Surgery Plays a Leading Role in Breast Cancer Treatment for Patients Aged ≥90 Years: A Large Retrospective Cohort Study.

BACKGROUND: The population aged ≥90 years is increasing worldwide, yet nearly 50% of elderly breast cancer (BC) patients receive suboptimal treatments, resulting in high rates of BC-related mortality. We analyzed clinical and survival outcomes of nonagenarian BC patients to identify effective treatment strategies. METHODS: This single-institution retrospective cohort study analyzed patients aged ≥90 years diagnosed with stage I-III BC between 2007 and 2018. Patients were categorized into three treatment groups: traditional surgery (TS), performed according to local guidelines; current-standard surgery (CS), defined as breast surgery without axillary surgery (in concordance with 2016 Choosing Wisely guidelines) and/or cavity shaving; and non-surgical treatment (NS). Clinicopathological features were recorded and recurrence rates and survival outcomes were analyzed. RESULTS: We collected data from 113 nonagenarians with a median age of 93 years (range 90-99). Among these patients, 43/113 (38.1%) underwent TS, 34/113 (30.1%) underwent CS, and 36/113 (31.9%) underwent NS. The overall recurrence rate among surgical patients was 10.4%, while the disease progression rate in the NS group was 22.2%. Overall survival was significantly longer in surgical patients compared with NS patients (p = 0.04). BC-related mortality was significantly higher in the NS group than in the TS and CS groups (25.0% vs. 0% vs. 7.1%, respectively; p = 0.01). There were no significant differences in overall survival and disease-free survival between the TS and CS groups (p = 0.6 and p = 0.8, respectively), although the TS group experienced a significantly higher overall postoperative complication rate (p < 0.001). CONCLUSIONS: Individualized treatment planning is essential for nonagenarian BC patients. Surgery, whenever feasible, remains the treatment of choice, with CS emerging as the best option for the majority of patients.

Intraoperative Ultrasound-Guided Conserving Surgery for Breast Cancer: No More Time for Blind Surgery.

BACKGROUND: Breast-conserving surgery (BCS) still remains a blind surgery despite all available tumor localization methods. Intraoperative ultrasound (IOUS) allows real-time visualization during all resection phases. METHODS: This was a prospective observational cohort study conducted at the Veneto Institute of Oncology between January 2021 and June 2022. Patients with ductal carcinoma in situ, T1-2 invasive cancer, or post-neoadjuvant tumors, suitable for BCS, were recruited. All breast cancer lesion types were included, i.e. solid palpable, solid non-palpable, non-solid non-palpable, and post-neoadjuvant treatment residual lesions. Eligible participants were randomly assigned to either IOUS or traditional surgery (TS) in a 1:1 ratio. The main outcomes were surgical margin involvement, reoperation rate, closest margin width, main specimen and cavity shaving margin volumes, excess healthy tissue removal, and calculated resection ratio (CRR). RESULTS: Overall, 160 patients were enrolled: 80 patients were allocated to the TS group and 80 to the IOUS group. IOUS significantly reduced specimen volumes (16.8 cm3 [10.5-28.9] vs. 24.3 cm3 [15.0-41.3]; p = 0.015), with wider closest resection margin width (2.0 mm [1.0-4.0] vs. 1.0 mm [0.5-2.0] after TS; p < 0.001). Tumor volume to specimen volume ratio was significantly higher after IOUS (4.7% [2.5-9.1] vs. 2.9% [0.8-5.2]; p < 0.001). IOUS yielded significantly better CRR (84.5% [46-120.8] vs. 114% [81.8-193.2] after TS; p < 0.001), lower involved margin rate (2.5 vs. 15%; p = 0.009) and reduced re-excision rate (2.5 vs. 12.5%; p = 0.032). CONCLUSIONS: IOUS allows real-time resection margin visualization and continuous control during BCS. It showed clear superiority over TS in both oncological and surgical outcomes for all breast cancer lesion types. These results disfavor the paradigm of blind breast surgery.

Tumor immune microenvironment in therapy-naive esophageal adenocarcinoma could predict the nodal status.

