Incurable Lesions Research Articles

Why every colorectal surgeon should learn endoluminal surgery

Endoscopic submucosal dissection (ESD) is an advanced therapeutic technique used to remove non-malignant polyps (NMP) and early cancers. Benefits include reducing unnecessary colectomies, cost, and morbidity of NMP treatment. Other roles for ESD and associated skills are likely to expand in the future, including in the non-operative management of rectal cancer. The learning curve is feasible with established training methods. Colorectal surgeons already perform routine endoscopy and manage endoscopic complications and endoscopically incurable lesions- endoluminal surgery (ELS) is a natural extension of this. Expanding technologies will only improve our ability to resect these lesions endoluminally moving forward. Collaboration with gastroenterologists and acquiring, rather than abandoning, this skillset is important and obtainable. Colorectal surgeons have the tools and professional duty to stay at the forefront of managing colorectal diseases endoscopically. Despite substantial barriers to mastering ELS, the value to our patients and profession means all colorectal surgeons should learn these techniques.

OBSERVATIONS ON THE DEVELOPMENT OF FETAL ATTACHMENT RETENTION IN INTENSIVELY BREEDING COWS

"The evolution of the puerperium is conditioned by the course of parturition - eutopic or dystocic, but also by possible placental retention or uterine atony and not rarely by infection with bacterial germs. After parturition, energy consumption increases with uterine involution, the volume of milk production and the needs determined by local and general self-defence. The puerperal period is one of the most important stages in the reproductive cycle of cows. Early and correct diagnosis of conditions during this period can lead to appropriate and more effective treatment regimens. Research in the literature indicates that special attention should be paid to high milk-producing females, especially in the intensive breeding system, as it is known that some diseases can easily develop in the genital tract during the puerperal period. An important aspect of reproduction in cows is sterility or inability to reproduce due to incurable lesions of the genital tract following dystocic parturitions. The aim of this paper is to complete the existing research and studies in the literature with some major aspects of reproductive pathology in cows, namely to highlight some of the factors that can generate the anaesthesia syndrome. In the first year of observation (2021), the incidence of fetal adnexal retention was 12.4% of the 242 cows monitored, and in 2022 out of a total of 270 cows, 9.6% of females were diagnosed with this condition. Analyzing the incidence of fetal appendix retention by calendar month, it was found that in 2021 no cases were reported in August, one case (0.4%) was recorded in June and July, and the highest level was recorded in February, 2.5%. In 2022, similar incidence of fetal appendage retention was recorded including the highest level of 1.8% being reported also in February. The incidence of fetal attachment retention in cows correlates with the level of milk production per lactation increasing progressively with the volume of milk production. Thus, in the year 2021 in cows with milk production ranging between 5000-5500 liters of milk/lactation the lowest level was obtained, i.e. 0.8% of fetal attachment retention.in the herd of 26 monitored females. Of the 45 cows with milk production between 7001-7500 l milk/lactation 3.3% of the females showed fetal attachment retention."

TMIC-33. UNDERSTAND AND TARGET ASTROCYTE REACTIVITY IN BRAIN TUMORS TO PREVENT RADIORESISTANCE

Abstract Glioblastoma multiforme (GBM) is the most aggressive type of glioma and deadliest brain tumor. Despite aggressive treatments including surgery, chemo-, and radiotherapy, tumors invariably recur as incurable lesions, and the median survival is approximately 15 months after diagnosis. Recurrence is tightly linked to tumor cell resistance to ionizing radiation (IR), a feature that in turn is linked to stem cell characteristics of tumor cells. Previous results from our lab indicate that stromal astrocytes respond to IR with a reactive phenotype that in turn promotes therapeutic resistance of neighboring tumor cells. Our objectives were to i) identify pathways involved in IR-induced astrocyte reactivity; ii) identify compounds able to inhibit IR-induced astrocyte reactivity. We used two complementary approaches to meet our objectives. Using an antibody array we found that JNK and ABL pathways were activated following IR in primary human astrocytes. To validate their involvement in the induction of astrocyte reactive phenotype we used an image-based readout combining the changes in the expression of reactivity markers and in the morphology of astrocytes. For the second approach, we used a similar readout to perform an image-based drug screen which aimed to identify compounds able to inhibit IR-induced astrocyte reactivity. The drug libraries used consisted of approved drugs to get candidates with potential for drug repurposing. We identified 20 compounds inhibiting IR-induced astrocyte reactivity and amongst them, 10 are brain-penetrant compounds that could make them good candidates for repurposing in GBM. An in vivo test is now ongoing with 2 of these compounds in a PDGFA/PDGFB-driven mouse model of GBM to validate their efficiency to increase radiosensitivity of the tumor cell by inhibiting astrocyte reactivity

