Outcomes of chemotherapy/chemoradiation vs. R2 surgical debulking vs. palliative care in nonresectable locally recurrent rectal cancer.

Locally recurrent rectal cancer is resected with clear margins in only 50% of cases, and these patients achieve a three-year survival rate of 50%. Outcomes and therapeutic strategies for nonresectable locally recurrent rectal cancer have been much less explored. The aim of the study was to assess the three-year progression-free survival and the three-year overall survival in locally recurrent rectal cancer patients treated by chemotherapy/chemoradiation only vs. chemotherapy/chemoradiation and R2 surgical debulking vs. palliative care. A total of 86 patients affected by nonresectable locally recurrent rectal cancer were included: three-year progression-free survival was 15.8% with chemotherapy/chemoradiation vs. 20.3% with R2 surgical debulking (Log-rank p=0.567), but both rates were higher than best palliative care (0.0%, Log-rank p=0.0004). Three-year overall survival rates were respectively 62.0%, 70.8% and 0.0% (Log-rank p<0.0001). Chemotherapy/chemoradiation (HR 0.33, p=0.028) and R2 surgical debulking with or without chemotherapy/chemoradiation (HR 0.23, p=0.005) were independent predictors of improved progression-free survival on multivariate analysis. In conclusion, both chemotherapy/chemoradiation alone and R2 surgery with or without chemotherapy/chemoradiation provide a survival benefit over palliative care in nonresectable locally recurrent rectal cancer. However, considering that pelvic debulking is burdened by a high rate of complications, and considering its negligible impact on progression-free survival and overall survival when associated to medical therapy, surgery should be avoided in this setting.

Extraperitoneal lateral pelvic sidewall excision: a novel rectal-sparing approach for lateral locally recurrent rectal cancer.

Locally recurrent rectal cancer (LRRC) involving the lateral pelvic sidewall requires a complex approach to maximize the likelihood of R0 resection, which is the only predictor of survival. The purpose of this report is to describe a novel technique to resect a localized lateral pelvic sidewall LRRC. A 63-year-old male patient was referred for a 15-mm LRRC near the right internal iliac vessels. Endoscopic ultrasound and magnetic resonance imaging excluded any involvement of the pelvic colon or residual rectum. A combined extraperitoneal antero-lateral approach and gluteal access were used to optimize vascular control on the internal iliac vessels, to promptly identify the ureter and to achieve a better posterior exposition of the sciatic notch. This technique allowed a controlled and tailored resection of pelvic sidewall without entering into the abdominal cavity. The postoperative course was uneventful. The pathologic report confirmed clear margins (R0), with one involving obturator lymph node. At 3 months, the patient is alive and free from local re-relapse. A right lung metastasis has occurred, and it was treated by stereotactic radiotherapy. The present report proposes a novel extraperitoneal pelvic sidewall excision to resect lateral LRRC with a colorectal-sparing approach, thus minimizing the risk of exenterative surgery-related complications. A proper selection of patients is mandatory, as the proposed technique could not be generalized as the standard of care in all lateral LRRCs.

Special Issue "Current Management of Early and Advanced Rectal Cancer".

As expected, surgery for low or ultralow disease remains a challenging issue in rectal cancer treatment [...].

Impact of Microscopically Positive (≤1 mm) Distal Margins on Disease Recurrence in Rectal Cancer Treated by Neoadjuvant Chemoradiotherapy.

BACKGROUND: The adequate distal resection margin is still controversial in rectal cancer treated by neoadjuvant chemoradiotherapy (nCRT). The aim of this study was to assess the impact of a distal margin of ≤1 mm on locoregional recurrence-free survival (LRRFS). METHODS: Among 255 patients treated with nCRT and surgery at the National Cancer Institute of Milan, 83 (32.5%) had a distal margin of ≤1 mm and 172 (67.5%) had a distal margin of >1 mm. Survival analyses were performed to assess the impact of distal margin on 5-year LRRFS, as well as Cox survival analysis. The role of distal margin on survival was analyzed according to different tumor regression grades (TRGs). RESULTS: The overall 5-year LRRFS rate was 77.6% with a distal margin of ≤1 mm vs. 88.3% with a distal margin of >1 mm (Log-rank p = 0.09). Only stage ypT4 was an independent predictor of worse LRRFS (HR 15.14, p = 0.026). The 5-year LRRFS was significantly lower in TRG3-5 patients with a distal margin of ≤1 mm compared to those with a distal margin of >1 mm (68.5% vs. 84.2%, p = 0.027), while no difference was observed in case of TRG1-2 (p = 0.77). CONCLUSIONS: Low-responder rectal cancers after nCRT still require a distal margin of >1 mm to reduce the high likelihood of local relapse.