BACKGROUND: Currently, preoperative staging of esophageal adenocarcinoma (EAC) has modest reliability and accuracy for pT and pN stages prediction, which heavily affects overall survival. The interplay among immune checkpoints, oncogenes, and intratumoral and peritumoral immune infiltrating cells could be used to predict loco-regional metastatic disease in early EAC. METHODS: We prospectively evaluated immune markers expression and oncogenes status as well as intratumoral and peritumoral immune infiltrating cells populations in esophageal mucosa samples obtained from neoadjuvant therapy-naïve patients who had esophagectomy for EAC. RESULTS: Vascular invasion and high infiltration of lamina propria mononuclear cells resulted associated with nodal metastasis. Low infiltration of activated CD8+ CD28+ T cells was observed in both intratumoral and peritumoral mucosa of patients with nodal metastasis. Low levels of CD69, MYD88, and TLR4 transcripts were detected in the intratumoral specimen of patients with lymph node involvement. Receiver operating characteristic curve analysis showed good accuracy for detecting nodal metastasis for all the markers tested. Significant lower infiltration of CD8 T cells and M1 macrophages and a lower expression of CD8A, CD8B, and TBX21 were found also in Esophageal Adenocarcinoma TCGA panCancer Atlas in the normal tissue of patients with nodal metastasis. CONCLUSIONS: Our data suggest that immune surveillance failure is the main driver of nodal metastasis onset. Moreover, nodal metastasis containment also involves the immune microenvironment of the peritumoral healthy tissue.

Totally Implantable Venous Access Devices: A Randomized Controlled Trial on the Effect of Psychological Support on Quality of Life and Body Image (BI-PORT).

Background: The presence of totally implantable venous access devices (TIVADs), as any permanent or semipermanent medical devices, has an impact on the quality of life (QoL) of patients. Therefore, the purpose of this trial was to evaluate the efficacy of psychological support for patients undergoing this procedure. Methods: This randomized controlled trial (RCT) aimed to compare the efficacy of a psychological intervention vs. standard care on QoL in patients receiving TIVAD for chemotherapy treatment (ClinicalTrials.gov NCT02075580). The trial was conducted at the Veneto Institute of Oncology IOV-IRCCS (Padua, Italy) between October 2013 and September 2018. Participants were neoplastic adults receiving TIVAD for chemotherapy treatment for any cancer, not undergoing visible demolitive interventions, without psychopathological diagnosis and language understanding. The exclusion criteria were patients without a diagnosis of cancer, with psychopathological diagnosis, or with language misunderstanding. Results: The variation of C30-QL2 and BR32-BI was not statistically different between intervention and control arms in men and women. However, the variation of C30-SF was statistically better in the intervention than control arm in men [mean difference (MD) 22.3, 95% CI 3.5 to 41.0] but not in women (MD -2.7, 95% CI -24.0 to 18.7). The variations of the other secondary outcome measures were not statistically different between intervention and control arms. Conclusion: Psychological support did not show any clear advantages on global QoL and body image perception in patients at 15 days after TIVAD insertion for chemotherapy. In contrast, male patients might benefit from even a very short psychological counseling before or during chemotherapy even if they do not seem to ask for it.

Postsurgical Pyoderma Gangrenosum in a Breast Cancer Patient: A Case Report and Literature Review.

Pyoderma gangrenosum is a rare skin necrotizing disease that can arise on a site of surgical trauma. Its pathogenesis has recently been related to dysregulation of the immune system, with inflammatory bowel disease representing the most commonly underlying systemic conditions. Several authors have also reported an association with solid malignancies (especially gastrointestinal and breast cancer). We describe the case of a 39-year-old patient diagnosed with a locally advanced, triple-negative breast cancer who developed a pyoderma gangrenosum on the surgical wound after a CVC implant with systemic complications. As the diagnosis and management of postsurgical pyoderma gangrenosum can be challenging for clinicians, underlying conditions as autoimmune disease and solid tumors have to be considered in order to guide treatment.

QOLEC2: a randomized controlled trial on nutritional and respiratory counseling after esophagectomy for cancer.

