Patient-derived Organoid Model for Predicting the Chemoresponse in Patients With Colorectal Cancer.

BACKGROUND/AIM: Cancer mortality has decreased due to the contribution of extensive research on cancer treatment, including chemotherapy, radiation, and immunotherapy. However, histopathologically similar tumors originating from the same organ are treated with identical or similar chemotherapeutic regimens regardless of patient characteristics or cancer subtypes. The aim of this study was to evaluate the utility of organoids in predicting responses to chemotherapeutic agents. PATIENTS AND METHODS: This study retrospectively reviewed patient-derived organoids (PDOs) from 10 colorectal cancer patients to compare chemotherapy responses. Drug sensitivities for 5-fluorouracil (5-FU), cisplatin, oxaliplatin, and irinotecan were compared using GI50 (concentration that inhibits cancer cell growth by 50%). RESULTS: When organoids were treated with 5-FU, GI50 was the lowest compared to the other three chemotherapeutic agents (cisplatin, oxaliplatin, and irinotecan). The responsiveness to chemotherapeutic agents differed depending on specific patient characteristics including age, tumor location, stage, and gross type. The response of the patients' organoids to chemotherapeutic agents was consistent with the response to chemotherapy actually performed in those patients with cancer recurrence after surgery. CONCLUSION: PDOs may be useful as a preclinical model in predicting chemotherapy responses in cancer patients.

En-bloc resection including SMV and duodenum in patient of locally advanced colon cancer.

Tumor could directly invade or is adherent to other organs, but superior mesentery vein (SMV) and duodenum invasion are very rare. A 62-year-old woman was diagnosed with abdominal pain for several months. Multiple erythematous brownish skin patches and palpable mass were found at epigastric area. Computed tomography imaging showed focal wall thickening at the transverse colon that invaded to the rectus muscle and anterior abdominal wall. On exploration, we identified tumor invaded or was adherent to the duodenum and superior mesenteric vein and performed en-bloc resection. After surgery, the patient received chemotherapy and was followed up without any recurrence for 16 months. Adhesion and invasion of tumor to surrounding organs can be unexpectedly found during surgery. In our case, we found duodenum and SMV invasion and achieved R0 resection by SMV and duodenum resection, which could improve the patient's prognosis.

Conservative Treatment in Two Patients With Spontaneous Hepatic Artery Dissection.

BACKGROUND: Spontaneous dissection of the hepatic artery is a rare finding for which there is no specific treatment algorithm. Even though endovascular treatment and surgery have been used to treat other visceral artery dissections, these approaches can be challenging in the case of hepatic artery dissection because it is difficult to access the hepatic artery. CASE SUMMARY: 2 patients with spontaneous dissection of the hepatic artery were admitted due to epigastric pain. Although the liver function test results were normal, and there were no complications such as bleeding, shock, or ischemia in other organs, a subsequent computed tomography scan directly revealed the spontaneous dissection of the hepatic artery in both patients. The patients were treated with anticoagulants without surgery. Because it is difficult to perform surgery or endovascular treatment on the hepatic artery, we focused on preventing the progression of hepatic artery dissection and the formation of a new thrombus in the dissection. CONCLUSION: Considering the risk of surgical treatment for the hepatic artery and the condition of the patients, medical treatment with anticoagulants may be considered as an initial treatment and provide more benefits than surgical treatment.

Huge adrenal schwannoma: a rare type of adrenal tumor, misconceived as adrenocortical carcinoma.

Schwannoma is a benign and uncommon neoplasm arising from the neural crest cells. The most common tumor sites are the skin and subcutaneous tissue of the head and neck. Retroperitoneal schwannomas account for 1-3% of all schwannomas and are predominantly female. In particular, adrenal schwannoma is very rare, and due to its large size at the time of diagnosis, adrenal schwannoma is frequently misdiagnosed as adrenocortical carcinoma or pheochromocytoma. Adrenal schwannoma is difficult to distinguish it from other adrenal diseases based on imaging findings alone. In this report, we introduce the case of a huge left adrenal schwannoma.

Bowel perforation surgery due to fecal impaction immediately after hernia mesh surgery (TAPP).

