Esophageal cancer (EC) is one of the most common digestive system malignancies in the world. The combined modality treatment of EC is usually surgery and radiation therapy, however, its clinical efficacy for advanced patients is relatively limited. Ferroptosis, a new type of iron-dependent programmed cell death, is different from apoptosis, necrosis and autophagy. In recent years, many studies have further enlightened that ferroptosis plays an essential role in the occurrence, development and metastasis of tumors. Targeting ferroptosis stimulates a new direction for further exploration of oncologic treatment regimens. Furthermore, ferroptosis has a critical role in the immune microenvironment of tumors. This paper reviews the mechanism of ferroptosis and the ferroptosis research progress in the treatment of EC. We further elaborate the interaction between ferroptosis and immunotherapy, and the related mechanisms of ferroptosis participation in the immunotherapy of EC, so as to provide new directions and ideas for the treatment of EC.

The role of two- or three-field nodal dissection in the surgical treatment of esophageal and gastroesophageal junction cancer in the minimally invasive era is still controversial. This review aims to clarify the extension of nodal dissection in esophageal and gastroesophageal junctional cancer. A basic evidence-based analysis was designed, and seven research questions were formulated and answered with a narrative review. Reports with little or no data, single cases, small series and review articles were not included. Three-field lymph node dissection improves staging accuracy, enhances locoregional disease control and might improve survival in the group of patients with cervical and upper mediastinal metastatic lymph nodal involvement from middle and proximal-third esophageal cancer.

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is standard of care for locally advanced esophageal cancer in many countries. After nCRT up to one third of all patients have a pathologically complete response in the resection specimen, posing an ethical imperative to reconsider the necessity of standard surgery in all operable patients after nCRT. An active surveillance strategy following nCRT, in which patients are subjected to frequent clinical investigations after the completion of neoadjuvant therapy, has been evaluated in other types of cancer with promising results. In esophageal cancer, both patients who are cured by neoadjuvant therapy alone as well as patients with subclinical disseminated disease at the time of completion of neoadjuvant therapy may benefit from such an organ sparing approach. Active surveillance is currently applied in selected patients with esophageal cancer who refuse surgery or are medically unfit for major surgery after completion of nCRT, but this strategy is not (yet) adopted as an alternative to standard surgery or definitive chemoradiation. The available literature is scarce, but suggests that long-term oncological outcomes after active surveillance are noninferior compared to standard surgical resection, providing justification for comparison of both treatments in a phase III trial. This review gives an overview of the current knowledge regarding active surveillance after completion of nCRT in esophageal cancer and outlines future research perspectives.

This dose-escalation study was performed to determine the recommended phase II dose of oral capecitabine to be delivered concurrently with thoracic radiation therapy and weekly docetaxel in patients with locally advanced esophageal carcinoma.

Patients with operable stage II or III esophageal carcinoma were staged by endoscopic ultrasonography and computed tomography. Two cycles of docetaxel (80 mg/m) and carboplatin (target area under the concentration-time curve: 6 mg/ml × min) were delivered over 6 weeks. This was followed by concurrent weekly docetaxel (15 mg/m), thoracic radiotherapy (50.4 Gy in 28 fractions), and increasing doses of capecitabine (500-3500 mg) given before each fraction of radiotherapy. After restaging, responding patients continued to esophagectomy within 4 to 8 weeks of completing chemoradiotherapy.

Forty-four patients were enrolled, and 40 were assessable for the dose-ranging component of concurrent chemoradiotherapy. Endoscopic ultrasonography stages at enrollment were T3N1 (29 patients), T3N0 (4 patients), T2N1 (6 patients), and T4N0 (one patient). The maximum tolerated dose of capecitabine was 3500 mg. Thirty-six patients had surgery; 83% had R0 resection, and 17% had pathological complete response. Median overall survival was 23.5 months, with 34 and 27% alive at 3 and 5 years.

The recommended phase II dose of capecitabine is 3500 mg when given concurrently with 50.4 Gy of thoracic radiotherapy in 28 fractions and weekly docetaxel. This trimodality therapy for operable locally advanced esophageal carcinoma was very well tolerated and remarkably active. This regimen holds promise for the treatment of esophageal carcinoma and warrants further investigation.