BACKGROUND: Esophagectomy for cancer strongly impairs quality of life. The aim of this trial was to evaluate the effect of the nutritional and respiratory counseling on postoperative quality of life. METHODS: At hospital discharge, patients were randomized into four groups receiving respectively: nutritional and respiratory counseling, nutritional counseling alone, respiratory counseling alone, or standard care. The main endpoint was the impairment in quality of life in the first month after surgery. Linear mixed effect models were estimated to assess mean score differences (MDs) in quality of life scores. RESULTS: Patients receiving nutritional counseling reported less appetite loss (MD - 17.7, 95% CI - 32.2 to -3.3) than those not receiving nutritional counseling at 1 month after surgery. Dyspnea was similar between patients receiving vs. those not receiving respiratory counseling (MD - 3.1, 95% CI - 10.8 to 4.6). Global quality of life was clinically similar between patients receiving vs. those not receiving nutritional counseling over time (MD 0.9, 95% CI - 5.5 to 7.3), as well as in patients receiving vs. those not receiving respiratory counseling over time (MD 0.7, 95% CI - 5.9 to 7.2). CONCLUSIONS: Intensive postoperative care does not affect global quality of life even if nutritional counseling reduced appetite loss.

Immune surveillance activation after neoadjuvant therapy for esophageal adenocarcinoma and complete response.

After neoadjuvant chemoradiotherapy for esophageal adenocarcinoma, up to 29% of patients have a pathological complete response (pCR). What to do afterward is still under debate. The aim of this prospective study was to define which local markers of immune response might act as predictors of pCR and of recurrence after pCR. The peritumoral healthy mucosa of the surgical specimen was sampled at esophagectomy and analyzed by immunohistochemistry, flow cytometry and Real-Time PCR. One hundred and twenty-three patients received neoadjuvant therapy for esophageal adenocarcinoma and were included in the study. Significantly higher rate of natural killer (NK) cells (CD57+), intraepithelial CD8 + T lymphocytes and degranulating T- and NK-cells (CD107+) were observed in the healthy mucosa of patients with pCR. Moreover, pCR was characterized by a lower immune-check points gene expression level. T-cell activation markers mRNA levels were significantly lower in patients with pCR and recurrent disease, showing an excellent accuracy in the prediction of the postoperative recurrence. Costimulatory molecules mRNA relative levels tended to be lower in patients with pCR and recurrent disease, showing a good accuracy in the prediction of postoperative recurrence in patients with pCR. The immune profile identified in this study might further be tested in large prospective trials as marker of pCR after neoadjuvant therapy and as predictor of recurrence after pCR.

Cholecystectomy during esophagectomy is safe but unnecessary.

Background: Prophylactic cholecystectomy has been proposed as a concomitant procedure during upper gastrointestinal surgery. This study evaluates the safety and the need of concurrent cholecystectomy during esophagectomy for cancer.Methods: All consecutive esophagectomies for esophageal cancer at the Center for Esophageal Diseases in Padova (Italy) between 1992 and 2011 were included. The safety of concurrent cholecystectomy was evaluated by surgical outcomes (length of stay, postoperative mortality and perioperative complications). The need for concurrent cholecystectomy was evaluated by occurrence of biliary duct stones and of cholelithiasis/cholecystitis after esophagectomy.Results: Cholecystectomy was performed during 67 out of 1087 esophagectomies (6.2%). Cirrhosis or chronic liver disease was associated with receiving cholecystectomy during esophagectomy (OR: 1.99, 95%C.I. 1.10-3.56). Patients receiving and those not receiving cholecystectomy showed similar length of stay (median 14 days, p = .87), postoperative mortality (3.0% vs. 2.5%, p = .68), intraoperative complication (4.5% vs. 7.1%, p = .62), early complications (52.2% vs. 44.6%, p = .25) and late complications (20.9% vs. 24.8%, p = .56). Cholelithiasis/cholecystitis after esophagectomy occurred in 61 (6.1%) patients, with only four requiring cholecystectomy during follow-up. The biliary stone occurrence was nil. Only pathologic stage III-IV (OR: 2.17, 95%C.I. 1.19-3.96) was associated with cholelithiasis/cholecystitis after esophagectomy.Conclusion: Routine prophylactic cholecystectomy during esophagectomy could be safe but unnecessary.

