IDH1 inhibition potentiates chemotherapy efficacy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type IDH1 that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced ROS and increased TCA cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize reactive oxygen species through the generation of alpha-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of sub-therapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074).

Symptom duration is not associated with per oral endoscopic myotomy (POEM) failure.

INTRODUCTION: Per oral endoscopic myotomy (POEM) is a relatively novel technique to address achalasia; however, little is known about the efficacy of POEM for patients with long-standing achalasia. We hypothesize that patients with long-standing achalasia prior to intervention will be more recalcitrant to POEM than patients with symptoms for a short duration. METHODS: We performed a retrospective analysis of patients with achalasia who received a POEM at a single institution from 2012 to 2022. Patients were grouped into cohorts based on the time of symptom duration: < 1 year, 1-3 years, 4-10 years, > 10 years. POEM failure was defined as need for repeat intervention, symptom recurrence, and a high postoperative Eckart score. Demographic and clinical data were compared between cohorts. Measures of failure multivariable logistic regression analyzed the association between symptom duration and response to POEM. RESULTS: During the study period, 132 patients met inclusion criteria. Patient age at surgery, sex, BMI, Charleston-Deyo Comorbidity Index, and patients with diabetes with and without end organ complications, connective tissue diseases, and patients with ulcer diseases did not differ among cohorts. Patients who have had symptoms for greater than 10 years had significantly more endoscopic interventions prior to their POEM (30% vs, 60% p = 0.002). Patients in all cohorts experienced the same number of symptoms post-POEM. Manometric measurements did not vary across cohorts after POEM. Symptom recurrence, need for repeat endoscopic intervention, repeat surgical intervention, or repeat POEM also did not vary across cohorts. Having symptoms of achalasia > 10 years did not increase the odds POEM failure on multivariable logistical regression. CONCLUSIONS: These data suggest that longer symptom duration is not associated with increased rates of POEM failure. This is promising as clinicians should not exclude patients for POEM eligibility based on duration of symptoms alone.

Is Sarcomatoid Lung Cancer Associated With Inferior Overall Survival? A National Cancer Database Analysis.

INTRODUCTION: Sarcomatoid lung cancer has mainly been described in case series and single institution reviews. Although often associated with a poor prognosis, the overall survival compared to other forms of nonsmall cell lung cancer (NSCLC) is unknown. We hypothesize that sarcomatoid lung cancers have worse overall survival relative to other forms of NSCLC. MATERIALS AND METHODS: In this retrospective cohort study, we identified adult patients with nonmetastatic NSCLC from 2004 to 2018 in the National Cancer Database. Patients were categorized by histology as sarcomatoid, adenocarcinoma, or squamous cell carcinoma. We compared clinical and demographic characteristics between the groups. The primary outcome of overall survival was analyzed using Kaplan-Meier analysis. Multivariable Cox analysis was used to analyze factors associated with overall survival in sarcomatoid patients undergoing surgery. RESULTS: Among 1,259,109 patients with lung cancer, there were 5223 (0.4%) sarcomatoid cancers. Sarcomatoid patients were more likely to be male, of Hispanic ethnicity, have fewer comorbidities, and receive treatment at an academic program. Despite higher cT- and M-stages, patients with sarcomatoid cancer were more likely to undergo surgical resection in multivariate analysis (odds ratio = 1.8 [confidence interval 1.60-2.11]; P < 0.001). Among nonmetastatic patients, overall survival was lower for sarcomatoid cancer relative to other histologies in Kaplan-Meier analysis (median survival sarcomatoid 17.6 mo versus nonsarcomatoid 31.5 mo, P < 0.001). CONCLUSIONS: This National Cancer Database study confirms the findings of smaller studies that sarcomatoid cancer is associated with inferior overall survival compared to other NSCLCs. Given the inferior prognosis, further studies regarding optimal staging practices are appropriate.

Preoperative manometric data can predict symptom improvement after per oral endoscopic myotomy for treatment of achalasia.