TMIC-54. RADIOTHERAPY-INDUCED REMODELING OF THE GLIOBLASTOMA MICROENVIRONMENT

Abstract Radiotherapy (RT) is included in the standard of care for glioblastoma (GBM), and while primary tumors generally respond to RT, GBMs invariably recur as incurable lesions. We have previously demonstrated that RT generates a net tumor-supportive tumor microenvironment (TME), in part by inducing remodeling of the extracellular matrix, suggesting that there are therapeutic opportunities in targeting the altered TME of recurrent GBM. Here, we have used highly multiplexed immunohistochemistry in combination with single cell RNA sequencing to characterize the cellular composition and molecular alterations to the GBM TME as tumors progress from primary to irradiated to recurrent tumors, using a genetically engineered GBM mouse model. RT resulted in a phenotypic shift suggestive of a proneural-to-mesenchymal switch of lineage-traced tumor cells immediately after treatment, but proportions of tumor cell phenotypes were largely restored at the time of recurrence. Recurrent tumors displayed an altered immune landscape, as demonstrated e.g. by an increase in the proportion of CD8+ lymphocytes coupled to a decrease in the proportion of CD4+ cells. Together, our data suggest that RT remodels the GBM TME as well as alters the phenotype of bona fide glioma cells. Ongoing studies are aimed at understanding heterotypic cell-cell interactions unique to the irradiated and recurrent GBM TME.

Abstract 4858: A novel strategy for the selective and tissue specific inhibition of MMPs in active breast cancer to bone metastases

Abstract Bone metastasis is a common event during breast cancer progression: The delicate balance between bone matrix synthesizing osteoblasts and bone resorbing osteoclasts activities is typically subverted by the presence of tumor cells at the bone site. The resulting incurable lesions cause extensive osteolysis and severely impact the patient's quality of life. Understanding how active breast-to-bone metastases manipulate the bone microenvironment is critical for the development of new therapies to treat the disease. We have recently shown in preclinical animal models of breast to bone metastases that MMP-2 proteolytic activity is critical for the growth of the tumor and the associated osteolysis. We therefore hypothesized that the selective inhibition of MMP-2 at the tumor site would be a potent means through which to prevent the progression of the malignancy. Given that previous broad-spectrum MMP inhibitor (MMPI) trials were unsuccessful mainly because of consistent side effects, we took a novel chemical approach to generate a selective MMPI that would preferentially target the skeleton. To this end, we utilized a bisphosphonate backbone (tiludronate) to synthesize an MMPI (BMMPI) with high specificity for MMP-2 (IC50 0.14± 0.04μM). To test the efficacy of the BMMPI in vivo, we inoculated 6-week old immunocompromized female mice with a luciferase expressing osteolytic breast cancer cell line, PyMT-Luc (105 cells). Following tumor injection, mice (n=6/group) received saline, tiludronate (25mg/kg, to control for bisphosphonate effects) or BMMPI (25mg/kg) sub-cutaneously, twice weekly. Tumor growth was measured by quantitating luminescence over time. Our results show that application of the BMMPI significantly reduced the breast cancer growth over a two-week period (p<0.05). Furthermore, using Faxitron analysis to determine the extent of tumor induced bone destruction, we observed significantly less osteolysis in the tibia images of BMMPI treated mice compared to the control group. Our initial studies also suggest that BMMPIs perform better than clinically used bisphosphonates such as tiludronate. We are currently following up our in vivo/ex vivo analyses with histomorphometrical and histology approaches. In conclusion, our data thus far demonstrate that an MMP-2 specific BMMPI may be an effective means to prevent the progression of breast to bone metastases while at the same time eliminating some of the noted off-target effects of broad-spectrum MMP inhibitors. Since bisphosphonates are well tolerated in the clinical setting, we predict that BMMPIs could be rapidly translated to the patient. Citation Format: Marilena Tauro, Antonio Laghezza, Paolo Tortorella, Conor C. Lynch. A novel strategy for the selective and tissue specific inhibition of MMPs in active breast cancer to bone metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4858. doi:10.1158/1538-7445.AM2014-4858

P-027 The Role of Interventional Therapy in Head and Neck Arteriovenous Malformations

IntroductionHead and neck arteriovenous malformations (H&N AVM) are challenging to treat, and impart clinical and psychosocial morbidity. We evaluated the role of endovascular therapy and its success with varying presentations...

