Development of Squamous Cell Carcinoma After Pulmonary Aspergillosis in the Native Lung of a Lung Transplant Recipient: A Case Report.

Lung transplant recipients have a significant incidence of posttransplant lung nodules. Such nodules can occur from various etiologies, both in the lung allograft or in the native lung. They most commonly originate from infections, such as Pseudomonas or Aspergillus species, or from posttransplant lymphoproliferative disorder. Lung cancer is challenging to diagnose in a native lung, especially with an underlying fibrotic disease. We present a case of a 75-year-old woman who presented with classic clinical features of pulmonary aspergillosis in the native right lung with idiopathic pulmonary fibrosis 5 years after left-sided single-lung transplant. She required a right lower lobectomy and antifungal treatment with isavuconazonium sulfate and inhaled amphotericin. A persistent right upper lobe lung nodule was noted during surveillance imaging and was initially presumed to be recurrent Aspergillus infection; however, growth of the nodule and change in its characteristics prompted additional examination. A navigational bronchoscopic biopsy was positive for squamous cell carcinoma. Her options for stage IIIA squamous cell carcinoma were limited to chemotherapy with paclitaxel and carboplatin plus radiation. Although initial surveillance scans showed adequate tumor response, metastatic squamous cell carcinoma was found in the liver 6 months later. She was eventually transitioned to palliative care. This case highlights the importance of a high index of suspicion for examination of nodules in the native lung of lung transplant recipients, even in cases of a known diagnosis, owing to the high morbidity and mortality associated with primary lung cancer in this population.

Thoracoabdominal pressure gradient and gastroesophageal reflux: insights from lung transplant candidates.

Advanced lung disease is associated with gastroesophageal reflux disease (GERD). The thoracoabdominal pressure gradient (TAPG) facilitates gastroesophageal reflux, but the effects of TAPG on gastroesophageal reflux in patients with pulmonary disease have not been well defined. Patients diagnosed with end-stage lung disease are expected to have the most extreme derangement in respiratory mechanics. The aim of this study is to explore the relationship between TAPG and reflux in lung transplant (LTx) candidates. We reviewed LTx recipients who underwent pretransplant esophageal high-resolution manometry and a 24-hour pH study. Patients were excluded if they were undergoing redo LTx, had manometric hiatal hernia, or had previously undergone foregut surgery. TAPG was defined as the intra-abdominal pressure minus the intrathoracic pressure during inspiration. Adjusted TAPG was calculated by the TAPG minus the resting lower esophageal sphincter (LES) pressure (LESP). Twenty-two patients with normal esophageal function tests (i.e., normal esophageal motility with neither manometric hiatal hernia nor pathological reflux on 24-hour pH monitoring) were selected as the pulmonary disease-free control group. In total, 204 patients underwent LTx between January 2015 and December 2016. Of these, 77 patients met inclusion criteria. We compared patients with obstructive lung disease (OLD, n = 33; 42.9%) and those with restrictive lung disease (RLD, n = 42; 54.5%). 2/77 patients (2.6%) had pulmonary arterial hypertension. GERD was more common in the RLD group than in the OLD group (24.2% vs. 47.6%, P = 0.038). TAPG was similar between the OLD group and the controls (14.2 vs. 15.3 mmHg, P = 0.850); however, patients in the RLD group had significantly higher TAPG than the controls (24.4 vs. 15.3 mmHg, P = 0.002). Although TAPG was not correlated with GERD, the adjusted TAPG correlated with reflux in all 77 patients with end-stage lung disease (DeMeester score, rs = 0.256, P = 0.024; total reflux time, rs = 0.259, P = 0.023; total number of reflux episodes, rs = 0.268, P = 0.018). Additionally, pathological reflux was seen in 59.1% of lung transplant candidates with adjusted TAPG greater than 0 mmHg (i.e., TAPG exceeding LESP); GERD was seen in 30.9% of patients who had an adjusted TAPG ≤ 0 mmHg. In summary, TAPG varies based on the underlying cause of lung disease. Higher adjusted TAPG increases pathological reflux, even if patients have normal antireflux anatomy and physiology (i.e., no hiatal hernia and manometrically normal LES function). Adjusted TAPG may provide further insights into the pathophysiology of GERD.

