Simone Zanotti

Can elderly patients with colorectal cancer tolerate planned surgical treatment? A practical approach to a common dilemma

Aim  Analysing the effectiveness of a surgical procedure is mandatory in every modern health‐care system. The aging of the population stresses the need for a good standard of care. This study tests the hypothesis that porthsmouth‐physiologic operative severity score for enumeration of morbidity and mortality (P‐POSSUM) and colorectal‐POSSUM (CR‐POSSUM) would be useful clinical auditing tools in colorectal cancer surgery for aged patients.

Microarray-based identification and RT-PCR test screening for epithelial-specific mRNAs in peripheral blood of patients with colon cancer.

BackgroundThe efficacy of screening for colorectal cancer using a simple blood-based assay for the detection of tumor cells disseminated in the circulation at an early stage of the disease is gaining positive feedback from several lines of research. This method seems able to reduce colorectal cancer mortality and may replace colonoscopy as the most effective means of detecting colonic lesions.MethodsIn this work, we present a new microarray-based high-throughput screening method to identifying candidate marker mRNAs for the early detection of epithelial cells diluted in peripheral blood cells. This method includes 1. direct comparison of different samples of colonic mucosa and of blood cells to identify consistent epithelial-specific mRNAs from among 20,000 cDNA assayed by microarray slides; 2. identification of candidate marker mRNAs by data analysis, which allowed selection of only 10 putative differentially expressed genes; 3. Selection of some of the most suitable mRNAs (TMEM69, RANBP3 and PRSS22) that were assayed in blood samples from normal subjects and patients with colon cancer as possible markers for the presence of epithelial cells in the blood, using reverse transcription – polymerase chain reaction (RT-PCR).ResultsOur present results seem to provide an indication, for the first time obtained by genome-scale screening, that a suitable and consistent colon epithelium mRNA marker may be difficult to identify.ConclusionThe design of new approaches to identify such markers is warranted.

Displayed correlation between gene expression profiles and submicroscopic alterations in response to cetuximab, gefitinib and EGF in human colon cancer cell lines.

BackgroundEGFR is frequently overexpressed in colon cancer. We characterized HT-29 and Caco-2, human colon cancer cell lines, untreated and treated with cetuximab or gefitinib alone and in combination with EGF.MethodsCell growth was determined using a variation on the MTT assay. Cell-cycle analysis was conducted by flow cytometry. Immunohistochemistry was performed to evaluate EGFR expression and scanning electron microscopy (SEM) evidenced the ultrastructural morphology. Gene expression profiling was performed using hybridization of the microarray Ocimum Pan Human 40 K array A.ResultsCaco-2 and HT-29 were respectively 66.25 and 59.24 % in G0/G1. They maintained this level of cell cycle distribution after treatment, suggesting a predominantly differentiated state. Treatment of Caco-2 with EGF or the two EGFR inhibitors produced a significant reduction in their viability. SEM clearly showed morphological cellular transformations in the direction of cellular death in both cell lines treated with EGFR inhibitors. HT-29 and Caco-2 displayed an important reduction of the microvilli (which also lose their erect position in Caco-2), possibly invalidating microvilli absorption function. HT-29 treated with cetuximab lost their boundary contacts and showed filipodi; when treated with gefitinib, they showed some vesicles: generally membrane reshaping is evident. Both cell lines showed a similar behavior in terms of on/off switched genes upon treatment with cetuximab. The gefitinib global gene expression pattern was different for the 2 cell lines; gefitinib treatment induced more changes, but directly correlated with EGF treatment.In cetuximab or gefitinib plus EGF treatments there was possible summation of the morphological effects: cells seemed more weakly affected by the transformation towards apoptosis. The genes appeared to be less stimulated than for single drug cases.ConclusionThis is the first study to have systematically investigated the effect of cetuximab or gefitinib, alone and in combination with EGF, on human colon cancer cell lines. The EGFR inhibitors have a weaker effect in the presence of EGF that binds EGFR. Cetuximab treatment showed an expression pattern that inversely correlates with EGF treatment. We found interesting cyto-morphological features closely relating to gene expression profile. Both drugs have an effect on differentiation towards cellular death.

