Surgical Therapy of Esophageal Adenocarcinoma—Current Standards and Future Perspectives

Transthoracic esophagectomy is currently the predominant curative treatment option for resectable esophageal adenocarcinoma. The majority of carcinomas present as locally advanced tumors requiring multimodal strategies with either neoadjuvant chemoradiotherapy or perioperative chemotherapy alone. Minimally invasive, including robotic, techniques are increasingly applied with a broad spectrum of technical variations existing for the oncological resection as well as gastric reconstruction. At the present, intrathoracic esophagogastrostomy is the preferred technique of reconstruction (Ivor Lewis esophagectomy). With standardized surgical procedures, a complete resection of the primary tumor can be achieved in almost 95% of patients. Even in expert centers, postoperative morbidity remains high, with an overall complication rate of 50–60%, whereas 30- and 90-day mortality are reported to be <2% and <6%, respectively. Due to the complexity of transthoracic esophagetomy and its associated morbidity, esophageal surgery is recommended to be performed in specialized centers with an appropriate caseload yet to be defined. In order to reduce postoperative morbidity, the selection of patients, preoperative rehabilitation and postoperative fast-track concepts are feasible strategies of perioperative management. Future directives aim to further centralize esophageal services, to individualize surgical treatment for high-risk patients and to implement intraoperative imaging modalities modifying the oncological extent of resection and facilitating surgical reconstruction.

Urothelial cancer: population-based analysis of the problem in Ukraine

The aim of this work was to conduct a population analysis on the basis of the National Cancer Registry with the primary goal: to determine the effectiveness of urothelial cancer treatment in Ukraine; and the secondary goal: to identify the main trends and approaches to therapy with an assessment of their impact on overall survival. Materials and methods. The design of the study was retrospective observational. The analysis was conducted based on the data of the National Cancer Registry from 2008 to 2020. A total of 12,698 patients with urothelial tumors of the upper urinary tract and bladder who underwent surgical treatment were analyzed. Statistical sampling was performed based on the creation of the most homogeneous groups of patients with bladder cancer (BC) and the upper urinary tract carcinoma (UUTc) who had the required number of notified parameters for further analysis. The primary objectives of the analysis were to determine: the average age of primary detection of the studied nosologies, level of detection depending on gender, frequency of diagnosis verification before surgery, extent of surgery, frequency of postoperative complications based on data on 30-day rehospitalization, the level of deviation of the principles for prophylactic medical patients’ examination from generally accepted recommendations. The secondary objective was to assess the cumulative survival of patients with urothelial tumors depending on the localization of the primary tumor and the type of surgery (organ-sparing or radical). Results. Organ-sparing treatment was more typical for BC, while radical treatment was performed in 15 % of patients with carcinomas. Organ-sparing treatment was more typical for UUTc (40 %). It should be noted that in this nosology it is accep­table for invasive forms of urothelial cancer. The level of 30-day hospita­lization was low in both pathologies, with a slightly greater advantage of UUTc. The level of complications is grade III according to the Clavien-Dindo classification, averaging 0.2 % for the entire pool of patients. For BC, the overall survival rates by stages were: I — 73 %, II — 49 %, III — 18 % and IV — 11 % (chi-square = 1,807.207; p = 0.000001). For UUTc, the levels of 5-year overall survival correspond to the literature data, but there is a significant negative tendency to decrease the latter after a ­10-year period for all stages (chi-square = 146.298; p = 0.000003). In Ukraine, organ-sparing treatment for UUTc was not inferior to radical nephroureterectomy in the context of 5-year survival (51.3 vs. 51 %; log-rank test). The obtained data testify in favor of the 15% advantage of the total survival of patients who underwent radical nephroureterectomy at the premises of the National Cancer Institute (high volume center), compared to other regions of Ukraine. Levels of 5- and ­10-year survival in both nosologies were characterized by a statistically non-significant advantage of UUTc over BC of 7 %. Conclusions. Superficial and locally advanced tumors are the most complex ones in the treatment of urothelial cancer of the bladder and upper urinary tract in Ukraine. Superficial tumors require the most radical surgeries and subsequent effective local treatment. Locally advanced tumors require a comprehensive approach to treatment, adequate systemic therapy influences the final indicators of overall survival. In cases of surgical resectability and preservation of renal function, UUTc requires organ-sparing treatment; this approach aims to increase creatinine clearance in patients before systemic chemotherapy and to reduce the likelihood of progression of comorbidities and associated mortality.

