Neoadjuvant PD-1 Blockade Combined With Chemotherapy Followed by Concurrent Immunoradiotherapy in Locally Advanced Anal Canal Squamous Cell Carcinoma Patients: Antitumor Efficacy, Safety and Biomarker Analysis

BackgroundAnal canal squamous cell carcinoma (ACSCC) is an exceedingly rare malignant neoplasm with challenges in sphincter preservation, treatment toxicities and long-term survival. Little is known concerning the activity of PD-1 antibodies in locally advanced ACSCC. This study reports on the efficacy and toxicities of a neoadjuvant PD-1 blockade combined with chemotherapy followed by concurrent immunoradiotherapy in ACSCC patients, and describes biomarkers expression and mutation signatures.MethodsIn this cohort study, patients were treated as planned, including four cycles of neoadjuvant PD-1 antibody toripalimab combined with docetaxol and cisplatin, followed by radiotherapy and two cycles of concurrent toripalimab. Multiplex immunofluorescence staining (mIHC) with PD-L1, CD8, CD163, Pan-Keratin and DAPI was performed with the pretreatment tumor tissue. Whole exome sequencing was performed for the primary tumor and peripheral blood mononuclear cells. The primary endpoint was the complete clinical response (cCR) rate at 3 months after overall treatment. Acute and late toxicities graded were assessed prospectively.ResultsFive female patients with a median age of 50 years old (range, 43-65 years old), finished treatment as planned. One patient had grade 3 immune related dermatitis. Two patients had grade 3 myelosuppression during neoadjuvant treatment. No severe radiation-related toxicities were noted. Four patients with PD-L1 expression >1% achieved a cCR after neoadjuvant treatment. and the other patient with negative PD-L1 expression also achieved a cCR at 3 months after radiotherapy. All the patients were alive and free from disease and had a normal quality of life, with 19.6-24 months follow up. Inconsistent expression of PD-L1 and CD163 was detected in 3 and 5 patients, respectively. TTN, POLE, MGAM2 were the top mutation frequencies, and 80 significant driver genes were identified. Pathway analysis showed enrichment of apoptosis, Rap1, Ras, and pathways in cancer signaling pathways. Eight significantly deleted regions were identified.ConclusionsThis small cohort of locally advanced ACSCC patients had quite satisfactory cCR and sphincter preservation rate, after neoadjuvant PD-1 antibody toripalimab combined with chemotherapy followed by concurrent immunoradiotherapy, with mild acute and long-term toxicities.

Research on Anal Squamous Cell Carcinoma

Anal canal and peri-anal squamous cell carcinomas (ASCCs) are relatively rare cancers that affect approximately 8000 patients per year in the United States [...]

Morphological evaluation of anal canal wound healing after combined operations for combined anorectal pathology

The urgency of the problem of postoperative wound healing after combined operations for combined pathology of the anal canal and rectum is quite high and contributes to the introduction into the practice of coloproctologists of new modern surgical technologies for the treatment of this pathology. The aim of the study was to conduct a comparative morphological assessment of postoperative wound healing in patients with combined pathology of the anal canal and rectum after combined operations using modern high-frequency electrosurgical and radiosurgical technologies. The results of surgical treatment of 689 patients with combined pathology of the anal canal and rectum using high-frequency electrosurgery and radiowave surgery with morphological assessment of wound healing on 3, 5, 7, 14, 21 days of the postoperative period, which were divided into 4 study groups. Using of “Surgitron” and “KLS Martin” devices for the treatment of patients with combined pathology of the anal canal and rectum was accompanied by the formation of the thinnest layers of coagulation necrosis in tissues with a depth of 0.189±0.085 mm and 0.194±0.090 mm respectively and as result patients of the first and fourth study groups had the shortest duration of inpatient treatment, which was 3-5 days and the average time of wound healing, which was 14-15 days. Patients in these study groups had the lowest inflammatory neutrophil reaction in postoperative wounds on day 3, which rapidly disappeared by day 5, on days 7-14 they had active reparative processes with the appearance of fibroblasts and connective tissue fibers, and on 21 day squamous epithelial cells, which indicated the processes of active epithelialization of wounds. The effect on the tissues of the devices “EFA” and “ERBE ICC 200” was deeper than in the above groups, forming a layer of coagulation tissue necrosis with a depth of 0.208±0.097 mm and 0.302±0.107 mm respectively, which was accompanied by patients of the third and second study groups with longer terms of inpatient treatment, which amounted to 5-7 days and increase the duration of wound healing, which amounted to 16-19 days. Patients in the 2nd and 3rd study groups showed a more pronounced inflammatory neutrophilic reaction in postoperative wounds on the 3rd day, which did not disappear until the 5th day and in half of the cases the presence of a significant number of segmental neutrophils and bacterial accumulations persisted. On days 7-14 they had weak reparative processes with the appearance of single fibroblasts and a small number of connective tissue fibers and on the 21st day single squamous epithelial cells, which indicated slow processes of wound epithelization. Using of radio-wave surgery and high-frequency electrosurgery devices promotes active epithelialization of tissues preventing scar strictures of the anal canal and improves the rehabilitation of patients in the postoperative period.