Liver Transplantation for Hepatic Metastases from Colorectal Cancer: Current Knowledge and Open Issues.

More than 40% of patients with colorectal cancer present liver metastases (CRLM) during the course of their disease and up to 50% present with unresectable disease. Without surgical interventions, survival for patients treated with systemic therapies alone is dismal. In the past, liver transplantation (LT) for patients with unresectable CRLM failed to show any survival benefit due to poor selection, ineffective chemotherapeutic regimens, unbalanced immunosuppression and high perioperative mortality. Since then and for many years LT for CRLM was abandoned. The turning point occurred in 2013, when the results from the Secondary Cancer (SECA I) pilot study performed at Oslo University were published reporting a 60% 5-year overall survival after LT in patients with unresectable CRLM. These results effectively reignited the interest in LT as a potential therapy for CRLM, and several trials are undergoing. The aims of this article are to give a comprehensive overview of the available evidence on LT for CRLM, discuss the open issues in this rapidly evolving field, and highlight possible ways to address the future of this fascinating therapeutic alternative for selected patients with CRLM.

Low baseline neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict increased overall survival in locally recurrent rectal cancer despite R1 margins.

BACKGROUND: Prognostic features in locally recurrent rectal cancer (LRRC), beyond R0 surgery, are unknown. AIMS: Aim of the present study was to evaluate the prognostic role of peripheral immune estimators, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), on survival outcomes in LRRC patients. METHODS: 184 LRRC patients treated at the National Cancer Institute of Milan (Italy) were included. Optimal cut-off values for NLR and PLR were determined. Kaplan-Meier curves and multivariate Cox analyses were used to assess the 5-yr overall survival (OS) according to NLR and PLR, also considering margins status. RESULTS: NLR >3.9 (hazard ratio [HR] 3.96, P = 0.049), PLR >275 (HR 5.39, P = 0.002) and size on imaging (HR 1.36, P = 0.044) were associated to worse OS. R+ patients with NLR >3.9 showed a significantly lower 5-yr OS compared to NLR ≤3.9 (13.5% vs. 36.7%, P < 0.0001). Also PLR >275 was related with a lower 5-yr OS compared to PLR ≤275 in R+ patients (6.4% vs. 36.8%, P = 0.0003). Conversely, NLR and PLR were irrelevant in case of R0 surgery. CONCLUSION: NLR and PLR predict 5-yr OS in LRRC, also identifying a subset of R+ patients with a similar expected survival compared to R0 cases.

Prediction of R0/R+ surgery by different classifications for locally recurrent rectal cancer.

A widely adopted classification system for locally recurrent rectal cancer (LRRC) is currently missing, and the indication for surgery is not standardized. To evaluate all the published classification systems in a large monocentric cohort of LRRC patients, assessing their capability to predict a radical (R0) resection. A total of 152 consecutive LRRC patients treated at the National Cancer Institute of Milan (NCIM) from 2009 to 2017 were classified according to Pilipshen, Mayo Clinic, Memorial Sloan-Kettering Cancer Center (MSKCC), Wanebo, Yamada, Boyle, Dutch TME Trial, Royal Marsden and National Cancer Institute of Milan (NCIM) classification systems. Central location of LRRC was significantly predictive of R0 resection across all classification systems. R + resection was predicted by the "anterior" category of MSKCC (OR 2.66, p = 0.007), the "S2b" (OR 3.50, p = 0.04) and the "S3" (OR 2.70, p = 0.01) categories of NCIM, "pelvic disease through anastomosis" of Pilipshen (OR 2.89, p = 0.002), "fixed at 2 sites" of Mayo Clinic (OR 2.68, p = 0.019), and "TR4" of Wanebo (OR 3.39, p = 0.002). The NCIM was the most predictive classification for R0 surgery. The NCIM classification seems to be superior among the others in predicting R0 surgery. Generally, lateral invasive and high sacral invasive relapses are associated with reduced probability of R0 surgery and unfavorable outcomes.