BACKGROUND: While per oral endoscopic myotomy (POEM) has been shown to be efficacious in the treatment of achalasia, it can be difficult to predict who will have a robust and durable response. Historically, high lower esophageal sphincter pressures have been shown to predict a worse response to endoscopic therapies such as botox therapy. This study was designed to evaluate if modern preoperative manometric data could predict a response to therapy after POEM. METHODS: This was a retrospective study of 144 patients who underwent a POEM at a single institution by a single surgeon over an 8-year period (2014-2022) who had high-resolution manometry performed preoperatively and had an Eckardt symptom score performed both preoperatively and postoperatively. The achalasia type and integrated relaxation pressures (IRP) were then tested for potential correlation with need for any further achalasia interventions postoperatively as well as the degree of Eckardt score reduction using univariate analysis. RESULTS: The achalasia type on preoperatively manometry was not predictive of need for further interventions or degree of Eckardt score reduction (p = 0.74 and 0.44, respectively). A higher IRP was not predictive of need for further interventions however it was predictive of a greater reduction in postoperative Eckardt scores (p = 0.03) as shown by a nonzero regression slope. CONCLUSION: In this study, achalasia type was not a predictive factor in need for further interventions or degree of symptom relief. While IRP was not predictive of need for further interventions, a higher IRP did predict better symptomatic relief postoperatively. This result is opposite that of other endoscopic treatment modalities. Therefore, patients with higher IRP on high-resolution manometry would likely benefit from myotomy which provides significant symptomatic relief postoperatively.

Do preoperative endoscopic interventions predict symptom recurrence or reintervention after peroral endoscopic myotomy?

BACKGROUND: Studies assessing outcomes of patients undergoing peroral endoscopic myotomy (POEM) after botulinum injection or dilation have had various results with respect to failure, although this has not been differentiated between lack of clinical response and recurrence. We hypothesize that patients with previous endoscopic intervention(s) are more likely to recur than treatment-naïve patients. METHODS: This is a retrospective cohort study of patients that underwent POEM for achalasia at a single tertiary care center between 2011 and 2022. Patients were excluded if they had previous myotomy (POEM or Heller). The remaining patients were stratified into treatment-naïve patients (TN), those with previous botulinum injection (BTX), those with previous dilatation (BD), and those with both previous endoscopic interventions (BOTH). Primary outcome was recurrence indicated by clinical symptoms or need for repeat endoscopic intervention or surgery after originally having clinical resolution (Eckardt ≤ 3). Multivariate logistic regression using preoperative and intraoperative factors was completed to assess odds of recurrence. RESULTS: A total of 164 patients were included in the analysis, 90 TN, 34 BD, 28 BTX, and 12 BOTH. There were no other significant differences in demographics or in preoperative Eckardt score (p = 0.53). There was no difference in the proportion of patients that had postoperative manometry (p = 0.74), symptom recurrence (p = 0.59), surgical intervention (p = 0.16). BTX (14.3%) and BOTH (16.7%) patients had a higher rate of repeat endoscopic intervention than BD and TN patients (5.9% and 1.1%). In the logistic regression analysis, there was no association among the BTX, BD, or BOTH groups compared to the TN group. No odds ratios achieved statistical significance. CONCLUSIONS: There were no increased likelihood of recurrence with botulinum injection or dilatation prior to POEM, implying that they are similarly good candidates compared to treatment-naïve patients.

Preoperative patient factors and anatomy do not predict who will develop reflux after per oral endoscopic myotomy.

BACKGROUND: Per oral endoscopic myotomy (POEM) has been shown to be an efficacious and safe therapy for the treatment of achalasia. Compared to laparoscopic Heller myotomy however, no antireflux procedure is routinely combined with POEM and therefore the development of symptomatic or silent reflux is of concern. This study was designed to determine if various patient factors and anatomy would predict the development of gastroesophageal reflux disease post-operatively. METHODS: This was a retrospective cohort study of all patients who underwent a POEM at a single institution by a single surgeon over an eight-year period (2014-2022). It has been our practice to obtain a postoperative ambulatory pH test on all patients 6 months after POEM off all acid reducing medications. Patients without a postoperative ambulatory esophageal pH monitoring test were excluded. Age, sex, obesity (BMI > 30), achalasia type, presence of a hiatal hernia, history of prior endoscopic achalasia treatments or myotomy were analyzed using univariate analysis as predictive factors for the development of postoperative GERD (DeMeester score > 14.7 on ambulatory pH monitoring). RESULTS: There were 179 total patients included in the study with 42 patients (23.5%) having undergone postoperative ambulatory pH testing. The majority of patients (137 or 76.5%) were lost to follow up and did not undergo ambulatory pH testing. Twenty-three out of those 42 patients (55%) had evidence of GERD on ambulatory pH testing. Multiple preoperative patient characteristics including demographics, manometric results, EGD findings, and history of prior achalasia interventions did not correlate with the development of post-operative GERD. CONCLUSIONS: Despite the high rate of reflux after POEM, there does not appear to be any reliable preoperative indicators of which patients have a higher risk of developing post-operative GERD after POEM.