Effectiveness of Sentinel Lymph Node Intraoperative Examination in 753 Women With Breast Cancer: Are We Overtreating Patients?

Objective:The goal of our study was to evaluate the sensitivity and specificity of sentinel lymph node biopsy (SLNB) frozen section (FS) examinations to detect metastatic lymph nodes and also its potential role in avoiding unnecessary demolitive axillary surgery. Background:SLNB is the standard of care in surgical oncology of the breast. Intraoperative evaluation of the SLN seems to achieve sufficient sensitivity for macrometastasis (Ma), leading to axillary lymph node dissection (ALND) only when strictly necessary. Is it equally as clear when to perform ALND if micrometastasis (Mi) or isolated tumor cells (ITCs) are detected? Methods:All consecutive patients from January 2005 to September 2010 operated on for breast cancer were prospectively enrolled. All patients underwent an FS SLNB. The sensitivity and specificity of SLN FSs in detecting Ma, Mi, and ITCs was calculated. All patients with Ma or Mi at FS underwent ALND. For all patients who underwent ALND, the number of metastatic non-SLNs was recorded and correlated to the size of the SLN metastasis. Results:A total of 753 patients were enrolled. FS examination had an overall 54% sensitivity and 100% specificity in detecting metastatic disease (Ma/Mi/ITCs). The sensitivity rises to 89% if only Mas were considered and to 64% if Mas and Mis were counted together. All patients with Mas or Mis detected at FS had a completion ALND during the same procedure (156/222). All patients with Mas detected at final pathology (16 false negatives, 2.6%) and 50 women with Mis or ITCs (119 false negatives, 20%) underwent a delayed ALND. When Mis or ITCs were detected in the SLN, only 8 of 73 (10.9%) and none of 4 (0%) patients, respectively, had at least 1 metastatic non-SLN after ALND. Two patients (2/460, 0.43%) who had negative SLNs showed local axillary recurrence. After a mean follow-up of 32 months, none of the 71 patients with Mis or ITCs who did not undergo a second operation showed local recurrence. Conclusions:SLNB FS is highly effective in detecting the subgroup of patients who may benefit from completion ALND during the same surgical procedure. The role of Mi/ITCs in the SLN(s) is still unclear, but our data lean toward a less aggressive surgical approach.

Has breast cancer in the elderly remained the same over recent decades? A comparison of two groups of patients 70 years or older treated for breast cancer twenty years apart

OBJECTIVES Breast cancer (BC) in the elderly population is by far the most frequent malignancy in Western countries; however, little evidence is available regarding the specific management of this group. The purpose of this study was to identify how the biological and clinical characteristics of cancer have changed over the past 20years by comparing two groups of elderly patients with breast cancer operated on 20years apart. The secondary endpoint was to underline potential changes in surgical strategy over the past 20years. MATERIALS AND METHODS One group of consecutive elderly patients undergoing surgery for BC between January 1990 and December 1993 (Group A), and one group undergoing surgery between January 2008 and December 2011 (Group B) were identified and analyzed. Data regarding surgical treatment, stage, tumor grading, hormonal and HER2/neu receptors, and Ki-67 were collected and compared. RESULTS A total of 422 elderly patients underwent surgical treatment, 142 in Group A and 280 in Group B. An earlier stage at presentation was detected in Group B, T1 (57.5% B vs. 31.6% A) and N0 (64.6% B vs. 54.2% A). Surgical treatment in the first group was more extensive while conservative procedures were more frequently performed in the second group. Despite the earlier presentation, tumor grade was higher in Group B (G3 10.6% A vs. 32.1% B, p<0.05). Overexpression of Ki-67 was again more frequent in Group B (56.2% B vs. 32.5% A, p<0.05). Hormonal and HER2/neu receptor expression was comparable. CONCLUSIONS Nowadays, elderly patients with BC are more likely to present at an early stage; therefore, conservative surgery is a feasible option. Despite potential bias related to changes of pathology and immunohistochemistry examination techniques over the decades, the biological characteristics of recent patients with BC seem to be consistent with more aggressive tumors. Tailored treatment should be offered with regard to biological age, the cancer-specific profile and active life expectancy.