Minimally invasive transhiatal esophagectomy for esophageal cancer includes mediastinoscopic and laparoscopic transhiatal esophagectomy. It is inadequate in both two techniques. It is impossible to dissect the lower esophagus with single mediastinoscopy or the upper and middle esophagus with single laparoscopy. We use mediastinoscopy combined with laparoscopy to dissect the whole esophagus and stomach including lymph node dissection. In addition, laparoscopic gastric mobilization leads to less trauma than an open gastroplasty.

40 cases of video-assisted mediastinoscopic transhiatal esophagectomy were performed and divided into two groups.32 patients were received surgical therapy of single mediastinoscopic esophagectomy with open gastroplasty in group A, while 8 patients were received surgical therapy of mediastinoscopic esophagectomy combined with laparoscopic lower esophageal and gastric dissection in group B. The perioperative complications were recorded.

Video-assisted mediastinoscopic transhiatal esophagectomy was performed successfully both in group A and B. It suggested that mediastinoscopy combined with laparoscopy be better than single mediastinoscopy because of less blood loss, less pain, shorter ICU stay and complete lower mediastinal lymph nodes resection.

Video-assisted mediastinoscopic transhiatal esophagectomy combined with laparoscopy is a safe and minimally invasive technique with whole esophagus and mediastinal lymph node dissection in the clear visualization of the mediastinum, reducing the abdominal trauma.

Extended lymph node dissection helps increase the curativeness of resection, the accuracy of surgical-pathological staging, and the prognosis of thoracic esophageal carcinoma. However, it is also associated with significantly increased surgical morbidity and has noticeable negative effects on the quality of life after surgery. Current trends for selective lymph node dissection based on clinical evidence may be helpful in reducing surgical risks while assuring the completeness of resection.

Oesophageal cancer, in particular adenocarcinomas, has shown a rapid and largely unexplained increase in incidence in the Western world. Despite advances in diagnostic and surgical techniques and improved pre- and postoperative care, the prognosis of most patients is poor. This Review will focus on the use of chemotherapy as part of multimodal treatment and for patients with metastatic disease. Randomised phase III trials have, for the most part, failed to demonstrate a survival advantage with the use of chemotherapy. It must be emphasised that many of these phase III trial were underpowered and do not meet today's standards. Recent phase II trials have suggested some progress when chemotherapy is incorporated into the management of patients with oesophageal cancer. However, confirmatory and adequately powered and designed phase III studies are urgently needed to improve patient outcomes and for better palliation of symptoms.

We have previously reported a favourable response rate in patients with advanced esophageal cancer after treatment with a biweekly regimen of paclitaxel and cisplatin. In this study we investigate the feasibility and efficacy of this regimen in a neo-adjuvant setting.

Patients with resectable squamous cell carcinoma of the esophagus received paclit-axel 180 mg/m(2) and cisplatin 60 mg/m(2) every 2 weeks. Patients received three courses and responding patients received three additional courses; thereafter, patients were referred for surgery. Patient characteristics of 50 eligible patients were as follows: male, 60%; median age, 62 years (range 45-78); median World Health Organization performance status of 1 (range 0-2).

Ninety-four per cent of patients received at least three courses of chemotherapy. Haematological toxicity consisted of National Cancer Institute-Common Toxicity Criteria grade 3 or 4 neutropenia in 71% of patients, with neutropenic fever occurring in only two patients (4%). The overall response rate was 59%. Pathological examination showed tumour-free margins in 38 patients. In seven patients no residual tumour was found. The median overall survival was 20 months and the 1- and 3-year survival rates were 68% and 30%, respectively.

This dose-dense schedule of paclitaxel and cisplatin administered biweekly is well tolerated and the observed overall and complete response rates are promising.