Neoadjuvant (re)chemoradiation for locally recurrent rectal cancer: Impact of anatomical site of pelvic recurrence on long-term results.

BACKGROUND: Selection criteria to propose neoadjuvant (re)chemoradiation (CHRT) in locally recurrent rectal cancer (LRRC) are required, since re-irradiation is sometimes associated to severe adverse effects. Aim of the present study was to compare chances of R0 surgery and disease-free survival (DFS) in LRRC patients (pts) treated by neoadjuvant (re)CHRT followed by surgery vs. upfront surgery, stratifying pts by each localization of LRRC. METHODS: LRRC pts treated at the National Cancer Institute of Milan (Italy) were retrospectively divided into two groups: neoadjuvant (re)CHRT vs. upfront surgery. According to our Milan classification, LRRC were categorized as S1, if located centrally (S1a-b) or anteriorly (S1c) within the pelvis; S2, in case of sacral involvement; S3, in case of lateral pelvic wall infiltration. RESULTS: 152 pts were candidate for multimodal treatment: 49 (32.2%) by neoadjuvant (re)CHRT and surgery, including 33 re-irradiations, vs. 103 (67.8%) by upfront surgery. No difference was observed in R0 resection rates (respectively 47.6% vs. 51.0%). However, neoadjuvant (re)CHRT followed by surgery improved the DFS (p = 0.028), also in R1 procedures (p = 0.013), compared with upfront surgery. At multivariate analysis, the R+ surgery (p < 0.0001) strongly predicted unfavorable DFS, while neoadjuvant (re)CHRT followed by surgery was independently associated to better DFS (p = 0.0197). Stratifying by LRRC localization, the combined approach significantly improved DFS in the S1c (p = 0.029) and S2 (p = 0.004) subgroups compared to upfront surgery, but not in S1a-b and S3 pts. CONCLUSION: Anterior (S1c) and sacral-invasive (S2) pelvic recurrences significantly benefit in terms of DFS by combination of neoadjuvant (re)CHRT and radical surgery, also after R1 resection.

A proposal of an updated classification for pelvic relapses of rectal cancer to guide surgical decision-making.

BACKGROUND AND OBJECTIVES: Selection of patients affected by pelvic recurrence of rectal cancer (PRRC) who are likely to achieve a R0 resection is mandatory. The aim of this study was to propose a classification for PRRC to predict both radical surgery and disease-free survival (DFS). METHODS: PRRC patients treated at the National Cancer Institute of Milan (Italy) were included in the study. PRRC were classified as S1, if located centrally (S1a-S1b) or anteriorly (S1c) within the pelvis; S2, in case of sacral involvement below (S2a) or above (S2b) the second sacral vertebra; S3, in case of lateral pelvic involvement. RESULTS: Of 280 reviewed PRRC patients, 152 (54.3%) were evaluated for curative surgery. The strongest predictor of R+ resection was the S3 category (OR, 6.37; P = .011). Abdominosacral resection (P = .012), anterior exenteration (P = .012) and extended rectal re-excision (P = .003) were predictive of R0 resection. S3 category was highly predictive of poor DFS (HR 2.53; P = .038). DFS was significantly improved after R0 surgery for S1 (P < .0001) and S2 (P = .015) patients but not for S3 cases (P = .525). CONCLUSIONS: The proposed classification allows selection of subjects candidates to curative surgery, emphasizing that lateral pelvic involvement is the main predictor of R+ resection and independently affects the DFS.

Neoadjuvant chemo-radiotherapy for cT3N0 rectal cancer: any benefit over upfront surgery? A propensity score-matched study.