CD80 expression promotes immune surveillance in Barrett's metaplasia.

Esophageal adenocarcinoma (EAC) is the final step of a pathway starting with esophageal reflux disease, Barrett's metaplasia and Barrett's dysplasia. Positive costimulatory ligands such as CD80 have been suggested to contribute to anti-tumor T-cell efficacy. Here we report for the first time the role of CD80 in the inflammatory esophageal carcinogenesis and characterize the immune environment of EAC. Mucosa samples from cancer were obtained during esophagectomy from patients affected by EAC. Fresh biopsies were obtained from patients who underwent endoscopy for screening or follow-up. A rodent model of reflux induced esophageal carcinogenesis was created with an esophago-gastro-jejunostomy. CD80 expression was increased in epithelial cells during metaplasia in the inflammatory esophageal carcinogenesis cascade. Cd80 null mice as well as WT mice that received antiCD80 antibodies showed a higher rate of dysplasia and KI-67+ cells. These results suggest that CD80 mediates an active immune surveillance process in early inflammation-driven esophageal carcinogenesis.

PD-L1 expression, CD8+ and CD4+ lymphocyte rate are predictive of pathological complete response after neoadjuvant chemoradiotherapy for squamous cell cancer of the thoracic esophagus.

BACKGROUND: Neoadjuvant chemoradiotherapy (CTRT) can effectively downstage esophageal squamous cell carcinoma (SCC) in patients with locally advanced disease and prolonged survival have been observed in patients with a pathological complete response (ypCR). AIMS AND METHODS: This exploratory study aimed to identify immunological predictors of pCR after neoadjuvant CTRT within SCC microenvironment. The tumor regression after neoadjuvant therapy was measured according to the Mandard score system. Eighty-eight consecutive patients with SCC of the thoracic esophagus who received neoadjuvant CTRT were included in this retrospective study. Inclusion criteria were neoadjuvant CTRT and the availability of representative histological samples taken at diagnosis. We investigated immunohistochemical expression of CD4, Tbet, FoxP3, CD8, CD80, PD-L1, and PD-1, in the pretreatment biopsies and correlated the immunohistochemical profiles to patients' outcomes. RESULTS: After neoadjuvant CTRT, 23 patients had pCR, while 65 ones had partial response, stable disease or progression. PD-L1 expression and CD8+ and CD4+ lymphocyte rate were significantly higher in patients who had ypCR compared to those who had not (10 (0-55) vs 0 (0-0), P = 0.004, 73 (36-147) vs 21 (7-47), P = 0.0006 and 39 (23-74) vs 5 (0-13), P < 0.0001 respectively). The accuracy of expression of PD-L1+, CD8+, and CD4+ lymphocyte rate in identifying responders was AUC = 0.76 (P = 0.001), AUC = 0.81 (P = 0.0001) and AUC = 0.75 (P = 0.0001), respectively. Within the ypCR group, all patients with high infiltration of CD4+ T cell recurred/relapsed while only the 38.9% of those with low CD4+ T cell infiltration did the same (P = 0.058). CONCLUSIONS: PD-L1 expression and CD8+ and CD4+ lymphocyte rate were predictive of ypCR after neoadjuvant CTRT for SCC of the thoracic esophagus with adequate accuracy. Furthermore, recurrence/relapse was associated with high level of CD4+ T cell infiltration. However, the small sample size prevented to draw definitive conclusions; further studies are necessary to evaluate the prognostic role of these markers.

Time to diagnosis in esophageal cancer: a cohort study.

BACKGROUND: The association between shorter time to diagnosis and favorable outcome is still unproven in esophageal cancer. This study aims to evaluate the effect of time to diagnosis on patient prognosis. MATERIAL AND METHODS: Retrospective cohort study of all 3613 symptomatic patients referred for esophageal cancer to our center from 1980 to 2011. Time to diagnosis was calculated as the number of days from first symptom onset to the diagnosis of esophageal cancer. The main outcome measures were: resectability and severe malnutrition at diagnosis; postoperative morbidity, mortality and survival. RESULTS: Longer time to diagnosis was significantly associated with severe malnutrition at diagnosis (odds ratio (OR): 1.003, 95% confidence interval (C.I.).: 1.001-1.006) but not with resectability (OR: 0.997, 95% C.I.: 0.994-1.001). Longer time to diagnosis was not associated with postoperative morbidity (OR: 1.000, 95% C.I.: 0.998-1.003), postoperative mortality (OR: 1.002, 95% C.I.: 0.998-1.006), five-year overall survival (hazard ratio (HR): 0.999, 95% C.I.: 0.997-1.001) or five-year disease free survival (HR: 0.999, 95% C.I.: 0.998-1.001). CONCLUSION: Longer time to diagnosis did not affect resectability, postoperative morbidity or survival. Further campaigns to raise awareness of cancer among population and primary health care providers may have limited effect on clinical outcome.