WHY NOT TO MAKE A SMILE ON YOUR FACE AND YOUR PATIENT'S FACE

Every now and then, we face the problem of terminally ill patient or what looks incurable lesion, like disseminated malignancy. Certainly, all of us prefer not to face such a bitter reality. But sadly, this is unavoidable. Problems almost always arise from this type of patients if not from their relatives, hence, the importance of proper handling, fine communication, gentle words and precise estimation of the surgeon's sentences. By doing so, the surgeon can spare himself a lot of problems. Sorry to say, some surgeons fall in this trap because they mishandle these peculiar and difficult patients. It is vital to appreciate the psyche of those miserable patients, sympathize with them as much as possible, make them feel that you are serious and keen to help them, and you are a friend rather than a physician.

E-041 Combined endovascular embolization and surgical resection of a massive lumbosacral arteriovenous malformation in a patient with Cobb syndrome

Objective and importanceCobb syndrome is a rare condition that includes a cutaneous nevus with an associated spinal vascular lesion at the same dermatome. We present a challenging case of a...

PTH-001 “Prophylactic” placement of self-expandable metal stent in colorectal cancer prior to obstruction: is this of any value?

<h3>Introduction</h3> Colorectal cancer (CRC) is one of the most prevalent malignancies in the world and is the second most common cancer cause of death in the UK. Colonic obstruction is usually a late presentation of CRC and is more characteristic of an advanced and incurable lesion. 40% of CRC present as a surgical emergency with either obstruction or perforation. Emergency presentation is associated with a poorer outcome. Colonic stents are a routine part of management of CRC, being used for palliation and as a “bridge to surgery“ for patients presenting with bowel obstruction thus minimising morbidity and mortality. It can be argued that the tighter the CRC stricture the more difficult the process of placement of colonic stent. For this reason, it has been suggested by some that “prophylactic” stent placement in the palliation of CRC patients who have stricturing but not yet obstruction may be an appropriate step in management. This may reduce failure rate of stent placement during obstruction and thus prevent emergency surgical decompression. <h3>Methods</h3> To aim was to assess the number of patients presenting with a stricturing CRC tumour that subsequently obstructs. This was a retrospective analysis was performed on consecutive patients with CRC during 2006–2007, presenting with a stricture as identified on colonoscopy and deemed for palliation following a multidisciplinary assessment. An analysis of whether or not these patients subsequently developed obstruction was performed. Data were obtained from the Unisoft endoscopy software and a database of patients with CRC. <h3>Results</h3> 17 patients (9 males, mean age of 78 (52 to 96 years)), were found to have a malignant stricturing lesion at colonoscopy and had palliative treatment. Four patients presented with obstruction as part of their symptom complex and underwent successful colonic stent placement. One patient underwent a defunctioning stoma operation for bowel obstruction 1 month following diagnosis. In the 12 cases (70%) that were not stented, none re-presented with bowel obstruction. 16 /17 patients died from causes unrelated to bowel obstruction, with all dying within 18 months due to disease progression and chemotherapy related complications. One patient who initially presented with obstructive symptoms and was subsequently stented is still alive to date. <h3>Conclusion</h3> The majority (70%) of CRC presenting with stricturing at colonoscopy do not require treatment for obstruction (ie, stenting or operation) and seem to die from disease progression prior to occurrence of clinical obstruction. “Prophylactic” stent placement to prevent obstruction, when CRC presents with a stricturing lesion is not suggested by this study.

Upregulation of Hypoxia-Inducible Factor (HIF)-1α and HIF-2α in Leptomeningeal Vascular Malformations of Sturge-Weber Syndrome

Cutaneous and leptomeningeal vascular malformations are hallmarks of the Sturge-Weber Syndrome (SWS), resulting in chronic ischemic tissue damage. The mechanisms underlying the pathobiology of these progressive lesions are unknown. Aberrant expression of angiogenic factors has been implicated in the genesis and maintenance of vascular malformations. To assess the role of angiogenesis in SWS vascular lesions we determined the expression of key angiogenic factors by immunohistochemistry and in situ hybridization in 8 SWS patients (age: 8 months to 18 years). We observed increased expression of vascular endothelial growth factor (VEGF), its cognate receptors VEGFR-1, VEGFR-2, and neuropilin (NP)-1 as well as Tie2 in leptomeningeal SWS blood vessels. Intriguingly, these factors are known to be transcriptionally induced by hypoxia-inducible factor (HIF). The HIF system has emerged as the key regulatory system of responses to hypoxia. Immunohistochemical analysis demonstrated markedly elevated nuclear HIF-1alpha and HIF-2alpha protein levels in SWS vessels. Concomitantly, SWS vessels revealed signs of enhanced endothelial cell (EC) turnover as evidenced by increased EC proliferation and apoptosis. Thus, in terms of angiogenesis, vascular malformations in SWS are not static lesions but constitute dynamic structures. Our observation of a dysregulated HIF-alpha expression in SWS vessels are in agreement with recent findings that EC-specific HIF activation provides a setting which supports and sustains angiogenesis and could be of potential use for developing therapeutic strategies to treat these currently incurable lesions.