The aim of this study was to evaluate the effect of preoperative chemotherapy on metastatic lymph nodes and on the outcome of patients who underwent esophagectomy for advanced squamous cell carcinoma of the esophagus. Fifty-nine patients with potentially resectable squamous cell carcinoma of the esophagus were studied. Twenty patients (group A) were treated by preoperative chemotherapy with cisplatin, 5-fluorouracil, and leucovorin, followed by surgery. Thirty-nine patients underwent surgery alone (group B). A total of 2591 resected lymph nodes were histologically evaluated for metastasis and the effect of chemotherapy. The metastasis rate in the resected lymph nodes, the number of metastatic lymph nodes, and outcome of the patients were statistically analyzed between groups. In group A, the clinical and pathological response rates were 75% and 75% respectively. The metastasis rate in the resected lymph nodes was significantly higher in group B (P < 0.01). The mean number of metastatic lymph nodes was significantly lower in group A (P < 0.05). Furthermore, the mean number of metastatic lymph nodes was significantly lower in the chemotherapy responders than in non-responders. The survival rate in group A was better than in group B (P = 0.07). Preoperative chemotherapy reduced the number of metastatic lymph nodes and may contribute to improving the outcome of the patients who have undergone esophagectomy for squamous cell carcinoma of the esophagus.

Laser therapy of esophageal carcinoma has been limited to management of malignant dysphagia. To investigate its cytoreductive potential, Nd:YAG laser tumor debulking was added to multimodality therapy.

From 1994-1998, 29 patients with advanced locoregional esophageal carcinoma were enrolled in a prospective experimental study of high-dose neoadjuvant chemoradiotherapy together with endoscopic Nd:YAG laser photoablation. Comparisons were made to a retrospective cohort of 31 patients treated from 1990 to 1994 who underwent similar neoadjuvant chemoradiotherapy without laser debulking.

Laser dosage ranged from 3457 to 67,443 J (mean 21,832 [SD 16,999]) delivered in 1 to 6 (mean 2.6 [1.4]) treatment sessions. Actuarial analysis showed improved survival in the laser-treated group versus the reference group (30.1 months vs. 16.5 months; p = 0.047). Multivariable analysis of the impact of age, T-stage, N-stage, completion of neoadjuvant therapy, and laser debulking that included all patients in both treatment groups showed completion of therapy to be the most significant variable associated with survival. There were 3 complications related to laser therapy. Relief of dysphagia was achieved in 19 of 29 patients (66%) in the laser group versus 13 of 31 (42%) in the reference group.

Malignant dysphagia may be more effectively treated by the addition of Nd:YAG laser therapy to aggressive multimodality therapy. Improved survival with the addition of laser debulking warrants longer follow-up and a prospective comparative trial.

Between 1983 and 1989, 211 patients with inoperable squamous cell carcinoma of the oesophagus were randomised in a study comparing split-course irradiation (two courses of 20 Gy in five fractions of 4 Gy, separated by a rest of 2 weeks) (arm A) and the same split-course irradiation in combination with cisplatin (CDDP) (3-4 days before each of the two courses of radiotherapy, repeated every 3-4 weeks, for a total of six cycles) (arm B). The Cox's regression model with retrospective stratification was used to compare the two arms to correct for the imbalance at randomisation of the T classification. The median overall survival was 7.9 (95% confidence interval (CI) 7.3-9.4) months in arm A and 9.6 (95% CI 8-13.5) months in arm B. The difference in overall survival was only borderline significant (P=0.048) with a reduction of the instantaneous rate of death of 24%. The 1 and 2 year overall survival rate were respectively 29% (95% CI 21-37%) and 15% (95% CI 8-22%) in arm A and 45% (95% CI 36-54%) and 20% (95% CI 13-27%) in arm B; thereafter, the survival curves became similar. The median progression free survival (PFS) was 5.0 (95% CI 4.6-5.7) versus 6.9 (95% CI 5.3-8.7) months (P=0.028) and the median time to local progression was 6.2 (95% CI 5.1-7.6) months versus 10.9 (95% CI 8.1-15.5) months (P=0.018), respectively, in arms A and B. Haematological toxicities were slightly more commonly observed in the combined group (1% versus 6%). This study shows that split-course irradiation in combination with CDDP is very well tolerated and should be preferred to radiotherapy alone.