Long-term quality of life after esophagectomy with gastric pull-up.

BACKGROUND AND OBJECTIVES: Data on long-term health-related quality of life (HRQL) after esophagectomy for cancer show contradictory results. The aim was to analyze long-term HRQL at 3 or more years after esophagectomy. METHODS: Survivors were identified among patients who had undergone esophagectomy during 2007-2013 using the local clinic database. Quality of life was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and OG25 questionnaires. Specific aspects were selected a priori and compared with published scores from European healthy subjects (mean difference, MD). RESULTS: Sixty-five long-term survivors (median follow-up 4 years) were identified. All functional scales and most symptom scales were clinically similar between EC long-term survivors and European healthy subjects. Survivors reported more problems concerning eating (MD 13.1, 95% C.I. 10.6-15.6) and reflux (MD 19.7, 95% C.I. 15.9-23.5). HQRL variation from discharge to long term was available in 27 participants who reported improvements in role functioning (MD 40.1, 95%C.I. 24.3-56.0) and dysphagia (MD -41.9, 95% C.I. -51.7 to 32.0). CONCLUSIONS: Long-term HRQL after esophagectomy is similar between EC survivors and European healthy subjects, despite persisting reflux and eating problems. Further research may focus on improvements of postoperative alimentary habits.

Esophageal Cancer Clinical Presentation: Trends in the Last 3 Decades in a Large Italian Series.

OBJECTIVE: The aim of this study was to investigate trends in patients' characteristics and comorbidities in esophageal cancer (EC) patients. BACKGROUND: Identifying changing pattern is essential to understand and predict further changes and to plan surgical procedures and resource allocation. METHODS: Trends in patients' characteristics and comorbidities were evaluated in 4440 EC patients at the Center for Esophageal Diseases in Padova, Italy, during 1980 to 2011. Joinpoint regression analysis was performed to evaluate trends and to estimate annual percentage changes (APCs). RESULTS: During the study period, there has been a statistically significant increment of the rate of esophageal adenocarcinoma (APC 3.70). The rates of elderly and of asymptomatic patients increased over time (APCs 0.98 and 6.24), whereas the rates of malnutrition, alcoholic drinking, and gastric ulcer decreased (APCs -1.50, -1.72, and -5.20). Reflux rate increased until 1997 and decreased thereafter (APCs 6.96 and -4.48), whereas the rate of Barrett esophagus increased until 1992 (APC 35.84) and then leveled. The rates of patients with previous neoplasms increased over time (APCs 3.22 and 4.86). There have been significant changes in systemic comorbidities, with an increase of hypertension and cardiac disease (APCs 7.56 and 1.86) and a decrease of advanced liver disease and pulmonary disease (APCs -2.67 and -1.74). CONCLUSION: The current EC patient has more often an esophageal adenocarcinoma and is more frequently elderly, asymptomatic, a survivor of previous neoplasms, and a patient with hypertension and cardiac disease than 30 years ago. On the contrary, malnutrition, alcoholic drinking, gastric ulcer, pulmonary disease, and advanced liver disease decreased.

Potential curability and perception of received information in esophageal cancer patients.