PURPOSE: Benefits of neoadjuvant chemo-radiotherapy (CRT) are well known for locally advanced and/or node-positive rectal cancer, but the best timing for CRT has been less explored for cT3N0 patients. The aim of the present study was to compare the 5-year disease-free survival (DFS) probability between neoadjuvant CRT and upfront surgery in patients affected by cT3N0 rectal cancer. METHODS: A retrospective review of 105 patients affected by cT3N0 rectal cancer, staged by pelvic magnetic resonance imaging and treated at the National Cancer Institute of Milan between 2011 and 2017, was performed: 42 (40.0%) were treated by neoadjuvant CRT and 63 (60.0%) by upfront surgery. Propensity score matching was performed to avoid selection bias, and Cox multivariate regression was used to analyze outcomes. RESULTS: The 5-year DFS probability was 87.5% in neoadjuvant CRT patients vs. 90.0% in upfront surgery cases (Log-rank p = 0.76). The 5-year loco-regional recurrence-free survival probability was respectively 96.8% vs. 96.3% (Log-rank p = 0.954). On multivariate analysis, neoadjuvant CRT had no impact on DFS when compared to upfront surgery (adjusted HR 0.71, 95%CI 0.18-2.70, p = 0.613), but 61.9% of upfront surgery cases were treated by adjuvant chemo-radiation (adjusted HR 0.41, 95%CI 0.11-1.57, p = 0.196). The only independent predictor of improved DFS was age at diagnosis (adjusted HR 0.95, p = 0.017). CONCLUSION: CRT should be considered for cT3N0 patients, but its timing (neoadjuvant vs. adjuvant) seems not to affect the disease-free survival in the present cohort of patients.

Minimizing the surgical approach for a rare disease: transanal endoscopic microsurgery for rectal schwannoma.

OBJECTIVE: Rectal schwannomas are extremely rare tumors and their surgical treatment is widely variable in literature. Transanal endoscopic microsurgery (TEM) approach could be a reasonable option for such lesions, offering an organ-sparing strategy, but evidence is scarce. METHODS: We report a 69-year-old man with a rectal submucosal lesion at 10 cm from the anal verge, treated by TEM. A systematic literature review on surgical approaches in rectal schwannoma was performed. RESULTS: The patient was successfully treated by TEM, with adequate excision of the submucosal lesion. Histopathology revealed a rectal schwannoma. No recurrence was found at 1-year endoscopic follow-up. Previous studies reported 23 cases of rectal schwannoma and several treatment options, but only 2 cases were treated by TEM. Anterior rectal resection was generally adopted in cases of large, symptomatic masses with inconclusive preoperative biopsy, while lesions with features suggestive of stromal tumors were preferentially treated by endoscopy or, if located in distal rectum, by transanal approaches. CONCLUSIONS: An organ-sparing minimally invasive approach should be the standard of care for rectal schwannomas. TEM could extend the indication for their endoscopic treatment, providing adequate excision even for larger schwannomas of the middle-upper rectum.

Rectus Abdominis Myofascial Flap for Vaginal Reconstruction After Pelvic Exenteration.

BACKGROUND: Several techniques for vaginal reconstruction after pelvic exenteration such as myocutaneous and myoperitoneal flaps are available. However, the use of a myofascial flap has not been previously described. Thus, the objective of this article is to present our experience of vaginal reconstruction with rectus abdominis myofascial (RAMF) flap. METHODS: Between May 2008 and March 2017, 16 patients underwent anterior, posterior, or total pelvic exenteration with RAMF flap vaginal reconstruction. Patient records were systematically reviewed; demographic, clinic and pathologic, operative details, flap-related and non-flap-related complications, and risk factors for wound healing are reported. Quality of life and sexual function were also investigated. RESULTS: Eleven (68.8%) of 16 patients died during the follow-up (29.1 ± 25 months), whereas 5 (31.3%) are still alive. Early complications were reported in 7 patients (43.8%), with 2 (12.5%) flap-related and 5 (31.3%) non-flap-related complications. Similarly, late complications were reported in 5 patients (31.3%), with 2 (12.5%) flap-related and 3 (18.8%) non-flap-related complications. Quality of life measured by SF-36 (Survey Short Form 36) significantly improved at 12-month follow-up in comparison with baseline (physical component summary 31.5 ± 4.8 vs 26.8 ± 2.9; P = 0.027; mental component summary 29.5 ± 6.0 vs 25.9 ± 2.0; P = 0.042). CONCLUSIONS: This study demonstrates for the first time that RAMF flap vaginal reconstruction after pelvic exenteration is an efficacious and safe technique. Furthermore, it is associated with a significant improvement of quality of life and sexual function in those women who had sexual intercourse before surgery.