Positive predictive value of breast lesions of uncertain malignant potential (B3): Can we identify high risk patients? The value of a multidisciplinary team and implications in the surgical treatment

BACKGROUND AND AIM The use of conventional needle core biopsy for palpable masses and vacuum-assisted needle core biopsy for microcalcifications has significantly increased the preoperative diagnosis rate, but the strategy for those patients with lesions of uncertain malignant potential (B3) still remains controversial. The aim of this study was to evaluate the positive predictive value (PPV) of the malignancy of B3 lesions in order to establish their correct management in the setting of a multidisciplinary care pathway. METHODS Data from all patients who had a Needle Core Biopsy (NCB) or a Vacuum-Assisted Needle Core Biopsy (VANCB) between 2005 and 2014 were retrospectively collected and analyzed. The B3 patients were discussed by the Multidisciplinary Team (MDT) deciding for surgery or for follow-up, based on a score in which clinical-instrumental factors and environmental factors were considered. The PPV of malignancy of all surgically excised B3 lesions was calculated. RESULTS One hundred and seventy-eight B3 NCBs were included in the study and Atypical Epithelial Proliferation of Ductal Type (AEDPT) was the most represented subcategory. The final histopathology report of the 128 patients operated on showed 94 benign and 34 malignant lesions. The PPV of B3 patients referred to surgery was 26.5%. CONCLUSION B3 patients should be evaluated by a breast MDT in order to make the right therapeutic decision, in particular for patients with contrasting clinical/diagnostic findings. Larger prospective studies are required to assess the definitive PPV of each B3 subcategory.

Reply to letter: "effectiveness of sentinel lymph node intraoperative examination in 753 women with breast cancer: are we overtreating patients?".

W e read with interest the comment by Di Saverio et al regarding our article.1 We strongly disagree with the majority of their statements. Right from their very first comment, it is obvious that they probably misunderstood the aim of our straightforward article, which, however, was well defined right from the beginning (Objective, first line in the abstract) and which was limited to defining the effectiveness of the intraoperative evaluation of the sentinel lymph nodes (SLNs) in detecting metastatic disease. At that time, our intent was not to justify less aggressive treatment but instead to point out that intraoperative analysis of the SLN leads to fewer procedures [completion axillary lymph node dissection (ALND)] for the same patient as compared with a final pathology examination alone (which nowadays is still performed in many centers across the United States and Europe). This was clearly shown to be possible as SLN frozen section (FS) examination has almost 90% sensitivity and 100% specificity, leading the surgeon to perform only necessary ALNDs and, more importantly, during the same procedure. Whatever Di Saverio et al sought in demanding more detailed information regarding the primary disease, the number of SLNs involved, extranodal extent, and so on might have a valuable role in promoting a nomogram to decide whether an ALND should be performed in cases of positive SLN; however, this was not the aim of our study. The inclusion criteria are clear and are reported in the article. They also stated the following: “How can you make recommendations and question the significance of micrometastases in SLNs and eventually the benefit of subsequent

