Personalizing non-small cell lung cancer treatment through patient-derived xenograft models: preclinical and clinical factors for consideration.

PURPOSE: In the pursuit of creating personalized and more effective treatment strategies for lung cancer patients, Patient-Derived Xenografts (PDXs) have been introduced as preclinical platforms that can recapitulate the specific patient's tumor in an in vivo model. We investigated how well PDX models can preserve the tumor's clinical and molecular characteristics across different generations. METHODS: A Non-Small Cell Lung Cancer (NSCLC) PDX model was established in NSG-SGM3 mice and clinical and preclinical factors were assessed throughout subsequent passages. Our cohort consisted of 40 NSCLC patients, which were used to create 20 patient-specific PDX models in NSG-SGM3 mice. Histopathological staining and Whole Exome Sequencing (WES) analysis were preformed to understand tumor heterogeneity throughout serial passages. RESULTS: The main factors that contributed to the growth of the engrafted PDX in mice were a higher grade or stage of disease, in contrast to the long duration of chemotherapy treatment, which was negatively correlated with PDX propagation. Successful PDX growth was also linked to poorer prognosis and overall survival, while growth pattern variability was affected by the tumor aggressiveness, primarily affecting the first passage. Pathology analysis showed preservation of the histological type and grade; however, WES analysis revealed genomic instability in advanced passages, leading to the inconsistencies in clinically relevant alterations between the PDXs and biopsies. CONCLUSIONS: Our study highlights the impact of multiple clinical and preclinical factors on the engraftment success, growth kinetics, and tumor stability of patient-specific NSCLC PDXs, and underscores the importance of considering these factors when guiding and evaluating prolonged personalized treatment studies for NSCLC patients in these models, as well as signaling the imperative for additional investigations to determine the full clinical potential of this technique.

Empyema Secondary to Pneumonia: Whom Should We Operate?

Introduction: Empyema secondary to pneumonia is a common condition. A significant number of patients will require surgical intervention for drainage and decortication. The aim of this study was to identify predictive factors for surgical intervention. Materials and Methods: The medical records of patients who were diagnosed with empyema secondary to pneumonia between the years 2010 and 2019 in a university hospital were included in the study. Patients who underwent surgical intervention were defined as group A and nonoperative treatment as group B. Clinical and laboratory data were collected from medical records and patients' chest computerized tomography (CT) scans were reviewed. Results: A total of 194 patients were included in the study-86 patients were included in group A and 108 patients in group B. Several parameters on admission were found to have a statistically significant correlation with surgical intervention: younger age, higher systolic blood pressure, and elevated white blood count. Multivariant analysis showed that younger age was found to have a statistically significant correlation with operative intervention (adjusted odds ratio = 0.971, P = .023). A statistically significant correlation between surgical intervention and survival (adjusted hazard ratio [HR] = 1.762, P = .046) and an inverse correlation between age and survival (adjusted HR = 0.050, P < .001) were found. Surgical intervention was associated with increased survival irrespective of age. A total of 42 CT scans were available for review. The mean density of the empyema fluid in group A was higher by 4.3 hounsfield units compared to group B (P < .067). Conclusions: Younger age was found to be associated with surgical intervention among patients suffering from empyema secondary to pneumonia. Surgical intervention was associated with increased long-term survival, irrespective of patients' age. Several radiologic characteristics were associated with the need for surgery in this study: empyema fluid density, pleural thickening, and fluid loculations. Additional prospective studies are required to ascertain these results.

Thoracic surgery in Israel.