Abdominosacral resection for locally recurring rectal cancer.

AIM: To investigate feasibility and outcome of abdominal-sacral resection for treatment of locally recurrent rectal adenocarcinoma. METHODS: A population of patients who underwent an abdominal-sacral resection for posterior recurrent adenocarcinoma of the rectum at the National Cancer Institute of Milano, between 2005 and 2013, is considered. Retrospectively collected data includes patient characteristics, treatment and pathology details regarding the primary and the recurrent rectal tumor surgical resection. A clinical and instrumental follow-up was performed. Surgical and oncological outcome were investigated. Furthermore an analytical review of literature was conducted in order to compare our case series with other reported experiences. RESULTS: At the time of abdomino-sacral resection, the mean age of patients was 55 (range, 38-64). The median operating time was 380 min (range, 270-480). Sacral resection was performed at S2/S3 level in 3 patients, S3/S4 in 3 patients and S4/S5 in 4 patients. The median operating time was 380 ± 58 min. Mean intraoperative blood loss was 1750 mL (range, 200-680). The median hospital stay was 22 d. Overall morbidity was 80%, mainly type II complication according to the Clavien-Dindo classification. Microscopically negative margins (R0) is obtained in all patients. Overall 5-year survival after first surgical procedure is 60%, with a median survival from the first surgery of 88 ± 56 mo. The most common site of re-recurrence was intrapelvic. CONCLUSION: Sacral resection represents a feasible approach to posterior rectal cancer recurrence without evidence of distant spreading. An accurate staging is essential for planning the best therapy.

Epidural analgesia does not influence anastomotic leakage incidence after open colorectal surgery for cancer: A retrospective study on 1,474 patients.

BACKGROUND: Anastomotic leakage is a major cause of morbidity after colorectal surgery. Epidural analgesia is the most effective method for postoperative pain relief after major abdominal surgery. Anyhow, its effect on anastomotic leakage rate is still controversial. This study aimed to compare epidural versus intravenous analgesia as risk factor for anastomotic leakage requiring reoperation in patients undergoing open colorectal surgery for cancer. METHODS: A retrospective study on 1,474 patients was performed. The Cox proportional hazards model was used to study the relation between primary and secondary factors of risk and anastomotic leakage occurrence within 30 days after elective operation. RESULTS: Overall 30-day anastomotic leakage requiring reoperation was 4.9% (95%CI: 3.8-6.0%). No difference in anastomotic leakage occurrence was observed between the epidural analgesia group and the intravenous analgesia group (Hazard ratio: 0.94; 95%CI: 0.53-1.67%; P = 0.8338). Females had a rate of anastomotic leakage 43% lower than males (P = 0.0301). The diverting stoma resulted to be protective for anastomotic leakage occurrence (P = 0.0052). AL significantly increased postoperative median length of stay but not in-hospital mortality. CONCLUSIONS: Epidural analgesia does not influence the AL risk after open colorectal surgery for cancer.

Giant condyloma acuminatum of the anorectum: successful radical surgery with anal reconstruction.

Buschke-Löwenstein tumor, or giant condyloma acuminatum, is a relatively uncommon lesion of the anus with aggressive local invasive behavior which may present as a large warty tumor of the genital region with expansive and destructive growth. Many sporadic reports have been published suggesting various therapeutic strategies. We report a case of Buschke-Löwenstein tumor treated with conservative surgery followed by reconstructive procedures without a loop colostomy

LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites.