Contribution of Genomics to the Surgical Management and Study of Oral Cancer

Background Oral squamous cell carcinoma (OSCC) is the most frequent type of tumor arising from the oral cavity. Surgery is the cornerstone of the treatment of these cancers. Tumor biology has long been overlooked as an important contributor to the outcome of surgical procedures, but recent studies are challenging this concept. Molecular analyses of tumor DNA or RNA provide a rich source of information about the biology of OSCC. Methods We searched for relevant articles using PubMed. We examined in particular the prospect of applying molecular methods for minimally invasive exploration of OSCC biology. Results We examined five potential applications of genomics to the surgical management and study of OSCC: i) assessing oral potentially malignant lesions; ii) tumor staging prior to surgery; iii) predicting postoperative risk in locally advanced tumors; iv) measuring minimal residual disease and optimizing the longitudinal monitoring of OSCC; and v) predicting the efficacy of medical treatment. Conclusions Genomic information can be harnessed in order to identify new biomarkers that could improve the staging, choice of therapy and management of OSCC. The identification of new biomarkers is awaited for better personalization of the surgical treatment of OSCC.

Calcium cytotoxicity sensitizes prostate cancer cells to standard-of-care treatments for locally advanced tumors

Therapy resistance is a major roadblock in oncology. Exacerbation of molecular dysfunctions typical of cancer cells have proven effective in twisting oncogenic mechanisms to lethal conditions, thus offering new therapeutic avenues for cancer treatment. Here, we demonstrate that selective agonists of Transient Receptor Potential cation channel subfamily M member 8 (TRPM8), a cation channel characteristic of the prostate epithelium frequently overexpressed in advanced stage III/IV prostate cancers (PCa), sensitize therapy refractory models of PCa to radio, chemo or hormonal treatment. Overall, our study demonstrates that pharmacological-induced Ca2+ cytotoxicity is an actionable strategy to sensitize cancer cells to standard therapies.

Expanding Uses of HIPEC for Locally Advanced Colorectal Cancer: A European Perspective

Locally advanced colorectal cancer is a challenge for surgeons and medical oncologist; 10 to 20% colorectal cancer debut as locally advanced disease, with tumors extending through the colon wall with perforation and/or invasion of adjacent organs or structures. Those locally advanced tumors have a worse prognostic at any stage due not only to systemic dissemination but also in a high percentage of patients, to locoregional recurrence, in fact, peritoneal carcinomatosis of colorectal origin is so predictable that we can assess the risk for each patient according to some histopathological and clinical features: small peritoneal nodules resected in the first surgery (70% probability), ovarian metastases (60%), perforated tumor onset or intraoperative tumor rupture (50%), positive cytology (40%), and pT4/mucinous pT3 up to 40%. Prophylactic or adjuvant hyperthermic intraperitoneal chemotherapy seems to be a promising strategy for patients with advanced colorectal cancer to prevent the development of peritoneal recurrence and improve prognosis of this group of patients.

Verrucous carcinoma of the esophagus with complete response after chemoradiotherapy

Background Verrucous carcinoma of the esophagus (VCE) is a rare tumor that is difficult to diagnose. In most cases, biopsies show nonspecific inflammatory and hyperkeratotic changes and do not show malignant findings. Most VCEs are slowly growing, locally advanced tumors with few metastases. Treatments for VCE are the same as for normal esophageal cancer, involving combined chemotherapy, surgical resection, and radiation therapy. However, it has been reported that VCE has a poor response to radiation or chemoradiotherapy (CRT). A case of VCE with complete response (CR) after CRT is presented. Case presentation A 70-year-old man was found to have white, irregular esophageal mucosa four years earlier. He had been followed-up as an outpatient as having candidal esophagitis. However, his tumor grew gradually, and biopsy was performed by endoscopic mucosal resection. He was finally diagnosed with VCE. He had no metastases to distant organs, but some lymph node metastases were suspected. The tumor invaded his left bronchus. First, the esophagostomy and gastrostomy were constructed. The patient then underwent definitive CRT. Four weeks after the end of CRT, two-stage esophagectomy was performed. First, he underwent esophagectomy with thoracic lymph node dissection. A latissimus dorsi flap was patched to the bronchus after primary suture of the hole. Six weeks later, reconstruction of the gastric tube was performed through the antethoracic route. The pathological findings showed complete response to CRT, with no proliferative cancer cells in the specimen. Six months after the first-stage operation, no recurrence has been observed. Conclusions A case of locally advanced VCE that achieved a complete response to CRT was presented. In cases in which local resection would be difficult, CRT might be an appropriate neoadjuvant treatment for VCE.

Laparoscopic-assisted left thoracoabdominal esophagectomy (LLTA): an innovative approach for locally advanced tumors of the gastroesophageal junction