Inguinal hernia repair using prosthetic mesh is used as a standard treatment in most countries and considered superior to primary suture repair. Although prosthetic mesh has greatly reduced the risk of recurrence, the risk of mesh infection remains. A 71-year-old man was diagnosed with symptomatic bilateral inguinal hernias. He underwent successful laparoscopic transabdominal preperitoneal (TAPP) repair and was discharged the same day. After 3 days, he was diagnosed with small bowel perforation, and underwent emergency surgery. We found perforation of the distal ileum caused by the fecal impaction and severe intra-abdominal contamination. We performed subtotal colectomy and ileosigmoid anastomosis, but did not remove the prosthetic mesh because the previous TAPP site was intact. The patient recovered well post-operatively. Therefore, contaminated or dirty surgery immediately after the hernia mesh surgery could be a feasible treatment.

Selected deceased donor liver transplantation in controlled Fournier's gangrene: a case report.

Bacterial infection represents a turning point in the natural history of cirrhosis, causing the development of acute-on-chronic liver failure. It significantly affects the outcome of patients listed for liver transplantation. We report the case of a 57-year-old man who had been regularly treated for hepatitis B virus, alcoholic liver cirrhosis, and hepatic failure. The patient was hospitalized again due to variceal bleeding and hepatic coma. He visited the emergency room with painful anal swelling, dysuria, icteric sclera, and serious abdominal distension. The painful anal swelling and necrosis progressed; thus, he was diagnosed with Fournier's gangrene. Enterococcus faecium and Candida albicans were detected in the blood. Gangrene wound debris was studied extensively. Despite appropriate antibiotic treatment, vancomycin-resistant enterococcus and C. albicans were continuously present in the blood. Wide debridement of the wound and T-colostomy were performed. After this, norepinephrine and vasopressin were used to maintain stable vital signs. It was difficult to establish a liver transplant operation. Despite repeated bleeding, bacterial infections improved with additional antibiotics. Finally, selected deceased donor liver transplantation in controlled Fournier's gangrene was successfully performed. Controlled infections may be allowed in transplantation surgery.

Initial experience with laparoscopic posterior retroperitoneal adrenalectomy in single tertiary center.

Purpose: Laparoscopic posterior retroperitoneal adrenalectomy (LPRA) is a surgical method that accesses the adrenal gland through the back. The aim of this study was to report initial experience of LPRA and evaluate possibilities for surgical application. Methods: From March 2018 to December 2019, a total of 30 consecutive patients diagnosed with adrenal tumor underwent surgical treatment at Pusan National University Hospital were enrolled. Clinicopathologic features and various peri- and postoperative parameters were analyzed by retrospective medical record review. The mean age of the patients was 48.20±13.66 years. Results: The mean body mass index (BMI) was 25.50±4.30 kg/m2. Primary hyperaldosteronism was the most frequently preoperative diagnosed disease (n=13, 43.4%), followed by adrenal incidentaloma (n=8, 26.6%), Cushing syndrome (n=5, 16.6%) and pheochromocytoma (n=4, 13.3%). The mean size of postoperative adrenal tumor was 2.72±1.76 cm. The mean operating time was 162±58.14 minutes. Among the 30 patients, 28 patients underwent total adrenalectomy (93.3%) and two patients underwent cortical sparing adrenalectomy (6.7%). When LPRA was performed for patients with BMI >23.16 kg/m2, the operating time was longer than the average (P=0.016). Conclusion: LPRA was suitable and safe for patients with benign adrenal tumors. BMI, retroperitoneal fat density and postoperative adrenal weight may be related to the operating time, so they should be considered when deciding on a surgical method for adrenalectomy.

Influence of Infrapopliteal Runoff Vessels on Primary Patency after Superficial Femoral Artery Angioplasty with Stenting in Patients with Claudication.