During the past 74 years since its establishment, Israel has evolved into a modernized country with well-established and effective public health care system. Thoracic surgeons in Israel play a central role in the diagnosis and treatment of patients with diseases of the chest wall, diaphragm, mediastinum, airways, Lung, and esophagus as well are taking part in designated trauma teams. Between 2,500-3,000 cases are being performed in 16 designated thoracic surgical units and departments across the country annually, the majority of them being performed in a minimally invasive fashion. Lung cancer is the leading cause of cancer related mortality in Israel and the second most common cancer in Israel. All types of thoracic oncologic cases are being presented routinely during designated multi-disciplinary conferences and treatment plans are designed according to the most up to date international guidelines. Each surgeon undergoes at least 6 years of formal training, followed by certifying exams. Advanced training is usually obtained overseas in centers of excellence. Israeli thoracic surgeons are part of an international societies and are actively involved in academic research. Despite the advancement of the Israeli health care system, thoracic surgeons in Israel are still facing few challenges that are limiting the early diagnosis of thoracic surgical malignancies such as lack of established national lung cancer screening program in Israel although a pilot program is being tested during these days. Tasked with taking care of diseases of the chest, and in order to remain at the forefront of diagnosis and treatment similar to our colleagues across the globe, Thoracic surgeons in Israel are continuously seeking to learn and evolve in order to improve and provide better care to our patients.

Generalization of Deep Learning Gesture Classification in Robotic-Assisted Surgical Data: From Dry Lab to Clinical-Like Data.

OBJECTIVE: Robotic-assisted minimally invasive surgery (RAMIS) became a common practice in modern medicine and is widely studied. Surgical procedures require prolonged and complex movements; therefore, classifying surgical gestures could be helpful to characterize surgeon performance. The public release of the JIGSAWS dataset facilitates the development of classification algorithms; however, it is not known how algorithms trained on dry-lab data generalize to real surgical situations. METHODS: We trained a Long Short-Term Memory (LSTM) network for the classification of dry lab and clinical-like data into gestures. RESULTS: We show that a network that was trained on the JIGSAWS data does not generalize well to other dry-lab data and to clinical-like data. Using rotation augmentation improves performance on dry-lab tasks, but fails to improve the performance on clinical-like data. However, using the same network architecture, adding the six joint angles of the patient-side manipulators (PSMs) features, and training the network on the clinical-like data together lead to notable improvement in the classification of the clinical-like data. DISCUSSION: Using the JIGSAWS dataset alone is insufficient for training a gesture classification network for clinical data. However, it can be very informative for determining the architecture of the network, and with training on a small sample of clinical data, can lead to acceptable classification performance. SIGNIFICANCE: Developing efficient algorithms for gesture classification in clinical surgical data is expected to advance understanding of surgeon sensorimotor control in RAMIS, the automation of surgical skill evaluation, and the automation of surgery.

Serratus Anterior Block for Long-Term Post-Thoracoscopy Pain Management.

PURPOSE: Neuropathic, chronic pain is a common and severe complication following thoracic surgery, known as post-thoracotomy pain syndrome (PTPS). Here we evaluated the efficacy of an ultrasound-guided serratus anterior plane block (SAPB) on pain control compared to traditional pain management with intravenous opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) six months after thoracic surgery. PATIENTS AND METHODS: In this retrospective observational study, we analyzed data from a questionnaire survey. We interviewed all patients who underwent elective video-assisted thoracoscopy surgery (VATS) at Soroka University Medical Center between December 2016 and January 2018. The responses of ninety-one patients were included. RESULTS: Participants reported PTPS in both groups, 43% of patients in the SAPB group and 57% of patients in the standard group, which failed to reach significance. However, we demonstrated that the percentage of pain occurrence trended lower in the SAPB group. There was significantly less burning/stitching or shooting, shocking, pressure-like, and aching pain in SAPB patients compared to the standard protocol group. Patients in the SAPB group had significantly less pain located in the upper and lower posterior thorax anatomical regions compared to the standard protocol group. Moreover, we found a significant difference in occurrence of PTPS depending on the type of thoracic surgery. From both study groups, 69% of patients who underwent lobectomy reported pain, compared with 41.9% of those in the segmental (wedge resection) procedure, and 42.1% of patients in other procedures. CONCLUSION: While the present study did not demonstrate a statistically significant reduction of PTPS after SAPB concerning postoperative pain control, there was a trend of a decrease. We also found significance in the type of pain and location of pain after thoracic surgery between the two groups, as well as a significant difference between pain occurrence in types of thoracic surgeries from both groups.