Swallow-induced esophageal shortening in patients without hiatal hernia is associated with gastroesophageal reflux.

Longitudinal esophageal body shortening with swallow-induced peristalsis has been reported in healthy individuals. Esophageal shortening is immediately followed by esophageal re-elongation, and the lower esophageal sphincter (LES) returns to the baseline position. High-resolution manometry (HRM) allows for objective assessment of extent of shortening and duration of shortening. In patients without hiatal hernia at rest, swallow-induced esophageal shortening can lead to transient hiatal hernia (tHH) which at times may persist after the completion of swallow. This manometric finding has not been investigated in the literature, but a question arises whether this swallow-induced transient herniation can effect on the likelihood of gastroesophageal reflux. This study aims to assess the relationship between gastroesophageal reflux and the subtypes of swallow-induced esophageal shortening, i.e. tHH and non-tHH, in patients without hiatal hernia at rest. After Institutional Review Board (IRB) approval, we queried a prospectively maintained database to identify patients who underwent HRM evaluation and 24-hour pH study between January to December 2015. Patients with type-I esophagogastric junction (EGJ) morphology (i.e. no hiatal hernia) according to the Chicago classification v3.0 were included. The patterns of the esophageal shortening with swallows were divided into two subtypes, i.e. tHH and non-tHH. tHH was defined as an EGJ double high-pressure zones (≥1 cm) at the second inspiration after the termination of swallow-induced esophageal body contraction. The number of episodes of tHH was counted per 10 swallows and tHH size was measured for each patient. In total, 41 patients with EGJ morphology Type-I met the inclusion criteria. The mean age was 47.2 years, 35 patients (85.4%) were women, and the mean body mass index was 33.9 kg/m2. The mean number of tHH episodes was 3 out of 10 swallows; mean maximal tHH size was 1.3 cm. Patients who had tHH in ≥3 out of 10 swallows (n = 16; 39.0%) were more likely to have abnormal DeMeester scores than patients with <3 swallows (56% vs. 28%; P = 0.070). Patients with maximal tHH ≥2 cm in at least 1 swallow (n = 17; 41.5%) were more likely to experience pathological reflux than patients with maximal tHH <2 cm (59% vs. 25%; P = 0.029). In conclusion, we showed that, in a subset of patients with Type-I EGJ morphology, swallowing induced transient EGJ double high-pressure zones (≥1 cm) after peristalsis. We have named this new manometric finding the swallow-induced tHH. A high prevalence of pathological reflux disease was observed in patients with maximal tHH ≥2 cm. The degree of swallow-induced tHH could be an early indicator of lower esophageal sphincter dysfunction in patients without manometric hiatal hernia.

Donor-Derived Exosomes With Lung Self-Antigens in Human Lung Allograft Rejection.

The immunological role of exosomes in allograft rejection remains unknown. We sought to determine whether exosomes are induced during lung allograft rejection and to define the antigenic compositions of HLA, lung-associated self-antigens (SAgs) and microRNAs (miRNAs). Exosomes were isolated from sera and bronchoalveolar lavage fluid from 30 lung transplant recipients (LTxRs) who were stable or who had acute rejection (AR) or bronchiolitis obliterans syndrome (BOS). Exosomes were defined by flow cytometry for CD63 and western blotting for annexin V SAgs, collagen V (Col-V) and Kα1 tubulin were examined by electron microscopy; miRNAs were profiled by a miRNA array. Donor HLA and SAgs were detected on exosomes from LTxRs with AR and BOS but not from stable LTxRs. Exosomes expressing Col-V were isolated from sera from LTxRs 3 mo before AR and 6 mo before BOS diagnosis, suggesting that exosomes with SAgs may be a noninvasive rejection biomarker. Exosomes isolated from LTxRs with AR or BOS also contained immunoregulatory miRNAs. We concluded that exosomes expressing donor HLA, SAgs and immunoregulatory miRNAs are present in the circulation and local site after human lung transplantation and play an important role in the immune pathogenesis of acute allograft rejection and BOS.

Regional topical hypothermia of the beating heart: preservation of function and tissue.

