Postoperative outcomes and costs of laparoscopic versus robotic distal pancreatectomy: a propensity-matched analysis.

BACKGROUND: Minimally invasive distal pancreatectomy (MIDP) has established advantages over the open approach. The costs associated with robotic DP (RDP) versus laparoscopic DP (LDP) make the robotic approach controversial. We sought to compare outcomes and cost of LDP and RDP using propensity matching analysis at our institution. METHODS: Patients undergoing LDP or RDP between 2000 and 2021 were retrospectively identified. Patients were optimally matched using age, gender, American Society of Anesthesiologists status, body mass index, and tumor size. Between-group differences were analyzed using the Wilcoxon signed-rank test for continuous data, and the McNemar's test for categorical data. Outcomes included operative duration, conversion to open surgery, postoperative length of stay, pancreatic fistula rate, pseudocyst requiring intervention, and costs. RESULTS: 298 patients underwent MIDP, 180 (60%) were laparoscopic and 118 (40%) were robotic. All RDPs were matched 1:1 to a laparoscopic case with absolute standardized mean differences for all matching covariates below 0.10, except for tumor type (0.16). RDP had longer operative times (268 vs 178 min, p < 0.01), shorter length of stay (2 vs 4 days, p < 0.01), fewer biochemical pancreatic leaks (11.9% vs 34.7%, p < 0.01), and fewer interventional radiological drainage (0% vs 5.9%, p = 0.01). The number of pancreatic fistulas (11.9% vs 5.1%, p = 0.12), collections requiring antibiotics or intervention (11.9% vs 5.1%, p = 0.12), and conversion rates (3.4% vs 5.1%, p = 0.72) were comparable between the two groups. The total direct index admission costs for RDP were 1.01 times higher than for LDP for FY16-19 (p = 0.372), and 1.33 times higher for FY20-22 (p = 0.031). CONCLUSIONS: Although RDP required longer operative times than LDP, postoperative stays were shorter. The procedure cost of RDP was modestly more expensive than LDP, though this was partially offset by reduced hospital stay and reintervention rate.

Solving the surgeon ergonomic crisis with surgical exosuit.

INTRODUCTION: The widespread adoption of laparoscopic surgery has put new physical demands on the surgeon leading to increased musculoskeletal disorders and injuries. Shoulder, back, and neck pains are among the most common complaints experienced by laparoscopic surgeons. Here, we evaluate the feasibility and efficacy of a non-intrusive progressive arm support exosuit worn by surgeons under the sterile gown to reduce pain and fatigue during surgery. METHODS AND PROCEDURES: This is a prospective randomized crossover study approved by the Internal Review Board (IRB). The study involves three phases of testing. In each phase, general surgery residents or attendings were randomized to wearing the surgical exosuit at the beginning or at the crossover point. The first phase tests for surgeon manual dexterity wearing the device using the Minnesota Dexterity test, the Purdue Pegboard test, and the Fundamentals of Laparoscopic Surgery (FLS) modules. The second phase tests the effect of the device on shoulder pain and fatigue while operating the laparoscopic camera. The third phase rates surgeon experience in the operating room between case-matched operating days. RESULTS: Twenty subjects were recruited for this study. Surgeons had the similar dexterity scores and FLS times whether or not they wore the exosuit (p value ranges 0.15-0.84). All exosuit surgeons completed 15 min of holding laparoscopic camera compared to three non-exosuit surgeons (p < 0.02). Exosuit surgeons experienced significantly less fatigue at all time periods and arm pain (3.11 vs 5.88, p = 0.019) at 10 min. Surgeons wearing the exosuit during an operation experienced significant decrease in shoulder pain and 85% of surgeons reported some form of pain reduction at the end of the operative day. CONCLUSION: The progressive arm support exosuit can be a minimally intrusive device that laparoscopic surgeons wear to reduce pain and fatigue of surgery without significantly interfering with operative skills or manual dexterity.