Epithelioid Hemangioendothelioma and Epithelioid Hemangioma: Pazopanib as a Potential Salvage Therapy.

Epithelioid hemangioma (EH) and epithelioid hemangioendothelioma (EHE) are both rare vascular tumors. EH tumors are often benign while EHE tumors have moderate malignant potential. Here, we present three unique cases at Soroka Medical Center, two featuring EH of the bone and one presenting EHE of the mediastinum. Each case demonstrates distinct treatment challenges due to the rarity of both diseases and lack of established guidelines. We propose three treatment approaches including pazopanib for salvage therapy of EH of the bone and minimally invasive surgical resection which in these cases lead to complete symptom relief and tumor stabilization upheld over time with close follow-up.

Clinical outcomes of critically ill multiple trauma patients with rib fractures. A prospective study with retrospective control.

INTRODUCTION: Rib fracture fixation is becoming more popular and widely accepted among trauma surgeons worldwide as the recommended treatment method for flail chest injury. Recent data demonstrate improved results when compared with non-operative treatment. Improved outcomes were reported regarding ICU stay, need for tracheostomy, length of hospital stay, ventilator-associated pneumonia (VAP), and even death. The objective of this study was to ascertain whether clinical respiratory para-meters are improved after rib fracture fixation procedure. MATERIAL AND METHODS: This is a prospective study using a retrospective cohort for control, which took place at the Soroka University Medical Centre, Israel. Inclusion criteria included all patients over 18 years of age with flail chest injury or multiple ribs fractures, who were admitted to the General Intensive Care Unit (GICU). Between October 2015 and December 2018, we identified 24 patients who had their rib fractures operatively fixed and compared them to 61 patients with flail chest and multiple rib fractures, who were admitted to our GICU between the years 2010 and 2015 and were treated non-opera-tively. In all the surgical cases operations were performed within 72 hours of arrival in accordance with our treatment algorithm. All fractures were fixed using specialised anatomic locking plates/nails. Demographic data were collected, and respiratory parameters before and after the surgery were recorded and analysed. RESULTS: We compared patients who had had their rib fractures fixed with a cohort group of patients who had been treated non-operatively in the past. No demographic differences were found between the 2 groups, nor were there any differences in their clinical trauma scoring, mechanical ventilation days, length of ICU stay, VAP, and death rates. The respiratory parameters (paO2/FiO2 ratio and chest wall compliance) were significantly higher during the 3 ensuing days after surgery and continued to improve in Group 1 (rib fixation group), in comparison to group 2 (non-operative) patients (P = 0.007 and P < 0.0001, respectively). The peak inspiratory pressure and PEEP para-meters were significantly lower in group 1 in comparison to group 2 during the 3 days, in favour of the operated group, with significant improvement noted over the 3 days post-surgery (P = 0.007 and P = 0.02, respectively). CONCLUSIONS: We suggest that surgical treatment of flail chest and multiple rib fractures has clinical benefit and improves respiratory parameters even in the presence of multiple trauma injuries.

A Huge Hydatid Pulmonary Cyst.

This case report describes a patient with an unusually large pulmonary hydatid cyst and discusses important management issues.

Predictors of survival after emergency department thoracotomy in trauma patients with predominant thoracic injuries in Southern Israel: a retrospective survey.