The use of 19F-NMR as a noninvasive probe to measure directly the pharmacokinetics of drugs at their target (effector) site(s) is illustrated in this article by human studies with 5-fluorouracil (5-FU). This drug, and several of its metabolites, have been measured in vivo in animals and in patients using standard clinical MRI systems. Using a pharmacokinetic imaging approach the parameter that can be measured most readily is the tumoral t(1/2) of 5-FU. Patients whose tumoral t(1/2) of 5-FU is equal to/greater than 20 min are designated as "trappers", and those whose tumoral t(1/2) of 5-FU is less are nontrappers. Trapping of 5-FU in tumors is a necessary, albeit not a sufficient condition, for response. Problems associated with the technical aspects of these measurements have been discussed, as well as how modulators and other agents will affect the tumoral t(1/2) of 5-FU. The rationale for the biological processes underlying the fate of 5-FU in humans has been illustrated with the use of a 12 compartment model, where several of the steps have been discussed and the consequences of their inhibition/stimulation related to the noninvasive studies that can be performed with modulators of the action of 5-FU. These 19F-NMR studies have now been extended to other fluoropyrimidines, some of which are prodrugs of 5-FU, and others where the fluorine atoms are on the ribose ring. These studies also reveal information that has both scientific and clinical significance. The studies presented here illustrate some of the potential and some of the usefulness of 19F-MRS in patient management and in drug development. It is a technique that has proven itself.

This study was done to evaluate the results of the combined use of chemo- and radiotherapy before surgery in a group of patients with squamous cell esophageal carcinoma after a median follow-up period of more than 5 years.

Between June 1987 and January 1995, 111 patients with squamous cell carcinoma of the thoracic esophagus were submitted to a preoperative course of radiotherapy (3000 cGy) and chemotherapy (cisplatin and 5-FU) before surgery in the First Division of General Surgery at the University of Verona.

The neoadjuvant treatment was completed in 90.9% of the cases (101/111). After an average of 29 days, 87 patients underwent surgery (operability rate: 78.3%) and, of these, 80 underwent esophagectomy (resectability rate: 91.9%). Histopathologic studies showed no residual disease in the specimen (T0) in 17 cases (21.2%), only microscopic clusters of neoplastic cells within the esophageal wall (Minimal Residual Disease, MRD) in 14 cases (17.5%) and in 5 cases the tumor did not extend beyond the submucosal layer (T1). The median overall survival time of the 111 patients who were eligible for the study protocol was 14 months, and the 2- and 5-year survival rates were 32.0% and 17.5%, respectively. Kaplan-Meier determination of survival showed a statistically significant difference between the good responders (T0, T1, and MRD) to the neoadjuvant treatment and the remaining cases. The 2- and 5-year survival rates were 50.3% and 34.9%, respectively, in the good responder group compared with 26.7% and 10.7%, respectively, in the other cases, with a median survival time of 24 months vs. 13 months, respectively.

The neoadjuvant treatment showed promising results, especially in the group of patients that had a good response. The identification of these patients may be the key to selecting which patients should be submitted to preoperative radio- and chemotherapy.

We have previously reported that interleukin (IL)-1beta decreases responsiveness of cultured human airway smooth muscle (HASM) cells to beta-agonists. The purpose of this study was to determine whether glucocorticoids inhibit this IL-1beta effect. Dexamethasone (Dex; 10(-6) M) had no effect on concentration-related decreases in cell stiffness in response to isoproterenol (Iso) in control cells as measured by magnetic twisting cytometry but prevented the decreased responsiveness to Iso observed in IL-1beta (20 ng/ml)-treated cells. In addition, Dex had no effect on Iso-stimulated cAMP formation in control cells but prevented the IL-1beta-induced reduction in Iso-stimulated cAMP formation. Similar effects on cell stiffness and cAMP responses were seen after pretreatment with the glucocorticoid fluticasone proprionate (FP). Dex and FP also prevented IL-1beta-induced hyporesponsiveness to PGE(2) stimulation. In contrast, neither IL-1beta nor glucocorticoids had any effect on cell stiffness responses to dibutyryl cAMP. We have previously reported that the IL-1beta effect on beta-adrenergic responsiveness is mediated through cyclooxygenase-2 expression and prostanoid formation. Consistent with these observations, IL-1beta-induced cyclooxygenase-2 expression was virtually abolished by FP at concentrations of 10(-10) M and greater, with a resultant decrease in PGE(2) formation. However, Dex did not inhibit IL-1beta-induced nuclear translocation of nuclear factor-kappaB or activator protein-1 in HASM cells. In summary, our results indicate that, in HASM cells, glucocorticoids alone do not alter responses to beta-agonists but do inhibit IL-1beta-induced beta-adrenergic hyporesponsiveness. Glucocorticoids mediate this effect by inhibiting prostanoid formation but without altering nuclear factor-kappaB or activator protein-1 translocation.