BACKGROUND: Protection of the myocardium during beating heart operations is paramount. The goal of this study is to determine if regional topical hypothermia (RTH) preserves myocardial viability and function during periods of temporary coronary artery occlusion. METHODS: Sixteen pigs were divided into two groups (RTH and control). Each group received 40 minutes of midleft anterior descending coronary occlusion followed by 3 hours of reperfusion. The RTH group (n = 10) received RTH and the control group (n = 6) received no cooling. Myocardial and core temperatures were measured with thermistors. Sonomicrometers and micromonameters were used to determine load independent indices of myocardial function. These indices were measured at base line, during coronary occlusion, and at 3 hours of reperfusion. The myocardium at risk and the infarct area were determined with monastral blue dye and triphenyl tetrazolium chloride staining. RESULTS: The mean myocardial temperature in the risk zone during coronary occlusion was significantly less in the RTH group (29.4 degrees C +/- 5.6 degrees C versus 35.7 degrees C +/- 1.1 degrees C, p < 0.05). After 40 minutes of coronary occlusion, both the RTH group and control had a significant reduction in regional elastance (9.38 +/- 3.54 and 11.05 +/- 1.67 mm Hg/mm) compared with base line measurements (14.70 +/- 2.42 and 16.80 +/- 4.79 mm Hg/mm), p < 0.05. However, after 3 hours of reperfusion, the elastance returned to base line levels in the RTH group (15.83 +/- 3.06 mm Hg/mm) but remained significantly depressed in the control group (9.97 +/- 3.63 mm Hg/mm, p < 0.04). Myocardial necrosis as a percentage of the risk zone was significantly less in the hypothermia group (25% +/- 2% versus 62% +/- 5%, p < 0.001). CONCLUSIONS: Regional topical hypothermia during isolated temporary coronary occlusion provides regional myocardial protection expressed as a return of function and decreased necrosis. Regional topical hypothermia may be clinically applicable to myocardial preservation during beating heart operations.

The effect of pleural adhesions on pediatric cystic fibrosis patients undergoing lung transplantation.

The degree of pleural scarring complicating cystic fibrosis (CF) lung disease is thought to impact on the outcome of adult lung transplantation. This has not been previously studied in the pediatric population. We studied all patients undergoing lung transplantation at Children's Hospital Los Angeles from 1993 through 2000. Operative times, grade of pleural scarring, blood product transfusion requirements, and perioperative mortality were compared for patients with cystic fibrosis (35) versus those without this diagnosis (11). Patients with CF were slightly older (14.7+/-3.8 vs 10.6+/-5.6 years; P = 0.01) but had similar weights (34.8+/-8.7 vs 34.4+/-12.3 kg). The degree of pleural scarring was greater in the CF group but was only severe in four patients. Scarring did not impact on operative times (237+/-46 vs 219+/-39 minutes; P = 0.22) or cardiopulmonary bypass times (127+/-40 vs 133+/-49 minutes). Total perioperative blood requirements for the two groups were similar (35.6+/-14.9 vs 42.8+/-76.7 cm3/kg; P = 0.82). Pleural scarring in the pediatric CF patients undergoing lung transplantation is only severe in a minority of patients. It does not increase duration of operation nor blood transfusion requirements. CT scanning is consequently unnecessary in the preoperative workup of CF patients being evaluated for transplantation. CF patients undergoing transplantation have perioperative outcomes similar to those of noncystic patients.

Laparoscopic ultrasonic epithelial ablation of the lower esophagus after nissen fundoplication in a porcine model: assessment of tissue damage and healing process.

A substantial population of patients with Barrett's esophagus has undergone antireflux surgery but still requires annual surveillance endoscopy. These patients would benefit from a definitive ablation of the Barrett's mucosa, which would remove the malignant potential of this disease. This study evaluates the efficacy of applying ultrasonic energy to remove the epithelium of the lower esophagus in a porcine model with prior Nissen fundoplication. Four Yakutan minipigs underwent laparoscopic Nissen fundoplication. After 2 weeks they underwent transgastric Cavitron ultrasonic surgical aspirator (CUSA; Valleylab, Boulder, CO) ablation of the lower esophageal epithelium. Healing of the mucosa was assessed by endoscopy at 2 weeks and pathological examination at 4 weeks after ablation. All pigs underwent successful laparoscopic Nissen fundoplication. Complete lower esophageal epithelial ablation was accomplished through the fundoplication in three animals. One pig developed a bezoar that prohibited ablation. At 2 weeks endoscopy showed patchy squamous epithelial regeneration, which was confirmed histologically. Esophageal specimens at 4 weeks showed complete regeneration of squamous epithelium with a partially healed small ulcer in one animal. No stricture formation was seen. We conclude that the CUSA technique can completely ablate Barrett's mucosa in the setting of a prior antireflux procedure. Healing with squamous mucosal regeneration is rapid and complete.