Near-infrared-conjugated humanized anti-carcinoembryonic antigen antibody targets colon cancer in an orthotopic nude-mouse model.

BACKGROUND: The success of a curative surgery for cancer is dependent on the complete removal of all cancer cells. Tumor visualization by the surgeon can be enhanced through fluorescent-antibody targeting. To further develop such technology, we selected humanized anti-carcinoembryonic antigen (CEA) conjugated to a near-infrared dye to target orthotopically-implanted human colon cancer in nude mice. MATERIALS AND METHODS: The HT-29 human colon cancer cell line was grown in culture and subcutaneously injected in mice. After 3 wk of growth, tumors were resected and cut into 2 mm3 fragments that were sutured to the cecum of five additional nude mice for orthotopic implantation. The tumors were allowed to grow for 4 wk at which point 3 had successful orthotopic tumor growth and were selected for injection of the humanized anti-CEA antibody conjugated to the near-infrared dye IRDye800CW (anti-CEA-IRDye800CW). The antibody-dye conjugate (75 µg) was administered via tail vein injection. Images were obtained with the Pearl Trilogy Small Animal Imaging System with both 700 and 800 nm channels and evaluated using Image Studio. RESULTS: Laparotomy was performed 24 h after labeling the tumors. When imaged through the 800 nm channel, the tumors were observed to be strongly labeled with anti-CEA-IRDye800. At 48 h, laparotomy was repeated which again demonstrated strong labeling of the tumors through the 800 nm channel, but with a lower absolute intensity (in relative units), than at 24 h. CONCLUSIONS: Humanized anti-CEA-IRDye800CW can rapidly and effectively label CEA-expressing human colon cancer in an orthotopic nude mouse model. Given the ability of this technology to target and label tumors with great specificity, the anti-CEA-IRDye800CW is currently being developed for clinical use in fluorescence-guided surgery.

Indocyanine green (ICG) fluorescence-guided laparoscopic adrenalectomy.

OBJECTIVE: Laparoscopic adrenalectomy has become the standard of care for many adrenal tumors. However, the success of the operation hinges on identifying the adrenal vein and complete tumor resection. We demonstrate the use of a commercially available near infrared fluorescent imaging system to clearly delineate the vascular anatomy of adrenal neoplasms and enhance the border between tumor and normal tissue. We hypothesize that this will increase the safety of laparoscopic adrenalectomy. MATERIALS AND METHODS: We performed laparoscopic adrenalectomy utilizing indocyanine green (ICG) and a specialized laparoscopic fluorescence imaging system on four consecutive patients undergoing laparoscopic adrenalectomy over a 4-month period. RESULTS: The adrenal arteries and vein were vividly enhanced with ICG fluorescence guidance, and the border between tumor and adjacent tissue was clearly demarcated. The operations were performed safely with minimal blood loss and short operative times. There were no complications. CONCLUSIONS: Adrenal neoplasms can be resected laparoscopically under ICG fluorescence guidance and can be used to clearly identify vascular structures and enhance the borders of the tumor. This technique allows for clear identification of the adrenal vein and has the potential to improve the safety of laparoscopic adrenalectomy.

Comparison of Spleen-Preservation Versus Splenectomy in Minimally Invasive Distal Pancreatectomy.