Research on the Possibility of Overcoming Traumatic Paraplegia and Its First Clinical Results

The interruption of the continuity of the spinal cord is still an incurable lesion. In contrast with the peripheral nerves, the axons regenerating from the mother cells of the brain do not progress inside the cord. The reasons of this "non-permissiveness" are still unclear. This article describes the attempts of the author to overcome this non-permissiveness by means of a research that began in 1980 on rats, and continued since 1993 on monkeys. Results of the research on experimental animals were good and convincing so that this operation has been performed on fully informed human being volunteers affected by total severance of the cord between T8 and T11. Results of the first clinical cases are presented regarding operations performed either by rerouting the ulnar nerve to the lower limbs, or connecting the rostral stump of the severed cord with peripheral nerves of the hip to obtain rudimentary, but efficient, walking. Recovery occurred well in advance of the expected time, and continued to improve up to allow the first patient operated on by connecting CNS with PNS to walk with sticks after having walked for some months with a walker. This connection functioned even if the axons activating the single muscles were from mother cells dispersed in different regions of the brain cortex. These cells fire together giving selective contraction of diverse muscles. Furthermore, function occurred although the upper motor neuron uses the neurotransmitter glutamate, whereas motor end plates use receptors for acetylcholine. These data are under further investigation to determine whether the upper motor neuron changes the transmitter, or if the motor end changes its receptors (as seems to be by the first results).

Amputation of tail in a Palm Civet Viverricula indica under xylazine and ketamine anaesthesia

Manuscript 1156; Received 28 February 2004; Revised received 7 May 2004; Finally accepted 20 September 2004; © Zoo Outreach Organisation; www.zoosprint.org 1721 December 2004 Amputation of tail is indicated for some incurable lesions as ulcers, a necrotic vertebra or malignant tumour of the tail in domestic animals (O’Conner, 1980), which may also be applied to wild animals. A case of necrotic wound in the tail of a Palm Civet (Viverricula indica) and its management by caudectomy under Xylazine and Ketamine anaesthesia is reported in this paper.

Preoperative assessment of pancreatic malignancy using endoscopic ultrasound.

Endoscopic ultrasound (EUS) has been regarded as the most accurate modality for locoregional staging of pancreatic malignancy. However, several recent studies have questioned this. The current study assessed the accuracy of EUS in determining preoperative resectability of pancreatic neoplasia. A retrospective review was performed of patients with pancreatic malignancy who had preoperative EUS and underwent surgery. EUS-predicted resectability was compared with surgical resectability. Where available, accuracies of vascular and nodal staging were also assessed. Forty-five patients were identified (mean age 60 years, age range = 36-79 years). All patients underwent surgical exploration; vascular staging was available in 32 cases and 17 cases underwent surgical resection. The sensitivity, specificity, and accuracy of EUS in determining unresectability were 66%, 100%, and 78% respectively. Overall EUS stage concurred with surgical stage in 56%, greater than surgical stage in 4%, and less than surgical stage in 40%. Vascular staging on EUS had a sensitivity of 69% and a specificity of 100%. Accuracy of nodal staging was 71%. EUS had a high specificity for assessing unresectable pancreatic malignancy. This technique should be used to avoid unnecessary surgical exploration of incurable lesions. However, EUS had only a moderate sensitivity, and a proportion of patients staged preoperatively as having resectable disease will not be surgically resectable.

Hypothermic Cardiac Standstill for Cerebral Aneurysm Surgery

Surgical management of giant cerebral aneurysms remains a major technical challenge for modern neurosurgeons. Endovascular approaches for giant aneurysms does not provide an acceptable alternative to direct surgical approaches. The use of deep hypothermic circulatory arrest as an adjunct during clipping of complex giant aneurysms shows promise as a treatment for otherwise incurable lesions. Patient selection and techniques of circulatory arrest surgery are discussed.

Preoperative "basal" chemotherapy in the management of cancer of the stomach.