PURPOSE: This study aimed to evaluate patients' perceived receipt of information according to the possibility of cure in esophageal cancer. METHODS: One hundred and twelve consecutive patients presenting at the multidisciplinary visit at the Veneto Institute of Oncology for esophageal cancer between 2014 and 2016 were included in the study. The Italian version of the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires C30 (core questionnaire), OG25 (esophago-gastric cancer module), and INFO25 (information module) were used. RESULTS: Candidates for palliative treatment were less informed about the disease (adjusted mean difference - 11.5, 95% CI - 23.0 to - 0.02) and less satisfied with information provided (adjusted mean difference - 18.3, 95% CI - 31.9 to - 4.7) than candidates for curative treatment. In addition, candidates for palliative treatment wanted to receive more information than candidates for curative treatment (adjusted mean difference 26.1, 95% CI 0.5 to 51.6). Better quality of life was associated with satisfaction of received information (ß = 0.77, p < 0.0001) and of receiving information about things that the patient can do to help himself (ß = 0.26, p = 0.04). More anxiety was associated to receiving more information about disease (ß = 0.46, p = 0.02) but less information about things that the patient can do to help himself (ß = - 0.38, p = 0.02). CONCLUSIONS: Candidates for palliative treatment were less satisfied with information about the disease and wanted to receive more information. Additionally, some aspects of quality of life were found to be associated with perceived receipt of information. Appropriate training in communication of prognostic information may improve clinical management of incurable cancer patients.

Immunonutrition before esophagectomy: Impact on immune surveillance mechanisms.

Preoperative oral immunonutrition was demonstrated to improve immune response and to decrease the infection rate in patients with cancer. This study aimed to assess how immunonutrition could influence the immune cell response in the mucosal microenvironment of esophageal adenocarcinoma. Therefore, A prospective cohort of consecutive patients undergoing esophagectomy for esophageal adenocarcinoma was enrolled. A subgroup of them was given preoperative oral immunonutrition with Oral Impact® and was compared to those who received no preoperative supplementation. Mucosal samples from healthy esophagus were obtained at esophagectomy. Histology, immunohistochemistry, gene expression analysis, and cytofluorimetry were performed. Markers of activation of antigen-presenting cells (CD80, CD86, and HLA-I), innate immunity (TLR4 and MyD88), and cytotoxic lymphocyte infiltration and activation (CD8, CD38, CD69, and CD107) were measured. In all, 50 patients received preoperative Oral Impact® and 129 patients received no nutritional support. CD80, CD86, MyD88, and CD69 messenger RNA expression was significantly increased in patients receiving immunonutrition compared to controls. In the subgroup of patients with stages I-II cancer, the rate of epithelial cells expressing CD80 and HLA-ABC was significantly higher in those receiving immunonutrition compared to controls as well as CD8+ CD28+ cell rate. Immunonutrition administration before surgery was significantly associated to increased degranulating CD8 and natural killer cells (CD107+) infiltrating the healthy esophageal mucosa. All the comparisons were adjusted for cancer stage and preoperative therapy. In conclusion, in healthy esophageal mucosa of patients undergoing esophagectomy, a 5-day course of immunonutrition enhances expression of antigen-presenting cells activity and increased CD8+ T cell activation and degranulating activity. Further studies are warranted to understand the clinical implication in terms of cancer recurrence.

Esophageal adenocarcinoma microenvironment: Peritumoral adipose tissue effects associated with chemoresistance.

Peritumoral microenvironment affects cancer development and chemoresistance, and visceral adipose tissue may play a critical role. We aimed to identify depot-specific adipose characteristics associated with carcinogenesis and resistance to neoadjuvant therapy in esophageal adenocarcinoma (EAC). We analyzed: (i) the peritumoral adipose tissue of rats following the induction of esophageal carcinogenesis; (ii) the peritumoral and distal (omental) adipose tissue of patients affected by EAC; (iii) adipose-derived stem cells (ADSC) isolated from healthy patients and treated with conditioned medium (CM), collected from tumoral and adipose tissue of patients with EAC. In peritumoral adipose tissue of rats, CD34, CD31 and vascular endothelial growth factor (VEGF) expression increased progressively during EAC development. In patients with EAC, expression of CD34, CD45, CD90 and nucleostemin (NSTM) was higher in peritumoral than in distal adipose tissue and decreased in the presence of neoadjuvant therapy. Moreover, expression of NSTM, octamer-binding transcription factor 4 (OCT-4) and VEGF was higher in peritumoral (but not in distal) adipose tissue of chemoresistant patients. In ADSC, treatment with peritumoral adipose tissue CM increased the adipogenic potential and the expression of CD34, CD90, NSTM and OCT-4. These effects were similar to those induced by cancer-derived CM, but were not observed in ADSC treated with distal adipose tissue CM and were partially reduced by a leptin antagonist. Last, ADSC treated with peritumoral CM of chemoresistant patients displayed increased expression of NSTM, OCT-4, leptin, leptin receptor, alpha-smooth muscle actin (α-SMA), CD34 and VEGF. These results suggest that peritumoral adipose tissue may promote, by paracrine signaling, the expression of depot-specific factors associated with therapeutic resistance.