We performed a multi-institutional randomized trial comparing preoperative chemotherapy followed by surgery with surgery alone for patients with local and operable esophageal cancer.

Preoperative chemotherapy for patients randomly assigned to the chemotherapy group included three cycles of cisplatin and fluorouracil. Surgery was performed two to four weeks after the completion of the third cycle; patients also received two additional cycles of chemotherapy after the operation. Patients randomly assigned to the immediate-surgery group underwent the same surgical procedure. The main end point was overall survival.

Of the 440 eligible patients with adequate data , 213 were assigned to receive preoperative chemotherapy and 227 to undergo immediate surgery. After a median possible study time of 55.4 months, there were no significant differences between the two groups in median survival: 14.9 months for the patients who received preoperative chemotherapy and 16.1 months for those who underwent immediate surgery (P=0.53). At one year, the survival rate was 59 percent for those who received chemotherapy and 60 percent for those who had surgery alone; at two years, survival was 35 percent and 37 percent, respectively. The toxic effects of chemotherapy were tolerable, and the addition of chemotherapy did not appear to increase the morbidity or mortality associated with surgery. There were no differences in survival between patients with squamous-cell carcinoma and those with adenocarcinoma. Weight loss was a significant predictor of poor outcome (P=0.03). With the addition of chemotherapy, there was no change in the rate of recurrence at locoregional or distant sites.

Preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with epidermoid cancer or adenocarcinoma of the esophagus.

Many options are available for palliation of inoperable malignant stenoses of the esophagus. We report our experience with different modalities of endoscopic therapy.

From 1986 to 1996, we treated 125 patients with dysphagia caused by unresectable malignant tumors with endoscopic therapy. Seventy patients were treated with laser therapy, 34 with a plastic endoprosthesis, and 21 with an expandable prosthesis. Therapeutic outcome and complication rates were analyzed for the three groups.

Mean dysphagia score decreased in the same manner in all three groups. Major and minor complications were significantly more common in the plastic endoprosthesis group and in the metallic stent group compared with the laser therapy group. Therapy and patient survival were not significantly different among the three groups.

Plastic and metal stents carry a high complication rate for a short period of palliation. Endoscopic laser therapy, in contrast, has a low complication rate. Laser therapy should be the first choice for palliation in malignant dysphagia in patients with a short life expectancy. Stents might be used when laser therapy fails, in the presence of fistulas, or in patients with a reasonable life expectancy.

The objective of this prospective, nonrandomized study was to evaluate the immediate and long-term results of first-line chemotherapy and possible surgery in locally advanced, presumably T4 squamous cell esophageal cancer.

Locally advanced esophageal cancer is rarely operable and has a dismal prognosis. For this reason, neoadjuvant cytoreductive treatments are more and more frequently used with the aim of downstaging the tumor, increasing the resection rate, and possibly improving survival.

From January 1983 to December 1991, 163 consecutive patients with a presumedly T4 squamous cell carcinoma of the thoracic esophagus (group A) received on average 2.5 cycles (range, 1-6) of first-line chemotherapy with cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 per day, in continuous infusion from day 1 through day 5). Chemotherapy was followed by surgery when adequate downstaging of the tumor was obtained.

Chemotherapy toxicity was WHO grade 0 to 2 in 80% of cases, but 3 toxic deaths (1.9%) occurred. Restaging suggested a downstaging of the tumor in 101 of 163 patients (62%), but only 85 patients (52%) underwent resection surgery; it was complete or R0 in 52 (32%) and incomplete or R1-2 in 33. Overall postoperative mortality was 11.7% (10 of 85), morbidity 41% (35 of 85). Complete pathologic response was documented in 6 patients, and significant downstaging to pStage I, IIA, or IIB occurred in 25 more patients. The overall 5-year survival was 11 % (median, 11 months). After resection surgery, the 5-year survival was 20% (median, 16 months); none of the nonresponders survived 4 years after palliative treatments without resection (median survival, 5 months). The 5-year survival rate of the 52 patients undergoing an R0 resection was 29% (median, 23 months). Stratifying patients according to the R, pT, pN, and pStage classifications, the survival curves were comparable to the corresponding data obtained in the 587 group B patients with "potentially resectable" esophageal cancer who underwent surgery alone during the same period. Furthermore, the results were improved in comparison with 136 previous or subsequent patients with a locally advanced tumor who did not undergo neoadjuvant treatments (group C). In these patients, the R0 resection rate was 7%, and the overall 5-year survival was 3% (median, 5 months).

