoperative contamination were independent predictors. The only predictor of severe (grade III/IV) AL was alcohol/smoking habits (p<0.05) while the absence of a diverting stoma was borderline significant (p<0.07). CONCLUSION: Our retrospective survey identified several risk factors for AL. This survey was a necessary step to construct prospective interventional studies and to establish benchmark standards for outcome studies.

An experimental swine model of small bowel cross transplantation.

AIM: In this study we evaluated the possibility of performing a cross small bowel transplantation (CrSBTx) in which, at the same time, 2 pigs were both donors and later recipients of intestinal grafts. The hemodynamic and metabolic impact of this original transplantation model on the animals was determined. METHODS: Ten large White adult female pigs underwent a 2 stage procedure. The principal intraoperative hemodynamic and metabolic parameters were measured at different times during the operation. In the 3 days that followed the operation, renal function, liver and pancreatic damage were investigated. RESULTS: Our surgical model permits us to keep excellent hemodynamic and metabolic stability with low mortality. CONCLUSION: The need of half of animals with respect to conventional models represents an ethical and economic advantage of CrSBTx and we propose it for intestinal transplant studies in large animals.