Management of adenocarcinoma of the pancreatic tail in the elderly.

INTRODUCTION: Elderly patients with adenocarcinoma of the pancreatic head can achieve reasonable survival with multimodal therapy. An analysis specific to cancers of the pancreatic tail has not been published. METHODS: We identified patients ≥65 years with localized adenocarcinoma of the pancreatic tail in the National Cancer Database (2011-2017). Patients were grouped by age (65-79 and ≥80 years) and categorized by treatment regimen. Postoperative outcomes and survival were analyzed using propensity score matching and multivariable logistical regression. RESULTS: 2168 patients were included: 73.9% were 65-79 years and 26.1% were ≥80 years. 34.1% of octogenarians did not receive any treatment, relative to 15.9% of younger patients (p < 0.001). Thirty-day mortality rates were similar in operatively managed patients; however, the 90-day mortality rate among octogenarians was greater (3.0% vs. 7.8%, p < 0.001; odds ratio [OR] = 1.85, 95% confidence interval [CI] = 1.07-3.19). Age ≥ 80 was not associated with survival on multivariable hazards regression (hazard ratio [HR] = 1.08, 95% CI = 0.95-1.24). After propensity matching, the addition of chemotherapy was not associated with improved survival relative to distal pancreatectomy alone among octogenarians (HR = 1.09, 95% CI = 0.72-1.65). CONCLUSIONS: Management of adenocarcinoma of the pancreatic tail varies based on patient age. Resection appears to play a key role in management, but there is substantial upfront risk. Shared decision making should be employed to balance the chance for long-term survival with the risk of early mortality.

Dual-Plane Gluteal Myocutaneous Flap for Reconstruction of Ischial Tuberosity Pressure Wounds.

PURPOSE: Ischial tuberosity pressure wounds are the most common type of pressure wound and contribute to a large percentage of the total cost of surgical and nonsurgical management of pressure wounds. Gluteal myocutaneous and fascocutaneous flaps are well-documented methods of coverage for ischial pressure wounds. This study aimed to describe results using a novel dual-plane gluteal myocutaneous flap technique for reconstruction of ischial tuberosity pressure wounds. METHODS: A retrospective chart review was performed of all patients who underwent dual-plane gluteus maximus myocutaneous flap reconstruction for ischial tuberosity pressure wounds performed by a single surgeon from 2012 to 2018. Patient demographic, clinical, and operative characteristics were reviewed. Outcomes were assessed by analyzing complication rates including recurrence, need for revision surgery, dehiscence, necrosis, wound infection, seroma, and hematoma. RESULTS: Eight dual-plane gluteus maximus myocutaneous flaps were performed for reconstruction of ischial tuberosity pressure wounds in 7 male patients with a mean age of 49.1 ± 14.9 years (mean ± SD) and mean body mass index of 26.7 ± 6.4 kg/m. All patients were nonambulatory secondary to spinal cord injury or congenital neurological disease. Two patients (28.6%) were diabetic, and 1 patient (14.3%) was an active smoker. The mean defect size after debridement of ischial pressure wounds was 60.7 ± 29.4 cm. After a mean follow-up of 16.4 months, partial wound dehiscence occurred in 1 patient (14.3%) and was managed with local wound care only. Infection and recurrence occurred in another patient (14.3%) and required revision surgery. CONCLUSIONS: The dual-plane gluteal myocutaneous flap is an effective method for reconstruction of ischial tuberosity pressure wounds. Partially elevating the cutaneous layer off the gluteus maximus muscle allows for greater mobility and rotation of the muscle flap into the ischial pressure wound defect and closure of the flap and donor site with the cutaneous layer.

The Double-reverse Wedge Excision Technique: A Novel Approach to Reconstruction of Stahl's Ear Deformity.

Stahl's ear deformity presents with an abnormal third crus of the antihelix and varying degrees of severity. This paper aims to describe a novel technique for reconstruction of Stahl's ear involving a double-reverse wedge excision of the third crus cartilage and skin, as well as use of Mustardé sutures to recreate the superior crus and Furnas sutures to complete the auricular setback. This novel technique for correction of Stahl's ear deformity produces a more stable aesthetic result versus classic otoplasty with desired auricular setback, minimal reduction in the size of the ear, and limited scarring on the anterior auricular surface. Reconstruction of Stahl's ear deformity can be accomplished using this double-reverse wedge excision technique of the third crus cartilage and skin with Mustardé and Furnas sutures to recreate the superior crus and complete auricular setback, effectively restoring anatomic harmony to the ear.