BACKGROUND: Spleen-preservation during minimally invasive distal pancreatectomy (MIDP) can be technically challenging and remains controversial. Our primary aim was to compare MIDP and splenectomy with spleen-preserving MIDP. Secondarily, we compared two spleen-preserving techniques. METHODS: Adults undergoing MIDP (2007-2021) were retrospectively included in this single-center study. Intraoperative and postoperative outcomes between spleen-preservation and splenectomy and between the two spleen-preserving techniques were compared using the Mann-Whitney U test for continuous data, and Fisher's exact test for categorical data. RESULTS: Of the 293 patients who underwent MIDP, preservation of the spleen was intended in 208 (71%) patients. Spleen-preservation was achieved in 174 patients (84%) via the Warshaw technique (130; 75%) or vessel-preservation (44; 25%). The spleen-preserving group had shorter length of stay (3 vs 4 days, p < 0.01), fewer conversions to open (1 vs 12, p < 0.01) and less blood loss (p < 0.01) compared to the splenectomy group. Operative (OR) times were comparable (229 vs 214 min, p = 0.67). Except for the operative time, which was longer for the Warshaw technique (245 vs 183 min, p = 0.01), no other differences between the two spleen-preserving techniques were found. At a median follow-up of 43 (IQR 18-79) months after spleen-preservation, only 2 (1.1%) patients had required splenectomy (1 partial splenectomy for infarct/abscess after Warshaw, 1 for variceal bleeding after vessel-preserving). CONCLUSIONS: Spleen-preservation is not associated with increased risk of blood loss, longer hospital stay, conversion, nor lengthy OR times. Late splenectomy is very rarely required. Given the immune consequences of splenectomy, spleen-preservation should be strongly considered in MIDP.

Indocyanine green fluorescence-guided parathyroidectomy for primary hyperparathyroidism.

BACKGROUND: Our aim was to evaluate the ease and utility of using indocyanine green fluorescence angiography for intraoperative localization of the parathyroid glands. METHODS: Indocyanine green fluorescence angiography was performed during 60 parathyroidectomies for primary hyperparathyroidism during a 22-month period. Indocyanine green was administered intravenously to guide operative navigation using a commercially available fluorescence imaging system. Video files were graded by 3 independent surgeons for strength of enhancement using an adapted numeric scoring system. RESULTS: There were 46 (77%) female patients and 14 (23%) male patients whose ages ranged from 17 to 87 (average 60) years old. Of the 60 patients, 43 (71.6%) showed strong enhancement, 13 (21.7%) demonstrated mild to moderate vascular enhancement, and 4 (6.7%) exhibited little or no vascular enhancement. Of the 54 patients who had a preoperative sestamibi scan, a parathyroid adenoma was identified in 36, while 18 failed to localize. Of the 18 patients who failed to localize, all 18 patients (100%) had an adenoma that fluoresced on indocyanine green imaging. The operations were performed safely with minimal blood loss and short operative times. CONCLUSION: Indocyanine green angiography has the potential to assist surgeons in identifying parathyroid glands rapidly with minimal risk.

Preventing Rescue Surgeries by Endoscopic Clipping: A Valuable Resource in the Surgeon's Toolbox.

AIM: Over-the-scope-clip (OTSC) System is a relatively new endoluminal intervention for gastrointestinal (GI) leaks, fistulas, and bleeding. Here, we present a single center experience with the device over the course of 4 years. METHODS: Retrospective chart review was conducted for patients who received endoscopic OTSC treatment. Primary outcome is the resolution of the original indication for clip placement. Secondary outcomes are complications and time to resolution. RESULTS: Forty-one patients underwent treatment with the OTSC system from 2011 to 2015 with average follow-up of 152 days. The average age is 53.7. The most common site of clip placement was in the stomach (44%). Clips were placed after surgical complication for 28 patients (68%), endoscopic complications for 8 patients (19%), and spontaneous presentation in 5 patients (12%). Technical success was achieved in all patients. Overall, 34 patients (83%) were successfully treated. Nine patients required multiple clips and three patients required additional treatment modalities after OTSC. Four patients used the OTSC as a bridging therapy to surgery. Using OTSC for palliation versus nonpalliative indications was associated with lower rates of treatment success (50% versus 86%, P = .028). Using OTSC for symptoms <6 months had higher rates of treatment success than those experiencing longer symptoms (88% versus 65%, P = .045). There were no major morbidities or mortalities directly associated with the OTSC system. Complications from clip use were pain in two patients (5%) and hematemesis in one patient (3%). CONCLUSIONS: The OTSC System can be a very successful treatment for iatrogenic or spontaneous GI leaks and bleeds. Treatment success is more likely in patients treated within 6 months of diagnosis and less likely to when used for palliation. It was also successfully used as bridging therapy in several patients.