Human natural regulatory CD4(+) T cells comprise 5-10% of peripheral CD4(+)T cells. They constitutively express the IL-2Ralpha-chain (CD25) and the nuclear transcription Foxp3. These cells are heterogeneous and contain discrete subsets with distinct phenotypes and functions. Studies in mice report that LAG-3 has a complex role in T cell homeostasis and is expressed in CD4(+)CD25(+) T regulatory cells. In this study, we explored the expression of LAG-3 in human CD4(+) T cells and found that LAG-3 identifies a discrete subset of CD4(+)CD25(high)Foxp3(+) T cells. This CD4(+)CD25(high)Foxp3(+)LAG-3(+) population is preferentially expanded in the PBMCs of patients with cancer, in lymphocytes of tumor-invaded lymph nodes and in lymphocytes infiltrating visceral metastasis. Ex vivo analysis showed that CD4(+)CD25(high)Foxp3(+)LAG-3(+) T cells are functionally active cells that release the immunosuppressive cytokines IL-10 and TGF-beta1, but not IL-2. An in vitro suppression assay using CD4(+)CD25(high)LAG-3(+) T cells sorted from in vitro expanded CD4(+)CD25(high) regulatory T cells showed that this subset of cells is endowed with potent suppressor activity that requires cell-to-cell contact. Our data show that LAG-3 defines an active CD4(+)CD25(high)Foxp3(+) regulatory T cell subset whose frequency is enhanced in the PBMCs of patients with cancer and is expanded at tumor sites.

Modified peptides in anti-cancer vaccines: are we eventually improving anti-tumour immunity?

The discovery of tumour antigens recognized by T cells and the features of immune responses directed against them has paved the way to a multitude of clinical studies aimed at boosting anti-tumour T cell immunity as a therapeutic tool for cancer patients. One of the different strategies explored to ameliorate the immunogenicity of tumour antigens in vaccine protocols is represented by the use of optimized peptides or altered peptide ligands, whose amino acid sequence has been modified for improving HLA binding or TCR interaction with respect to native epitopes. However, despite the promising results achieved with preclinical studies, the clinical efficacy of this approach has not yet met the expectations. Although multiple reasons could explain the relative failure of altered peptide ligands as more effective cancer vaccines, the possibility that T cells primed by modified tumour peptides might may be unable to effectively cross-recognize tumour cells has not been sufficiently addressed. Indeed, the introduction of conservative amino acid substitutions may still produce diverse and unpredictable changes in the HLA/peptide interface, with consequent modifications of the TCR repertoire that can interact with the complex. This could lead to the expansion of a broad array of T cells whose TCRs may not necessarily react with equivalent affinity with the original antigenic epitope. Considering the results presently achieved with this vaccine approach, and the emerging availability of alternative strategies for boosting anti-tumour immunity, the use of modified tumour peptides could be reconsidered.

Distal clearance margin of 1 cm or less: a safe distance in lower rectum cancer surgery.

PURPOSE: The purpose of this study was to investigate the prognostic role of distal clearance margin (DCM) in lower rectum cancer surgery. MATERIALS AND METHODS: Two-hundred-three cancer patients underwent total rectal resection, possibly followed by adjuvant chemoradiotherapy. DCM was classified as positive or negative (<1, > or =1 cm) and investigated with multivariable proportional hazard models. RESULTS: A total of 52 deaths, 19 local relapses, 40 distant metastases, and three second primaries were observed as first events. Five-year survival with positive, negative <1, or negative > or =1 cm DCM was 51%, 81%, and 69%, respectively (p = 0.018). The difference was significant between positive and negative DCM (p = 0.031), not between negative <1 and > or =1 cm (p = 0.106). Local and distant 5-year incidences according to DCM were 30%, 8%, and 8% (p = 0.006) and 38%, 26%, and 19% (p = 0.857), respectively. CONCLUSIONS: DCM, but not tumor size, is a prognostic factor after sphincter-saving surgery, which is safe whenever a negative margin is achieved.

Simultaneous idiopathic segmental infarction of the great omentum and acute appendicitis: a rare association.

Idiopathic segmental infarction of the greater omentum is an uncommon cause of acute abdomen. The etiology is still unclear and the symptoms mimic acute appendicitis. Its presentation simultaneously with acute appendicitis is still more infrequent. We present a case of a 47-year old woman without significant previous medical history, admitted with an acute abdomen, in which the clinical diagnosis was acute appendicitis and in whom an infarcted segment of right side of the greater omentum was also found at laparotomy. As the etiology is unknown, we highlighted some of the possible theories, and emphasize the importance of omental infarction even in the presence of acute appendicitis as a coincident intraperitoneal pathological condition.