Although nonrandomized, these results suggest that in locally advanced esophageal carcinoma, first-line chemotherapy increases the resection rate and improves the overall long-term survival. In responding patients who undergo R0 resection surgery, the prognosis depends on the final pathologic stage and not on the initial pretreatment stage.

Carcinoma of the esophagus is a disease with a poor prognosis. Surgery is considered the treatment of choice. Patients who are surgically unresectable may receive radiotherapy, plus or minus chemotherapy. While this offers reasonable palliation, a significant number of patients develop benign or malignant strictures. Frequent esophagoscopy with dilation is required if they are to swallow. Patients with strictures or malignancy of the esophagus are more prone to complications if they undergo an esophagoscopy. We examined the morbidity of esophagoscopy in a group of patients who had received radiotherapy for carcinoma of the esophagus. Over a 10-year period, 21 patients receiving irradiation for carcinoma of the esophagus were examined. All patients underwent esophagoscopy for staging and diagnosis. The tumor locations were upper (6), middle (6), and lower (9) esophagus. The T-stages were 1 (7), 2 (6), 3 (6), and 4 (2). Five patients had dilation of a malignant stricture at the time of diagnosis. Fever developed and resolved within 24 hours in 2 patients. Following completion of irradiation, a total of 83 esophagoscopies were performed (range 1 to 11 per patient). Six patients with no tumor or stricture underwent 8 esophagoscopies (3 rigid, 5 flexible). There was 1 episode of minimal bleeding and 1 fever that resolved within 24 hours. Ten patients with malignant strictures underwent 62 esophagoscopies (5 rigid, 57 flexible). There were 17 (27%) episodes of fever (all resolved within 24 hours) and 14 (22%) episodes of bleeding. Five patients with benign strictures underwent 13 esophagoscopies (2 rigid, 11 flexible). One patient had a perforation that resolved with conservative treatment, and 1 patient developed an epidural abscess 2 months following dilation. This patient is the only one that required surgical intervention and had prolonged hospitalization. Esophagoscopy of the irradiated esophagus can be performed relatively safely and excellent palliation obtained. Morbidity consisting of minimal bleeding, and fever lasting less than 24 hours, is frequent but self-limited.

TNM staging of gastroesophageal cancer is improved by the use of laparoscopy for the detection of occult metastases and endoscopic ultrasonography for T and possibly N staging. Laparoscopic ultrasonography may combine the strengths of both of these techniques. The purpose of this study was to compare TNM staging by means of laparoscopic ultrasonography (Lap US), laparoscopy, and conventional computed tomography (CT).

TNM stage was determined by using Lap US, laparoscopy, and CT scanning in 26 surgical candidates with gastric or esophageal cancer in a blinded fashion. CT scans were also reviewed separately by an expert radiologist. Validation of findings was by means of final pathologic examination.

Resectability for potential cure was determined by means of Lap US with a sensitivity of 100% and a specificity of 91% versus 100% and 73% for laparoscopy and 75% and 60% for CT, respectively. Overall TNM staging was 82% accurate for Lap US versus 67% for laparoscopy and 47% for CT (chi-squared, 8.64, p < 0.005, and 10.4, p < 0.005, respectively). Accuracies for Lap US versus laparoscopy versus CT for N stage were 92% versus 84% versus 70%, respectively, for T stage were 92% versus 42% versus 60%, respectively, and for M stage were 89% versus 44% versus 62%, respectively.

T and N staging by Lap US were comparable to published results for endoscopic ultrasonography, and overall TNM staging was better. Lap US may provide the optimal preoperative staging for gastric cancer and has the potential to complement endoscopic ultrasonography in staging esophageal cancer.