Identifying lost surgical needles with visible and near infrared fluorescent light emitting microscale coating.

BACKGROUND: Retained foreign bodies (RFOs) have substantial clinical and financial consequences. In laparoscopic surgery, RFOs can be a cause of needing to convert a minimally invasive surgery (MIS) procedure to an open operation. A coating for surgical models was developed to augment localization of needles using fluorescence appropriate for open and minimally invasive surgeries procedures. METHODS: An epoxy matrix containing both dansyl chloride and indocyanine green was coated as visible and near infrared labels, respectively. With ultraviolet excitation, dansyl chloride emits green fluorescence and with NIR excitation, the ICG dye emits radiation observable with specialized near infrared capable laparoscopes. To evaluate the coatings, open and laproscopic surgeries were simulated in rabbits. Surgeons blinded to the type of needles (coated or non-coated) were timed while finding needles in standard conditions and with the use of the adjunct coatings. Control needles not located within 300 seconds were researched with the corresponding near infrared or ultraviolet light. Localization time was evaluated for statistical significance, P < .05. RESULTS: All dual dye coated needles searched utilizing the near infrared camera (n = 26) or ultraviolet light (n= 26) were located within 300 seconds. Conversely, 9 needles in both control settings (no dye usage) were not located within 300 seconds. Mean time to locate control needles in open surgery and laparoscopic surgery was statistically 2-3× greater than time to localization with the use of dye as an adjunct (P = .0027 open, P < .001 laparoscopic). CONCLUSION: Incorporation of a dual-dye fluorescent coating on surgical needles improved the efficiency of locating needles, may minimize the need to convert minimally invasive surgeries procedures to open, and may decrease the consequences of a missed RFO.

MEK inhibitor trametinib in combination with gemcitabine regresses a patient-derived orthotopic xenograft (PDOX) pancreatic cancer nude mouse model.

Pancreatic cancer is resistant to treatment and needs precision individualized therapy to improve the outcome of this disease. Previously, we demonstrated that trametinib (TRA), a MEK inhibitor, could inhibit a pancreatic cancer patient-derived orthotopic xenograft (PDOX). In the present study, we show that gemcitabine (GEM) in combination with TRA was more effective than TRA alone. We implanted a patient pancreatic cancer orthotopically in the pancreatic tail of nude mice to establish the PDOX model. After seven weeks of tumor growth, we divided 32 pancreatic-cancer PDOX nude mice into 4 groups of eight: untreated control; GEM (once a week for 2 weeks); TRA (14 consecutive days); GEM + TRA (GEM: once a week for 2 weeks, TRA:14 consecutive days). We found that treated mice on day 14 had significantly reduced tumor volume in comparison to untreated control. TRA and the combination of GEM + TRA therapy significantly inhibited tumor development in comparison to GEM alone. However, GEM + TRA inhibited the PDOX tumor growth significantly greater than TRA alone. These results suggest the clinical potential of the combination of TRA and GEM for pancreatic cancer.

Fluorescent humanized anti-CEA antibody specifically labels metastatic pancreatic cancer in a patient-derived orthotopic xenograft (PDOX) mouse model.

Pancreatic cancer is a highly lethal disease in part due to incomplete tumor resection. Targeting by tumor-specific antibodies conjugated with a fluorescent label can result in selective labeling of cancer in vivo for surgical navigation. In the present study, we describe a patient-derived orthotopic xenograft model of pancreatic cancer that recapitulated the disease on a gross and microscopic level, along with physiologic clinical manifestations. We additionally show that the use of an anti-CEA antibody conjugated to the near-infrared (NIR) fluorescent dye, IRDye800CW, can selectively highlight the pancreatic cancer and its metastases in this model with a tumor-to-background ratio of 3.5 (SEM 0.9). The present results demonstrate the clinical potential of this labeling technique for fluorescence-guided surgery of pancreatic cancer.