Introduction: Emergency department thoracotomy (EDT), also termed "resuscitative thoracotomy", is indicated in some cases of life-threatening isolated thoracic injury, or as a part of CPR (cardiopulmonary resuscitation) in multiple trauma patients, or in thoracic trauma patients with massive bleeding (such as intra-abdominal exsanguination or injury to the great vessels). There is a lack of information in the literature concerning predictors of survival after EDT in patients with predominant or isolated thoracic trauma. Patients and methods: The study was retrospective and single-center. We collected clinical and laboratory data from all civil and military trauma patients admitted to our emergency department (ED) with predominant thoracic injuries who underwent EDT at Soroka Medical Center. A total of 31 patients were included in the study. Results: Of the patients in the study group, 58% presented with penetrating thoracic injuries and 42% presented with blunt thoracic injuries. 13 patients (42%) survived the EDT procedure. The following parameters predicted survival after EDT: signs of life and the presence of sinus rhythm on admission to the ED; heart rate at the end of the EDT procedure; short duration of EDT; and total positive balance (fluid and blood products) after EDT. Patients who sustained penetrating stab wound injuries had a better immediate post-operative survival rate after EDT than those who sustained penetrating gunshot wounds or predominant blunt chest trauma (30.8% vs 11.1%; p-0.034). Six patients (19%) survived until discharge from the hospital: 3 with penetrating injuries and 3 with blunt thoracic injuries. Conclusion: In patients undergoing EDT after thoracic injury we found that the clinical status on admission to the ED, the duration of the EDT procedure and the heart rate at the end of procedure were predictors of survival after EDT. We demonstrated a higher survival rate after EDT in patients with predominant penetrating thoracic trauma.

Ultrasound-guided serratus anterior plane block for analgesia after thoracic surgery.

BACKGROUND: Patients who undergo surgical procedures that impair the integrity of the chest wall frequently experience extremely severe postoperative pain. Opiates and weaker analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are not sufficiently effective in achieving control of severe pain and might cause respiratory and gastrointestinal complications. In the past decade, there has been an increased interest in the use of regional nerve blocks for post-thoracoscopy and post-thoracotomy analgesia. METHODS: This is a prospective, randomized, double-blind and single-center study. We recruited 104 patients who underwent elective thoracoscopy. Prior to surgery, the participating patients were randomized into one of two study groups: Group 1- the "standard control group" that received standard postoperative pain control with intravenous opioids, NSAIDs and acetaminophen (paracetamol) and Group 2- the "block group" that was treated by ultrasound-guided serratus anterior plane (SAP) block (a single injection of 0.25% bupivacaine hydrochloride 2 mg/kg plus dexamethasone 8 mg) with standard postoperative pain control regimen. We compared the clinical, laboratory, and postoperative pain assessment data of both groups. RESULTS: Patients in the SAP block Group 2 reported significantly lower levels of pain after thoracic surgery as assessed by their visual analog scale scores, as compared to the patients in the standard pain control Group 1 (P<0.001). The total dosage of morphine and tramadol required for pain relief during the first hours after surgery was significantly lower in the patients who received SAP block. Also, the incidence of vomiting after surgery was significantly lower among the patients who received SAP block than among the patients who received standard pain control. CONCLUSION: The results of the present study suggest that SAP block is an effective adjuvant treatment option for post-thoracic surgery analgesia. Compared to the current methods used for post-thoracic surgery pain relief, SAP block has some significant merits, particularly its ease of use and its low potential for side effects.

Peripheral blood telomere alterations in ground glass opacity (GGO) lesions may suggest malignancy.

A ground glass opacity (GGO) lung lesion may represent early stage adenocarcinoma, which has an excellent prognosis upon prompt surgical resection. However, GGO lesions have broad differential diagnoses, including both benign and malignant lesions. Our objective was to study telomere length and telomerase activity in patients with suspected lung cancer in which GGO was the predominant radiographic feature. Knowledge of telomere biology may help distinguish malignant from benign radiographic lesions and guide risk assessment of these lesions. Peripheral blood samples were taken from 22 patients with suspected adenocarcinoma with the GGO radiographic presentation. Multidisciplinary discussion confirmed the need for surgery in all cases. We used an age and gender-matched group without known lung disease as a control. Telomere length and aggregates were assessed by quantitative fluorescence in situ hybridization (QFISH) and quantitative PCR. Cell senescence was evaluated by senescence-associated heterochromatin foci. Subjects with GGO lesions had a higher percentage of lymphocytes with shorter telomeres (Q-FISH, P = 0.003). Furthermore, relative telomere length was also reduced among the GGO cases (qPCR, P < 0.05). Increased senescence was observed in the GGO group compared to controls (P < 0.001), with significant correlation between the senescence-associated heterochromatin foci and aggregate formation (r = -0.7 and r = -0.44 for cases and controls, respectively). In conclusion, patients with resectable early adenocarcinoma demonstrate abnormal telomere length and cell senescence in peripheral blood leukocytes compared to control subjects. Abnormal telomere biology in the peripheral blood may increase suspicion of early adenocarcinoma among patients with GGO lesions.