Purpose: The number of infrapopliteal runoff vessels seems to be one of the factors influencing arterial patency in patients who had undergone superficial femoral artery (SFA) angioplasty with stenting. However, the effectiveness of infrapopliteal runoff vessels in predicting patency during SFA angioplasty remains unclear. This study aimed to determine whether the number and quality of infrapopliteal runoff vessels affect the primary patency after SFA angioplasty with stenting in patients with claudication. Materials and Methods: This study reviewed a retrospective database of patients with claudication who underwent SFA angioplasty with stenting between March 2011 and December 2016. The preoperative computed tomography findings of all patients were reviewed to assess infrapopliteal runoff vessels. The Trans-Atlantic Inter-Society (TASC) II classification and modified Society for Vascular Surgery (SVS) runoff score were used for subsequent analysis. Kaplan-Meier survival curves were constructed, and Fisher's exact and chi-square tests were used for data analysis. Results: A total of 153 limbs of 122 patients (88.2% male, mean age: 69.1 years) underwent SFA angioplasty with stenting. The overall primary patency rates of TASC II A/B and C/D cases were 77.1% and 31.2%, respectively, at 36 months (P<0.001). The primary patency rates at 36 months using the modified SVS runoff scoring system were 64.6% and 49.8% for the good-to-compromised (≤9 points) and poor (≥10 points) runoff groups, respectively (P=0.011). Conclusion: The modified SVS runoff scoring system is effective in predicting primary patency after SFA angioplasty with stenting in patients treated for claudication.

Robot-assisted resection of GIST in the proximal jejunum.

Gastrointestinal stromal tumors (GISTs) are rare. Although most commonly found in the stomach, GISTs in the jejunum are among the rarest subtypes. A 46-year-old woman presented to the surgical department with proximal jejunal mass found in the examinations after abdominal pain and melena. Computed tomography imaging showed a 2.3 cm sized well-defined heterogenous enhancing mass in the proximal jejunum, and GIST was strongly suspected. The jejunal mass was identified 5 cm below the ligament of Treitz intraoperatively. She underwent robotic-assisted jejunal resection with intracorporeal robot-sewn anastomosis. The patient's postoperative course was uneventful, and she was discharged on the seventh postoperative day. A robotic approach for GIST in the proximal jejunum is a safe and feasible procedure with good surgical outcomes.

Application of minimal invasive technique for thyroidectomy without remote access in locally advanced thyroid carcinoma with gross extra-thyroidal extension.

INTRODUCTION: Minimally invasive thyroidectomy (MIT) is technically less damaging tissue and is better cosmetic results with small neck scar, decreasing postoperative pain and neck discomfort. We present the experience of MIT without remote access with case of grossly extra-thyroidal extension positive papillary thyroid carcinoma. PRESENTATION OF CASE: A 44-year-old, female presented 1.6 cm irregular hypoechoic nodule at upper pole in Right thyroid gland and diagnosed to papillary thyroid carcinoma. The tumor was suspicious to have extra-thyroidal extension. We performed MIT without remote access for this patient with 2 cm cervical incision. Postoperative course was uneventful and patient was discharged on the 3th postoperative day. At present, she is taking 100mcg levothyroxine and is free of disease 3 years post-surgery. CONCLUSION: If experienced surgeons can get sufficient resection margin and control bleeding of superior thyroid artery, MIT without remote access can be feasible method for thyroid carcinoma with gross extra-thyroidal extension, especially, upper pole carcinoma.

Defunctioning Protective Stoma Can Reduce the Rate of Anastomotic Leakage after Low Anterior Resection in Rectal Cancer Patients.

PURPOSE: This study aimed to identify risk factors for anastomotic leakage and to evaluate the impact of protective stoma on the rate of anastomotic leakage and subsequent management. METHODS: This retrospective study analyzed data from 4,282 patients who underwent low anterior resection between 2007 and 2014. Among these, 1,367 (31.9%) underwent surgery to create protective diverting stoma and 232 (5.4%) experienced anastomotic leakage. At 6-month timepoints, data were evaluated to identify any correlation between the presence of diverting stoma and the incidence of anastomotic leakage. In addition, clinicopathological parameters were investigated to identify risk factors for anastomotic leakage. RESULTS: Diverting stomas significantly reduced the rate of anastomotic leakage [HR 0.334, 95% CI 0.212.

Fournier's gangrene in a rectal cancer patient.