Laparoscopic Gastropleural Fistula Repair: A Minimally Invasive Solution for a Complex Problem.

INTRODUCTION: Gastropleural fistula (GPF) is a complex pathology that can present as a result of surgery, trauma, peptic ulcer disease, malignancies, radiation, or chemotherapy. Management typically includes endoscopic or surgical intervention along with intraabdominal or intrathoracic drainage of pre-existing infection. Traditionally, surgical approaches have been through exploratory laparotomy or thoracotomy, subjecting already ill patients to additional morbidity. CASE REPORT: We describe and demonstrate a laparoscopic minimally invasive approach to the management of a GPF with a wedge resection of the stomach, along with a review of the current literature regarding GPF treatment. CONCLUSION: GPF repair can be performed through laparoscopy and may lead to improved patient outcomes and faster recovery.

MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX).

A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p.o., 14 consecutive days, n = 7); carfilzomib (2 mg/kg, i.v., twice a week for 2 weeks, n = 7); bortezomib (1 mg/kg, i.v., twice a week for 2 weeks, n = 7); MK-1775 (20 mg/kg, p.o., 14 consecutive days, n = 7); BEZ-235 (45 mg/kg, p.o., 14 consecutive days, n = 7); vorinostat (50 mg/kg, i.p., 14 consecutive days, n = 7). Only the MEK inhibitors, cobimetinib and trametinib, regressed tumor growth, and they were more significantly effective than other therapies (p < 0.0001, respectively), thereby demonstrating the precision of the PDOX models of PDAC and its potential for individualizing pancreatic-cancer therapy.

Color-coded intravital imaging demonstrates a transforming growth factor-ß (TGF-ß) antagonist selectively targets stromal cells in a human pancreatic-cancer orthotopic mouse model.

Pancreatic cancer is a recalcitrant malignancy, partly due to desmoplastic stroma which stimulates tumor growth, invasion, and metastasis, and inhibits chemotherapeutic drug delivery. Transforming growth factor-ß (TGF-ß) has an important role in the formation of stromal desmoplasia. The present study describes the ability of color-coded intravital imaging to demonstrate the efficacy of a TGF-ß inhibitor to target stroma in an orthotopic mouse model of pancreatic cancer. The BxPC-3 human pancreatic adenocarcinoma cell line expressing green fluorescent protein (GFP), which also has a high TGF-ß expression level, was used in an orthotopic model in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). Fourteen mice were randomized into a control group (n = 7, vehicle, i.p., weekly, for 3 weeks) and a treated group (n = 7, SB431542 [TGF-ß receptor type I inhibitor] 0.3 mg, i.p., weekly, for 3 weeks). Stromal cells expressing RFP and cancer cells expressing GFP were observed weekly for 3 weeks by real-time color-coded intravital imaging. The RFP fluorescence area from the stromal cells, relative to the GFP fluorescence area of the cancer cells, was significantly decreased in the TGF-ß-inhibitor-treatment group compared to the control group. The present study demonstrated color-coded imaging in an orthotopic pancreatic-cancer cell-line mouse model can readily detect the selective anti-stromal-cell targeting of a TGF-ß inhibitor.

Cervical Cancer Patient-Derived Orthotopic Xenograft (PDOX) Is Sensitive to Cisplatinum and Resistant to Nab-paclitaxel.