Pre-Clinical Applications of High-Definition Manometry System to Investigate Pelvic Floor Muscle Contribution to Continence Mechanisms in a Rabbit Model

External anal sphincter (EAS), external urethral sphincters and puborectalis muscle (PRM) have important roles in the genesis of anal and urethral closure pressures. In the present study, we defined the contribution of these muscles alone and in combination to the sphincter closure function using a rabbit model and a high-definition manometry (HDM) system. A total of 12 female rabbits were anesthetized and prepared to measure anal, urethral, and vaginal canal pressures using a HDM system. Pressure was recorded at rest, and during electrical stimulation of the EAS and PRM. A few rabbits (n=6) were subjected to EAS injury and the impact of EAS injury on the closure pressure profile was also evaluated. Anal, urethral, and vaginal canal pressures recorded at rest and during electrical stimulation of EAS and PRM demonstrated distinct pressure profiles. EAS stimulation induced anal canal pressure increase whereas PRM stimulation increased the pressures in all the three orifices. Electrical stimulation of EAS after injury resulted in about 19% decrease in anal canal pressure. Simultaneous electrical stimulation of EAS and PRM resulted in an insignificant increase of individual anal canal pressures when compared to pressures recorded after EAS or PRM stimulations alone. Our data confirm that HDM is a viable system to measure dynamic pressure changes within the three orifices and to define the role of each muscle in the development of closure pressures within these orifices in preclinical studies.

Role of magnetic resonance imaging in diagnosis and grading of perianal fistulas

Background: Fistula-in-ano can be defined as a hollow tract or cavity which is lined by granulation tissue. In case of fistula-in-ano, one end of this fistula opens in the anal canal whereas the other end is located in perianal area. Fistula-in-ano can considerably affect quality of life of an individual because of perianal discharge of blood and pus. Imaging of these fistulas is an important part of management and MR imaging is important in assessing relationship between the fistulous tract and sphincter muscles. Moreover, MR imaging can reliably demonstrate transmural inflammation, secondary tracts/ramifications, and abscesses which cannot be diagnosed on the basis of conventional fistulography. Aims and Objectives: The aim of the study was to evaluate role of MRI in diagnosis and grading of perianal fistulae. Materials and Methods: This was a retrospective observational study, in which 60 patients with fistula-in-ano were included on the basis of a predefined inclusion and exclusion criteria. MR imaging of patients was done by 1.5 T MRI machine. Before MR imaging normal saline was injected in the fistulous tract from secondary/external opening, that is, opening around perianal area. Three plane images were obtained in all the cases. T1W, T2W, and STIR image sequences were obtained parallel to pelvic diaphragm. Coronal cuts were imaged parallel to anal canal. FAT suppressed T1W and T2W images in all cases. Type and grade of fistula were determined in all the cases. P < 0.05 was taken as statistically significant. Results: Out of total 60 patients, there were 46 (76.66%) males and 14 (23.33%) were females with a M:F ratio of 1:0.30. The mean age of male and female patients was found to be 41.93±8.96 years and 44.04±7.46 years, respectively. The most common type of fistula was found to be trans-sphincteric fistula which was seen in 31 (51.6%) cases followed by intersphencteric fistula 22 (36.6%). Extrasphincteric and suprasphincteric fistulae were relatively uncommon and were seen in 4 (6.66%) and 3 (5%) cases, respectively. MRI was accurate in diagnosis of the tract with position of internal opening and any abscess cavity or secondary tract in 23 patients. Therefore, the diagnostic accuracy of MRI was found to be 95.4%. Conclusion: MRI is an excellent tool in assessment of perianal fistula. It not only helps in precisely locating fistulous tract but also can demonstrate relationship between the fistulous tract and sphincter muscles. Moreover, it can very well demonstrate transmural inflammation, secondary tracts/ramifications, and abscesses which cannot be assessed by conventional fistulograms.