INTRODUCTION: Fournier's gangrene (FG) is caused by a variety of causes, but FG led by rectal cancer is rare. PRESENTATION OF CASE: A 62-year-old man presented with perineal pain for several days. Multiple black spots on the scrotum and perineum surrounded by erythema were found on a physical exam. Computed tomography showed diffuse air density with subcutaneous edema in the perineum, scrotum, anus, and left lower abdominal wall and showed 4.1 cm-size mass in anus. He was diagnosed with FG caused by rectal cancer. He underwent extensive debridement of the perineum, scrotum, medial buttocks, and diverting loop colostomy of transverse colon. After repeated debridement of some residual necrotic tissue, abdominal perineal resection was performed after 24 days after initial surgery. The patient received reconstruction surgery of the soft tissue defect and discharged on postoperative day 84. He is being followed up without any recurrence for 10 months. CONCLUSION: Prompt clinical diagnosis and urgent surgical management are crucial for patient's favorable outcome. The patient in our case study could be recovered by a combined modality therapy we provided.

Mechanical intestinal obstruction following laparoscopic inguinal hernia repair in a patient with abdominal cocoon syndrome.

Abdominal cocoon syndrome (ACS) is a rare condition characterized by partial or complete encasement of small intestine by a thick fibro-collagenous membrane. A 65-year-old man presented to the surgical department with left inguinal. He underwent laparoscopic transabdominal preperitoneal inguinal hernia. When we inserted a trocar into the peritoneal cavity, the small intestine was injured and repaired immediately. We identified a fibrotic membrane covering the small intestine, which was found as ACS. Two weeks later after discharge, he presented to the emergency department with mechanical intestinal obstruction. Conservative treatment had no effect on the patient and membrane excision, adhesiolysis and small intestine resection with anastomosis were performed. Unfortunately, the patient was hospitalized for a long time with bowel leakage and discharged on postoperative day 48. The preoperative diagnosis is quite challenging and most cases are diagnosed intraoperatively. When finding the ACS during the operation, careful attention should be needed.

FRET Reagent Reveals the Intracellular Processing of Peptide-Linked Antibody-Drug Conjugates.

Despite the recent success of antibody-drug conjugates (ADCs) in cancer therapy, a detailed understanding of their entry, trafficking, and metabolism in cancer cells is limited. To gain further insight into the activation mechanism of ADCs, we incorporated fluorescence resonance energy transfer (FRET) reporter groups into the linker connecting the antibody to the drug and studied various aspects of intracellular ADC processing mechanisms. When comparing the trafficking of the antibody-FRET drug conjugates in various different model cells, we found that the cellular background plays an important role in how the antigen-mediated antibody is processed. Certain tumor cells showed limited cytosolic transport of the payload despite efficient linker cleavage. Our FRET assay provides a facile and robust assessment of intracellular ADC activation that may have significant implications for the future development of ADCs.

Stabilizing a Tubulysin Antibody-Drug Conjugate To Enable Activity Against Multidrug-Resistant Tumors.

The tubulysins are promising anticancer cytotoxic agents due to the clinical validation of their mechanism of action (microtubule inhibition) and their particular activity against multidrug-resistant tumor cells. Yet their high potency and subsequent systemic toxicity make them prime candidates for targeted therapy, particularly in the form of antibody-drug conjugates (ADCs). Here we report a strategy to prepare stable and bioreversible conjugates of tubulysins to antibodies without loss of activity. A peptide trigger along with a quaternary ammonium salt linker connection to the tertiary amine of tubulysin provided ADCs that were potent in vitro. However, we observed metabolism of a critical acetate ester of the drug in vivo, resulting in diminished conjugate activity. We were able to circumvent this metabolic liability with the judicious choice of a propyl ether replacement. This modified tubulysin ADC was stable and effective against multidrug-resistant lymphoma cell lines and tumors.

Cathepsin B Is Dispensable for Cellular Processing of Cathepsin B-Cleavable Antibody-Drug Conjugates.