ABSTRACT Purpose To report a novel approach for locally advanced tumors located at the gastroesophageal junction (GEJ) using a laparoscopic abdominal phase and open left thoracotomy with the patient in a single right lateral decubitus position. Background The standard open left thoracoabdominal approach offers excellent exposure and access to the GEJ and lower esophagus. It also involves a single position for the procedure, shortening the operation time. The disadvantages are a large incision, division of the costochondral junction, and a low-level thoracotomy. The laparoscopic-assisted left thoracoabdominal esophagectomy (LLTA) is performed with the patient in the same right lateral decubitus position, but initially rolled away from the operator at 45° allowing laparoscopic gastric mobilization and lymphadenectomy. The patient is then tilted back to the lateral position for the thoracic phase. An anterolateral left thoracotomy is performed through the higher fifth intercostal space allowing a high intrathoracic anastomosis, just below the aortic arch. No disruption of the costochondral junction is made. Methods Consecutive patients selectively treated for locally advanced GEJ tumors with an LLTA approach between 2013 and 2019 were analyzed and compared to national standards (NOGCA). Results This series of 74 consecutive patients had a mean age of 63 years. The median operation time was 235 minutes. The median inpatient stay was 10 days (NOGCA 9 [11–17]). The tumors were predominantly adenocarcinoma (95%) and located at the GEJ (92%). The majority were locally advanced T3 or T4 tumors. Postoperative morbidity was low, Clavien–Dindo (C–D) 0 in 52.7% patients, C–D1 (1.4%), C–D2 (31.1%), C–D3a (5.4%), C–D4a (9.5%), and C–D5 (1.4%). The median number of total lymph nodes (LN) excised was 28 (NOGCA &gt;15); LN % yield ≥18 was 90% (NOGCA 82.5%). Positive nodes were located at the lesser-curve (40%), paraesophageal (32.4%), and subcarinal regions (2.7%). Positive circumferential resection margins (&lt;1 mm) were present in 28.4% of resected specimens (NOGCA 25.1%). This is reflective of the high proportion T3/T4 tumors selected for this approach. Hospital and 30-day mortality was 1.4% (NOGCA 2.7%). Recurrence after LLTA was 25.7% (local 5.4%, systemic 17.6%, mixed 2.7%) at a median of 311 days (62–1,158). Conclusion This series demonstrates a novel, safe, and reproducible approach for locally advanced cancer of the GEJ. It offers a better exposure of the hiatus than the right-sided approach and avoids division of the costochondral junction and low thoracotomy seen with the open left thoracoabdominal approach.

Mesothelial-to-Mesenchymal Transition Contributes to the Generation of Carcinoma-Associated Fibroblasts in Locally Advanced Primary Colorectal Carcinomas

During peritoneal metastasis, cancer cells spread from abdominal solid tumors, disseminate through the peritoneal fluid and attach to and invade through mesothelial cells (MCs) that line the peritoneum. Intestinal adenocarcinomas originating in the mucosa infiltrate the submucosa, muscle layer, and serosa in order to finally colonize the peritoneal cavity. However, the mechanism by which metastatic cells leave the primary tumor and reach the peritoneal cavity has not been previously described. Hence, we investigate whether MCs lining visceral peritoneum, through a mesothelial-to-mesenchymal transition (MMT), are a source of carcinoma-associated fibroblasts (CAFs), which could contribute to cancer progression toward the peritoneal cavity. CAFs detected in biopsies from patients with superficially invasive colorectal cancer differed from locally advanced tumors. An aberrant accumulation of myofibroblasts expressing mesothelial markers was found in the stroma of deeply infiltrative tumors located in the neighborhood of a frequently activated mesothelium. We suggest that MMT is a key event in the early stages of peritoneal dissemination.

CDK12 upregulation and adverse correlation with tumor-associated immune cell infiltrates in prostate cancer.

181 Background: Biallelic loss of CDK12 has recently been identified as a novel subtype of prostate cancer (PCa). CDK12 altered PCa associates with elevated neoantigen burden and thus may be suitable for checkpoint inhibition. Up to now, data about CDK12 refer to its genetic alterations in PCa while its characterization on protein level and its association with tumor infiltrating T-cells are lacking. Methods: Immunohistochemistry (IHC) for CDK12 was performed on a PCa cohort including 74 benigns, 391 primary tumors from 222 patients, 63 locally advanced tumors, 92 lymph node (LN) metastases, and 56 distant metastases. CDK12 was categorized into negative, weak, moderate and high expression. Density of tumor associated T-cells per tumor area was assessed by IHC for CD3 and graduated into negative (<1%), slight (1-5%), weak (5-10%), moderate (10-50%) and high (>50%). Results: CDK12 significantly increases during PCa progression showing highest levels in LN and distant metastases while benign samples harbor no or weak CDK12 expression (ANOVA p<0.001). Kaplan-Meier curve reveals 5-year-biochemical recurrence free survival rates of 89.5%, 69.1%, 59.1% and 20.0% for primary tumors expressing no, weak, moderate and high CDK12 (log-rank p=0.05). High CDK12 expression significantly associates with attenuated tumor associated T-cells (p=0.009) revealing CD3 negativity in 64.7% of CDK12 high expressing tumors. Intratumoral CDK12 and density of CD3 positive T-cells correlates adversely in particular in locally advanced tumors (p=0.007). Overall, tumor associated T-cells are significantly reduced in distant metastases compared to local PCa (p<0.001). Conclusions: Our study highlights the prognostic potential of CDK12 for PCa and its overexpression in advanced tumors. Of note, CDK12 overexpressing tumors can be designated as immunologic “cold” tumors which is in line with their more aggressive phenotype. Concordantly, distant metastases show attenuated tumor associated T-cells supporting the poor response to immunotherapy.