BACKGROUND: Cervical cancer is a world-wide problem that requires transformative therapeutic strategies. We have previously developed patient-derived orthotopic xenograft (PDOX) nude-mouse models of this disease. In the present report, we demonstrate that the standard drug, cisplatinum (CDDP), is highly-effective while the new, highly-touted agent, nab-paclitaxel (NAB-PTX) is ineffective. MATERIALS AND METHODS: Cervical PDOX tumors were grown on the cervix of nude mice for 4 weeks after surgical orthotopic implantation (SOI). Tumors were treated with CDDP or NAB-PTX. RESULTS: H&E staining demonstrated that the PDOX tumor recapitulated the original patient tumor. CDDP was highly-effective. One tumor that was treated with CDDP completely regressed. CDDP-treated tumors were smaller (tumor volume ratio: 0.42±0.36) than the control group (tumor volume ratio: 3.47±1.66) (p<0.01). In contrast, NAB-PTX did not show significant efficacy on the cervical cancer PDOX model (tumor volume ratio: 2.85±1.45) (p=0.47). CDDP-treated tumor weight (50±50 mg) was significantly less than control (238±114 mg) (p<0.01). NAB-PTX-treated tumors were not reduced in weight (246±136 mg) compared to control (p=0.91). There were no significant differences in mouse body weight between groups. Histological evaluation demonstrated that CDDP-treated tumors were fibrotic with scattered squamous cell nests compared to control or NAB-PTX-treated tumors. CONCLUSION: The results of the present study demonstrate the power of PDOX models of cervical cancer to distinguish efficacy of potential therapeutics for individual patients with this disease.

The irony of highly-effective bacterial therapy of a patient-derived orthotopic xenograft (PDOX) model of Ewing's sarcoma, which was blocked by Ewing himself 80 years ago.

William B. Coley developed bacterial therapy of cancer more than 100 years ago and had clinical success. James Ewing, a very famous cancer pathologist for whom the Ewing sarcoma is named, was Coley's boss at Memorial Hospital in New York and terminated Coley's bacterial therapy of cancer. A tumor from a patient with soft-tissue Ewing's sarcoma, who failed doxorubicin (DOX) therapy, was previously implanted in nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the Ewing's sarcoma PDOX was treated with tumor-targeting S. typhimurium A1-R expressing green fluorescent (GFP), alone and in combination with DOX. S. typhimurium A1-R-GFP was detected in the tumors after intratumor (i.t.) or intravenous (i.v.) injection. The combination of S. typhimurium A1-R and DOX significantly reduced tumor weight (37.8 ± 15.6 mg) compared to the untreated control (73.8 ± 10.1 mg, P < 0.01). S. typhimurium A1-R monotherapy-treated tumors tended to be smaller (50.9 ± 17.8 mg, P = 0.051). DOX monotherapy did not show efficacy (66.3 ± 26.4 mg, P = 0.82), as was the case with the patient. The PDOX model faithfully replicated the DOX resistance the Ewing's sarcoma had in the patient. S. typhimurium A1-R converted the Ewing's sarcoma from DOX resistant to sensitive. One can only wonder how bacterial therapy and immunotherapy of cancer would have developed over the past 80 years if Ewing did not stop Coley.

Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma.

Current status and future perspectives of fluorescence-guided surgery for cancer.

Curative cancer surgery is dependent on the removal of all primary tumor and metastatic cancer cells. Preoperative imaging, intraoperative inspection and palpation, as well as pathological margin confirmation aid the surgeon, but these methods are lacking in sensitivity and can be highly subjective. Techniques in fluorescence-guided surgery (FGS) are emerging that selectively illuminate cancer cells, enhancing the distinction between tumors and surrounding tissues with the potential for single-cell sensitivity. FGS enhances tumor detection, surgical navigation, margin confirmation, and in some cases can be combined with therapeutic techniques to eliminate microscopic disease. In this review, we describe the preclinical developments and currently-used techniques for FGS.

The benefits and limitations of robotic assisted transhiatal esophagectomy for esophageal cancer.

Robotic-assisted transhiatal esophagectomy (RATE) is a minimally invasive approach to total esophagectomy with less morbidity but equivalent efficacy when compared with the traditional open approach. The robotic platform offers numerous technical advantages that assist with the esophageal dissection, which allows the procedure to be completed without entry into the thoracic cavity. The major criticism of the transhiatal approach is that it forfeits the ability of the surgeon to perform a formal lymphadenectomy, but this does not appear to affect long-term survival.

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.