Antibody-drug conjugates (ADC) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline [VC(S)] linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsin B expression via CRISPR-Cas9 gene deletion or shRNA knockdown had no effect on the efficacy of ADCs with VC(S) linkers armed with a monomethyl auristatin E (MMAE) payload. Mass spectrometry studies of payload release suggested that other cysteine cathepsins can cleave the VC(S) linker. Also, ADCs with a nonprotease-cleavable enantiomer, the VC(R) isomer, mediated effective cell killing with a cysteine-VC(R)-MMAE catabolite generated by lysosomal catabolism. Based on these observations, we altered the payload to a pyrrolo[2,1-c][1,4]benzodiazepine dimer (PBD) conjugate that requires linker cleavage in order to bind its DNA target. Unlike the VC-MMAE ADCs, the VC(S)-PBD ADC is at least 20-fold more cytotoxic than the VC(R)-PBD ADC. Our findings reveal that the VC(S) linker has multiple paths to produce active catabolites and that antibody and intracellular targets are more critical to ADC efficacy. These results suggest that protease-cleavable linkers are unlikely to increase the therapeutic index of ADCs and that resistance based on linker processing is improbable. Cancer Res; 77(24); 7027-37. ©2017 AACR.

Transanal Minimally-Invasive Surgery for Treating Patients With Regressed Rectal Cancer After Preoperative Chemoradiotherapy.

PURPOSE: Although the standard treatment for patients with locally advanced rectal cancer managed by preoperative chemoradiotherapy (CRT) is a radical resection, local excisions are used in highly-selective cases. Recently, transanal minimally-invasive surgery (TAMIS) has emerged as a feasible technique for local excision of midrectal lesions. We assess the feasibility of using TAMIS to treat patients with locally advanced rectal cancer who showed good response to CRT. METHODS: From October 2010 to June 2013, 35 consecutive patients with rectal cancer managed by using preoperative CRT underwent TAMIS. After a single-incision laparoscopic surgery port had been introduced into the anal canal, a full-thickness local excision with conventional laparoscopic instruments was performed. We retrospectively reviewed a prospectively collected database of these cases. RESULTS: Of the 35 patients analyzed, 18 showed pathologic complete responses and 17 had residual lesions (2 ypTis, 4 ypT1, 9 ypT2, and 2 ypT3); 34 (97.1%) showed clear deep, lateral margins. The median distance of lesions from the anal verge was 5 cm. All procedures were completed laparoscopically, and the median operating time was 84 minutes. No intraoperative events or morbidities were seen in any of the patients, except one with wound dehiscence, who was treated conservatively. The median postoperative hospital stay and follow-up period were 4 days and 36 months, respectively. During the study period, no patients died, but 5 (14.3%) experienced recurrence, including one recurrence at the TAMIS site. CONCLUSION: TAMIS seems to be a feasible, safe modality for treating patients with locally advanced rectal cancer who show good response to preoperative CRT.

High-Resolution Accurate-Mass Mass Spectrometry Enabling In-Depth Characterization of in Vivo Biotransformations for Intact Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) represent a promising class of therapeutics for the targeted delivery of highly potent cytotoxic drugs to tumor cells to improve bioactivity while minimizing side effects. ADCs are composed of both small and large molecules and therefore have complex molecular structures. In vivo biotransformations may further increase the complexity of ADCs, representing a unique challenge for bioanalytical assays. Quadrupole-time-of-flight mass spectrometry (Q-TOF MS) with electrospray ionization has been widely used for characterization of intact ADCs. However, interpretation of ADC biotransformations with small mass changes, for the intact molecule, remains a limitation due to the insufficient mass resolution and accuracy of Q-TOF MS. Here, we have investigated in vivo biotransformations of multiple site-specific THIOMAB antibody-drug conjugates (TDCs), in the intact form, using a high-resolution, accurate-mass (HR/AM) MS approach. Compared with conventional Q-TOF MS, HR/AM Orbitrap MS enabled more comprehensive identification of ADC biotransformations. It was particularly beneficial for characterizing ADC modifications with small mass changes such as partial drug loss and hydrolysis. This strategy has significantly enhanced our capability to elucidate ADC biotransformations and help understand ADC efficacy and safety in vivo.