In-situ left-sided bilateral internal thoracic artery: elevated hemidiaphragm.

Background Procurement of the internal thoracic artery risks ipsilateral phrenic nerve injury and elevated hemidiaphragm. Anatomical variations increase the risk on the right side. Patients receiving left-sided in-situ right internal thoracic artery configurations appear to be at greatest risk. Methods From 2014 to 2016, 432 patients undergoing left-sided in-situ bilateral internal thoracic artery grafting were grouped according to right internal thoracic artery configuration: retroaortic via transverse sinus (77%) or ante-aortic (23%); targets were the circumflex and left anterior descending artery territories, respectively. Elevated hemidiaphragm was assessed by serial chest radiographs and categorized by side, complete (≥2 intercostal spaces) versus partial, and permanent versus transient. Results Right elevated hemidiaphragm occurred in 4.2% of patients. The incidence of radiological complete right elevated hemidiaphragm was 2.8% (12/432); 8 cases were transient with recovery in 3.5 ± 0.3 weeks. Permanent right elevated hemidiaphragm occurred in 0.9% (retroaortic group only). Permanent left elevated hemidiaphragm occurred in 0.9% and was significantly higher in the ante-aortic group (3/99 vs. 1/333, p = 0.039). No bilateral hemidiaphragm elevation was documented. Partial right elevated hemidiaphragm occurred in 1.4% and was not associated with adverse early or late respiratory outcomes. Conclusions Despite susceptible right phrenic nerve-internal thoracic artery anatomy, the incidence of permanent right elevated hemidiaphragm is low and no higher than left-sided in prone bilateral internal thoracic artery subsets. This reflects skeletonized internal thoracic artery procurement. Although statistical significance was not achieved, a retroaortic right internal thoracic artery configuration may constitute a higher risk of right phrenic nerve injury.

Clinical Outcome of Urgent Thoracotomy in Patients with Penetrating and Blunt Chest Trauma: A Retrospective Survey.

INTRODUCTION: In contrast to an emergency department of thoracotomy (EDT), an urgent thoracotomy (UT) is defined as a surgical thoracic intervention performed in the operating room within the first 48 hours of the patient's intensive care unit (ICU) stay. The factors affecting survival after UT are not fully understood. In this study, we retrospectively analyzed the clinical data and outcome of patients with blunt and penetrating chest injuries who underwent UT. METHODS: All adult patients who had blunt or penetrating chest trauma and who underwent UT, were included in the study. All data were collected from the patients' hospital and ICU records. Forty-five patients with thoracic injuries who underwent UT during the first 48 hours of ICU stay were analyzed. Of these, 25 had penetrating chest injuries, and 20 had blunt thoracic injuries. Of the penetrating injuries, 16 were stab wounds, and 9 were gunshot wounds. RESULTS: Overall ICU mortality was 29% (n = 13) and was significantly higher in the blunt chest trauma group than in the penetrating trauma group (45% vs 16%; p = 0.04). Lung parenchyma injuries (lacerations and contusions) were the most common intraoperative findings in both groups. The following independent predictors of in-hospital mortality were found: an Injury Severity Score (ISS) of >40; an Acute Physiology and Chronic Evaluation II (APACHE II) score of >30; prolonged duration of UT; low body temperature on admission to the ED; abnormal arterial blood lactate, bicarbonate, and pH at the end of UT; and use of vasopressors during the first 24 hours of ICU stay. CONCLUSION: Mortality after UT was higher in patients with blunt chest trauma. The UT should be performed in both penetrating and blunt chest trauma as quickly as possible and should be limited to damage control. It also emerges that acidosis and hypothermia in chest trauma patients need to be treated extremely aggressively before, during, and after UT.