Prepouch ileitis, myth or reality? The first case with acute abdomen

To the Editor: Restorative proctocolectomy with ileo pouch–anal anastomosis (IPAA) is a well-established procedure for ulcerative colitis (UC) in selected patients. Pouchitis is a common condition in many patients after restorative proctocolectomy. A similar condition, termed prepouch ileitis, characterized by inflammation proximal to the pouch, has also been recently described. This condition is poorly understood and generally considered of little clinical relevance. We describe the first case of a potential life-threatening complication from perforated ileitis of the new terminal ileum 2 years after restorative proctocolectomy for a nonresponder UC. In May 2004 a 62-year-old man with a history of UC nonresponding to medical treatment was referred for surgery. Restorative proctocolectomy (RPC) with IPAA and diverting loopileostomy was performed. The postoperative course was uneventful and 3 months later the patient underwent ileostomy closure with side-to-side mechanical anastomosis. In January 2006 the patient was diagnosed with rheumatic polymyalgia and uveitis and treated with immunosuppressants. In September 2006 he was admitted to the Emergency Department complaining of nausea, vomiting, fever, abdominal pain, and hematic diarrhea. Chest and abdominal x-rays were within normal limits. Pouchoscopy with biopsies was performed and he was treated for acute pouchitis with antibiotics and mesalazine with little improvement. Two weeks later he was transferred to our surgical unit with signs of peritonitis. The laboratory data were within normal limits. A double contrast computed tomography (CT) scan (intravenous and transanal) was performed: a copious amount of free abdominal air was detected and minimal leakage of the transanal contrast was found in the new terminal ileum (NTI); the pouch was regular (Fig. 1). A significant amount of purulententeric fluid was detected in the abdomen with clear signs of diffuse peritonitis (fluid culture was positive for E. coli and Enterococcus faecium). A double perforation was detected at the site of the side-to-side anastomosis (previously made for the ileostomy closure) located about 30 cm above the IPAA. Ileal resection, closure of the distal ileal stump, and end-ileostomy was performed. The postoperative period was complicated by prolonged septic status in the intensive care unit. Twenty-five days after surgery he was discharged in good condition. Two years later the patient is in good health. Laboratory analysis, pouchgram, pouchoscopy, and enteric magnetic resonance imaging (MRI) are all within normal limits. The macroscopic appearance of the specimen showed a severe ulcerating mucosa with 2 full-thickness discontinuities through the bowel (Fig. 2a). Villous atrophy alternated with pseudopolypoid lesions; mucosal chronic inflammatory cell infiltrate accompanied by neutrophils in the lamina propria were detected (Fig. 2b,c). Granuloma was not seen in any section. A second analysis of the previously resected colon and rectum excluded Crohn’s disease (CD) or indeterminate colitis (IC). A diagnosis of prepouch Ileitis (PI) was made according to the histopathological features reported by Bell et al. Pouchitis is a common condition after restorative proctocolectomy. Bell et al recently reported a series of 15 patients (2.6% of 571), with inflammation of the NTI after RPC with IPAA for pathologically confirmed UC. They describe this pathologic condition as a distinct disease called PI. Clinical and histochemical characteristics seem to overlap with pouchitis. PI seems to have a distinct etiopathogenesis and can occur independently of pouchitis, CD, or IC. Coexistent pouchitis was reported only in 7/15 patients (47%). Other authors have described this condition, which is often associated with chronic refractory pouchitis and mucosal changes that lessen in severity at the more proximal end. What we describe here is a case of acute abdomen following perforation of the NTI 2 years after RPC and IPAA. Terminal ileitis was not found to be associated with CD or IC. This is the first reported case of perforated PI. Endoscopic evaluation of the NTI should become mandatory for patients after proctocolectomy and IPAA who present with clinical symptoms of pouchitis, even in the absence of any direct evidence of pouch inflammation. Although nowadays no relation is identified with any risk factor, nevertheless a side-to-side ileostomy closure could be a circumstance predisposing for fecal stasis resulting in mucosal irritation and inflammation. This aspect should be considered in further analysis of the phenomenon. Despite the limited clinical magnitude, clinicians should be aware that perforation of the NTI can occur. This life-threatening complication should be included in the differential diagnosis of patients with abdominal pain after RPC.

The Neoadjuvant Net: A patient- and surgeon-friendly device to facilitate safe breast-conserving surgery in patients who underwent neoadjuvant treatment

The primary goal of the study was to describe an innovative and helpful tool in defining the minimal surgical margins necessary during breast-conserving surgery (BCS) after neoadjuvant treatment: the Neoadjuvant Net (NN). The secondary endpoint was to assess its usefulness in achieving postoperative disease-free margins and reducing Ipsilateral Breast Tumor Recurrences (IBRTs). The breast-conserving surgical technique together with the use of the Neoadjuvant Net is herein reported. Age, stage at diagnosis, clinical and pathological response, lymph node status, type of surgery, margin status, and incidence of local and distant recurrence were retrospectively analyzed. Seventy-five patients underwent BCS following medical treatment from 2000 to 2011. The majority of the patients had significant size reduction (63/75, 84%). Twenty-two had a complete clinical response but only 11 (11/75, 14.7%) showed a complete pathological response. Two patients (2/75, 2.67%) had infiltrated surgical margins. After a mean follow-up of seventy months, 3 patients (3/75, 4%) had IBRTs and 4 women had distant metastases (4/75, 5.34%). The NN is an easy-to-use, non-invasive instrument designed with the purpose of facilitating the surgeons task of reducing infiltrated margins and IBTRs.