Ultrasonic epithelial ablation of the lower esophagus without stricture formation. A new technique for Barrett's ablation.

BACKGROUND: The premalignant potential of Barrett's esophagus has stimulated efforts to find a way to ablate the columnar epithelium in order to reheal the area with squamous epithelium, thus obviating the cancer risk. This study describes and evaluates a new technique using ultrasonic energy to ablate the epithelium of the lower esophagus in a porcine model. METHODS: Eight young farm pigs were used to develop the technique of applying a laparoscopic Cavitron Ultrasonic Surgical Aspirator (CUSA) to the lower esophageal mucosa through an operating gastrostomy. A further 11 Yakutan minipigs then underwent CUSA epithelial ablation, followed by a laparoscopic Nissen fundoplication or postoperative acid suppression therapy. We then assessed the healing response in these subjects. RESULTS: Optimal CUSA energy settings enabled complete ablation of the squamous epithelium with preservation of the muscularis mucosa and submucosa. The integrity of the aspirated cells was sufficient for cytological analysis. Healing occurred by squamous regeneration without stricture formation. CONCLUSION: The CUSA technique holds promise for complete ablation of the Barrett's epithelium in a single setting. The unique tissue-selective nature of the ablative process allows complete mucosal reepithelialization without stricture formation.

Normal esophageal body function: a study using ambulatory esophageal manometry.

OBJECTIVE: The objective of this study was to establish normative ambulatory manometric data for contractions and contraction propagation in three levels of the esophagus. METHODS: Twenty-five healthy volunteers underwent simultaneous ambulatory 24 h manometry. Concomitant 24 h pH studies were performed to exclude the presence of increased esophageal acid exposure. Pressures were recorded over a complete circadian cycle while patients continued with their normal lifestyles including eating and sleeping. Data were analyzed with a software program that was previously modified and validated and that enables quantitation of contractions in terms of efficacy. RESULTS: The frequency of contractions was lowest during sleep, was increased when awake, and was highest during meals. Contraction amplitude increased during meals, providing a greater propulsive force for bolus transport. Similarly, the prevalence of peristaltic waves varied according to different physiologic states, ie., while eating, upright, awake, and sleeping. An increased amplitude and prevalence of peristalsis resulted in an increase in manometric efficacy during meals. CONCLUSIONS: This study provides normative data for ambulatory manometry for comparison when studying patients with disease.

Barrett's esophagus.

The columnar replacement of squamous epithelium in the lower esophagus is the result of gastroesophageal reflux. Whether the squamous cells are replaced or undergo metaplasia is still conjectural. This neoepithelium is unstable in the presence of continued reflux and prone to complications of stricture, ulceration, and adenocarcinoma. Considerable evidence supports the hypothesis that duodenal contents play a role in the development of Barrett's esophagus and its complications. The increasing incidence of adenocarcinoma in Barrett's esophagus is of concern in the Western World. Surveillance programs in some centers have been successful in early diagnosis, and excellent survival periods have been reported following resection in these cases. Both medical and surgical antireflux treatment is successful in symptom relief, but even in the absence of symptoms, reflux may continue. Surgery offers better overall results than proton pump inhibition of gastric acid and has been more popular since less aggressive (minimally invasive) techniques have been popularized. Mucosal ablation and antireflux measures by medicine or surgery are still in the experimental stages but hold considerable promise for the future.

Selection of patients for curative or palliative resection of esophageal cancer based on preoperative endoscopic ultrasonography.