Nodal skip metastasis in thoracic esophageal squamous cell carcinoma: a cohort study.

BACKGROUND: Nodal skip metastasis is a prognostic factor in some sites of malignancies, but its role in esophageal cancer is still unclear. The present study aimed to investigate occurrence and effect of nodal skip metastases in thoracic esophageal squamous cell carcinoma. METHODS: All 578 patients undergoing esophagectomy for thoracic esophageal squamous cell carcinoma at the Center for Esophageal Diseases located in Padova between January 1992 and December 2010 were retrospectively evaluated. Selection criteria were R0 resection, pathological M0 stage and pathological lymph node involvement. Patients receiving neoadjuvant therapy were excluded. RESULTS: The selection identified 88 patients with lymph node involvement confirmed by pathological evaluation. Sixteen patients (18.2%) had nodal skip metastasis. Adjusting for the number of lymph node metastases, patient with nodal skip metastasis had similar 5-year overall survival (14% vs. 13%, p = 0.93) and 5-year disease free survival (14% vs. 9%, p = 0.48) compared to patients with both peritumoral and distant lymph node metastases. The risk difference of nodal skip metastasis was: -24.1% (95% C.I. -43.1% to -5.2%) in patients with more than one lymph node metastasis compared to those with one lymph node metastasis; -2.3% (95% C.I. -29.8% to 25.2%) in middle thoracic esophagus and -23.0% (95% C.I. -47.8% to 1.8%) in lower thoracic esophagus compared to upper thoracic esophagus; 18.1% (95% C.I. 3.2% to 33.0%) in clinical N0 stage vs. clinical N+ stage. CONCLUSIONS: Nodal skip metastasis is a common pattern of metastatic lymph involvement in thoracic esophageal squamous cell carcinoma. However, neither overall survival nor disease free survival are associated with nodal skip metastasis occurrence.

A germline predictive signature of response to platinum chemotherapy in esophageal cancer.

Platinum-based neoadjuvant therapy is the standard treatment for esophageal cancer (EC). At present, no reliable response markers exist, and patient therapeutic outcome is variable and very often unpredictable. The aim of this study was to understand the contribution of host constitutive DNA polymorphisms in discriminating between responder and nonresponder patients. DNA collected from 120 EC patients treated with platinum-based neoadjuvant chemotherapy was analyzed using drug metabolism enzymes and transporters (DMET) array platform that interrogates polymorphisms in 225 genes of drug metabolism and disposition. Four gene variants of DNA repair machinery, 2 in ERCC1 (rs11615; rs3212986), and 2 in XPD (rs1799793; rs13181) were also studied. Association analysis was performed with pTest software and corrected by permutation test. Predictive models of response were created using the receiver-operating characteristics curve approach and adjusted by the bootstrap procedure. Sixteen single nucleotide polymorphisms (SNPs) of the DMET array resulted significantly associated with either good or poor response; no association was found for the 4 variants mapping in DNA repair genes. The predictive power of 5 DMET SNPs mapping in ABCC2, ABCC3, CYP2A6, PPARG, and SLC7A8 genes was greater than that of clinical factors alone (area under the curve [AUC] = 0.74 vs 0.62). Interestingly, their combination with the clinical variables significantly increased the predictivity of the model (AUC = 0.78 vs 0.62, P = 0.0016). In conclusion, we identified a genetic signature of response to platinum-based neoadjuvant chemotherapy in EC patients. Our results also disclose the potential benefit of combining genetic and clinical variables for personalized EC management.