A molecular signature of lung cancer: potential biomarkers for adenocarcinoma and squamous cell carcinoma.

Adenocarcinoma (AC) and squamous cell carcinoma (SCC), sub-types of non-small cell lung cancer (NSCLC), both present unique features at the genome, epigenome, transcriptome and proteome levels, as well as shared clinical and histopathological characteristics, but differ in terms of treatment. To ensure proper treatment, one must be able to distinguish between these sub-types. Here, we identify novel biomarker proteins in NSCLC, allowing for distinguishing between the AC and SCC sub-types. Proteomics analysis distinguished between healthy and tumor tissues, with the expression level of 1,494 proteins being altered, 378 of which showed a ≥|100|-fold change. Enrichment of proteins related to protein synthesis and degradation, and of proteins associated with mitochondria, metabolism, and apoptosis, was found. Network analysis defined groups of proteins, such as those associated with cell metabolic processes or with fatty acid/lipid metabolism and transport. Several biomarkers that enable for distinguishing between AC and SCC were identified here for the first time, and together with previous reports confirmed here, led us to propose a list of proteins differentially expressed in SCC and AC. Some of these biomarkers are clear signatures for AC or SCC and four of them are secreted proteins. The presence of the mitochondrial protein SMAC/Diablo in the nucleus was found to be a signature for SCC. Precise diagnosis of AC and SCC is essential for selecting appropriate treatment and thus, increasing patient life expectancy. Finally, the search for drugs that target some of these biomarkers may lead to new treatments for lung cancer.

Deep Neck Infection and Descending Mediastinitis as a Complication of Propionibacterium acnes Odontogenic Infection.

Propionibacterium acnes is an anaerobic, Gram-positive bacterium which causes numerous types of infections. Isolated Propionibacterium acnes deep neck infections are very rare. We present an interesting case of deep neck infection complicated by descending mediastinitis of isolated Propionibacterium acnes infection.

Two Paraneoplastic Autoimmune Syndromes: Limbic Encephalitis and Palmar Fasciitis in a Patient with Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is characterized by a relatively high rate of autoimmune phenomena. Paraneoplastic limbic encephalitis (PLE) is an autoimmune syndrome in which a non-neural tumor containing an antigen normally present in the nervous system precipitates an antibody attack on neural tissues. Patients with PLE usually present with rapidly progressive short-term memory deficits, confusion or even dementia. Palmar fasciitis and polyarthritis syndrome (PFPAS) is another autoimmune syndrome characterized by rheumatologic manifestations, especially involving the palms of the hands. We report a case of a 59-year old woman who presented with worsening neurological symptoms of two-week duration, and later coma. The combined clinical, serological, and imaging studies suggested a diagnosis of PLE. A chest computed tomographic scan showed a 1.2 cm-diameter mass in the upper lobe of the left lung that was surgically removed and showed SCLC. Following surgery, neurological symptoms rapidly improved, allowing the patient to receive adjuvant chemotherapy. While in remission for both SCLC and PLE, the patient developed pain, soft-tissue swelling, and stiffness in both palms, suggesting the diagnosis of PFPAS. Five months following the diagnosis of palmar fasciitis, SCLC relapsed with mediastinal and cervical lymphadenopathy. This case report underlines the continuous interaction of SCLC with the immune system, expressed by coexistence of two rare paraneoplastic diseases, PLE, and PFPAS, in a patient with SCLC. While symptoms related to PLE preceded the initial diagnosis of SCLC, other symptoms related to PFPAS preceded relapse.