OBJECTIVE: To assess the accuracy of pretreatment staging and the potential of using endosonographic findings to select patients for curative or palliative resection by comparing the preoperative endosonographic and computed tomographic (CT) findings with the histology of the surgical specimen. METHODS: Forty-two patients referred to our clinic with esophageal carcinoma underwent preoperative upper endoscopy with biopsy, endosonography, thoracic CT, and abdominal CT. Based on endoscopic ultrasonographic findings, patients with early-stage disease underwent en-bloc esophagogastrectomy, whereas those with advanced disease had a palliative transhiatal esophagectomy. Exceptions included patients with poor physiologic reserve who were treated by the transhiatal route. RESULTS: In eight patients, we were unable to pass the ultrasonographic endoscope. Seven of these eight had transmural tumors with nodal involvement on histologic study. Tumor length, based on endosonographic measurements, was correctly predicted in 34 patients (85%). Extent of wall penetration was accurately predicted in 26 (76%) of the 34, and regional lymph node status was accurately predicted in 28 (82%) of the 34. Of the patients with sonographic wall penetration, 80% had histologic evidence of one or more positive nodes. Using the WNM staging system, endoscopic ultrasonography correctly staged the cancer in 68% of the patients. Three patients were treated with an inappropriate procedure. CONCLUSION: Endosonography is a reliable method for the preoperative staging and selection of patients for curative or palliative resection. Endosonographic wall penetration appears to be a critical factor in determining tumor spread.

The effect of symptoms and nonspecific motility abnormalities on outcomes of surgical therapy for gastroesophageal reflux disease.

The outcome of Nissen fundoplication in patients with a nonspecific motility abnormality compared with the outcome in patients with normal motility is unknown. One hundred consecutive patients who underwent primary Nissen fundoplication were evaluated before and a median of 50 months after operation, with emphasis on the presence of a preoperative motility disorder and its relationship to preoperative and postoperative symptoms. Compared with patients who had normal motility, patients with a nonspecific motility abnormality had a greater prevalence and severity of heartburn and regurgitation before operation. These patients also had a greater esophageal exposure to gastric juice on pH monitoring as a result of poorer esophageal clearance function. The prevalence and severity of preoperative dysphagia was not related to the presence of a motility disorder. A 90% or a 95% actuarial success rate was achieved in the relief of heartburn and regurgitation over a 96-month period in patients with and without a motility abnormality. The overall actuarial success rate was 93%. Dysphagia was rarely caused or made more severe by the procedure; if present before the operation, it was relieved in most patients. The prevalence of persistent postoperative dysphagia was similar in patients with and without a motility abnormality. The success of Nissen fundoplication in properly selected patients is not affected by the presence of a nonspecific motility disorder.

Value of physiologic assessment of foregut symptoms in a surgical practice.

BACKGROUND: The aim of this study was to evaluate the reliability of symptoms in the diagnosis of gastroesophageal reflux disease and esophageal motility disorders as assessed by functional tests. METHODS: In 365 patients referred for suspected esophageal functional disease, symptomatic assessment was compared with the results of esophageal manometry and ambulatory 24-hour pH monitoring of the distal esophagus. RESULTS: Based on the patients' chief complaint, the symptomatic diagnosis was gastroesophageal reflux (44%), esophageal motor disorder (26%), chest pain of esophageal origin (9%), reflux and aspiration (8%), and abdominal pathology (12%). The symptomatic diagnosis was considerably altered by the results of the esophageal function tests: gastroesophageal reflux and motility disorders were found in all symptomatic diagnostic groups and a large number of patients in each group tested normal. The sensitivity and specificity of symptom-based diagnoses for functional disease were low. CONCLUSIONS: The results of this study showed that symptoms are an unreliable guide of esophageal abnormality, illustrating the need for objective testing in these patients, particularly to avoid inappropriate medical or surgical therapy.

Pharyngeal swallowing. The major factor in clearance of esophageal reflux episodes.

OBJECTIVE: This study defined the clearance mechanisms of naturally occurring reflux episodes in normal subjects and patients with gastroesophageal reflux disease. SUMMARY BACKGROUND: Previous studies on acid clearance have been performed in the laboratory setting in supine subjects using acid instillation and stationary motility. The mechanisms of clearance have not been studied using ambulatory pH and motility monitoring. METHODS: A new system capable of monitoring simultaneously for 24 hours pharyngeal pressure, esophageal motility, and pH was used to study the clearance of naturally occurring reflux episodes in 10 normal subjects and 18 patients with gastroesophageal reflux disease. Esophageal contraction waves were classified as primary (i.e., initiated by a pharyngeal swallow) and secondary (i.e., unrelated to a pharyngeal swallow). RESULTS: A total of 1288 reflux episodes were analyzed, during which 2781 contraction waves occurred. Clearance (i.e., restoration of pH to > 4) occurred after primary peristalsis in 83% of reflux episodes. An additional 11% were cleared by pharyngeal swallows without an esophageal body response. Secondary waves were rare and when they occurred, only 19% were peristaltic. Secondary peristalsis cleared only 9 of the 1288 reflux episodes. Patients and normal subjects cleared reflux episodes similarly. Baseline swallowing frequency was 0.87/min during the daytime and increased to 2.59/min (p < 0.01) during daytime reflux episodes. Swallowing frequency in response to nighttime reflux episodes was less (1.42/min; p < 0.05). CONCLUSIONS: Pharyngeal swallowing is the most important mechanism for esophageal acid clearance. Secondary waves are rare, usually disorganized, and unimportant in clearing a reflux episode. During sleep, the mechanisms of clearance are depressed.

Manual verification of computer analysis of 24-hour esophageal motility.

The application of solid-state technology to intraesophageal pressure monitoring over an entire circadian cycle has resulted in large amounts of data that require computer analysis. Recently available commercial software has yet to be validated. The aim of this study was to compare the analysis of ambulatory esophageal manometry by an automated computer program with manual analysis and make the software modifications necessary to validate the automated system for clinical use. Computer-aided analysis of a large number of esophageal contractions recorded during ambulatory esophageal manometry was compared with manual analysis by four experienced physicians. Good correlations were found between manual and computerized measurements of contraction amplitude and duration (r = 0.99 and r = 0.73, respectively). Software modifications resulted in correct identification of 94% of contractions and correct classification of 93.3% of these waves as peristaltic or simultaneous. These results demonstrate that the evaluated program for automated analysis of ambulatory esophageal manometry is accurate and reliable for research and clinical applications.

Concentration of refluxed acid and esophageal mucosal injury.

The hallmark of gastroesophageal reflux disease (GERD) is an increase in esophageal exposure to gastric juice. This exposure can result in complications such as esophagitis, stricture, and Barrett's esophagus. The aim of this study is to determine if there are specific pH exposure patterns that are associated with the development of these complications. The 24-hour esophageal pH data for 50 normal subjects and 154 patients with proven GERD were analyzed for time spent at different pH intervals. Increased esophageal acid exposure at a given interval occurred when the cumulative time of exposure exceeded the 95th percentile of that measured in the 50 normal subjects for that interval. The greatest prevalence of mucosal damage was found in the those patients with increased esophageal exposure to pH 0 to 2, corresponding to the known pKa of pepsin. This exposure was not related to a hypersecretory state. In addition, mucosal injury was associated with an increased esophageal exposure to pH 7 to 8. We conclude that mucosal injury in patients with GERD is related to the exposure time to gastric juice with a pH of less than 2 or greater than 7.

Effect of Nissen fundoplication on esophageal motor function.

The effect of Nissen fundoplication on the compromised esophageal body function in patients with gastroesophageal reflux disease is poorly understood. Stationary manometry of the distal esophageal body was performed in 50 normal volunteers and compared with that in 40 patients with increased esophageal acid exposure. The studies were performed before and 11 to 68 months (median, 30 months) after successful reflux control and healing of acute mucosal injury with Nissen fundoplication. Before the operation, patients had a lower mean amplitude of contractions, higher prevalence of low amplitude, and interrupted and simultaneous contractions in the distal esophagus compared with normal volunteers. Nissen fundoplication restored the lower esophageal sphincter to normal, increased contraction amplitude, and reduced the prevalence of low-amplitude contractions but did not improve contraction amplitude in patients with a mean amplitude below 35 mm Hg. Fundoplication improves esophageal contraction amplitude but should be performed before the mean contraction amplitude falls below 35 mm Hg.