Twenty-seven patients with infiltrating gastric carcinoma received chemotherapy as the first stage in management to reduce tumour extent and viability in preparation for subsequent surgery. All patients who had received no previous treatment for their cancers were included in the study, regardless of the type or extent of the primary gastric lesion; there was no patient selection. In 25 patients chemotherapy was administered by intra-arterial infusion, while in two patients it was given intravenously. Of 21 patients who underwent repeat gastroscopy before surgery, 11 (52%) showed endoscopic improvement. Gastric resection was carried out in 24 of the 27 patients. The perioperative mortality was 11% (three of 27 patients). Of the 27 patients, 14 were initially assessed as having advanced incurable lesions. Only two of these remain well and apparently free of tumour. The other 13 patients were considered to have resectable and potentially curable lesions at the time of referral. Of these, 11 remain well and apparently free of tumour between one and five years after diagnosis; the other two patients in this group died from postoperative complications.

Irradiation of meningioma: A prototype circumscribed tumor for planning high-dose irradiation of the brain

The purpose of this report is to provide specific data concerning the radiation dose required to destroy meningioma, and to demonstrate that radiation doses much greater than the alleged tolerance dose, can be administered to the brain in some patients. Most meningiomas are not responsive to irradiation, but, some surgically incurable lesions benefit from irradiation with radically high doses to small volumes of tissue. The arrest of 7 of 12 consecutive meningiomas in adults for periods of 2–17 years following maximum tumor doses up to 8800 R in 40 days is reported in this paper. All patients, when irradiated, had active tumor in the form of inoperable primary tumor, recurrence or known postoperative residual tumor. Three of the successful results were achieved with orthovoltage radiation. The incidence of brain damage may be acceptable to the patient when it is related to arrest of tumor growth but he must be forewarned of possible brain damage. The factors influencing the radioresponsiveness of meningioma are: the required tumor lethal dose, histology and vascularity of the tumor, anatomical site in the brain, treatment technique for each tumor site, small size of the treated volume, growth rate of the tumor, displacement of normal brain tissue by tumor, inherent individual variations of tumor and normal tissues, quality of the radiation, and tolerance of normal brain tissues. The role of these factors is discussed in the light of modern radiobiological concepts.

PREMATURE OBITUARY

Not long ago, it appeared as if the electrocardiograph, the fluoroscope, the phonocardiograph, and the cardiac catheter had joined in conspiracy to render the stethoscope obsolete. Mournful communications prophesied a future in which Laennec's great invention would be entirely forgotten. Wistful editorials made comment on the decline of auscultation. A renowned radiologist was rumored to have displayed a stethoscope as a museum piece in a glass case. The noble instrument which had served the physician so well was on its way out, it seemed. Subsequent developments did not bear out the sad expectation. If anything, the advent of surgery for congenital and rheumatic heart disease enhanced the value of cardiac auscultation. Listening for abnormal sounds is no longer a mere academic exercise in the diagnosis of incurable lesions, but an effort often well rewarded by therapeutic success. Usefulness of the stethoscope has also extended beyond the boundaries of the thoracic

The relative biological efficiency of 4 MeV and 300 kV radiations. VII. Human skin reaction.

A Wide variety of animal experiments has given closely similar results for the R.B.E. The clinician is concerned with the biological efficiency in man and particularly for localised high dose effects in radiotherapy. An estimate of the R.B.E. in such circumstances cannot be made with anything like the same precision as in an animal experiment. The main factors which prevent such an estimate are: (i) The variation from one individual to another of the degree of reaction and of the time when the maximum is reached. (ii) The necessarily different sites and volumes which must be irradiated. (iii) Differences in the extent and in the behaviour of tumours. (iv) The difficulty of measuring the degree of reaction. It must be emphasised, therefore, that this study of human skin reactions is in no sense a report of a controlled experiment. In August, 1954, when the initial calibration and depth dose measurements had been made for the linear accelerator, clinical application was commenced. It was decided to treat some patients who had advanced and incurable lesions with the object of bringing about palliation. These patients were treated at a time before any biological experiments had been completed and at a time when there was even some uncertainty about the measurement in absolute terms of the unit of dose. The unit employed was the “dosemeter unit” as defined in Part II.

Antibiotics in Non-Tuberculous Pulmonary Diseases

Penicillin, streptomycin, aureomycin and chloromycetin are all invaluable in the treatment of pulmonary infections. Penicillin is the drug of choice in all coccal pneumonias, suppurative diseases of the lungs, bronchiectasis, spirochaetal infections and actinomycosis of the lung. It is best given by the intramuscular route, using 50,000 units of crystalline penicillin G every three hours. When repeated injections are not feasable, 12 hourly injections of 400,000 units of penicillin containing 300,000 units of procaine penicillin G and 100,000 units of sodium or potassium penicillin G should be used. In suppurative lung lesions and bronchial infections, aerosol penicillin should be added, using 50,000 units of penicillin dissolved in 1 cc. of saline solution, three times daily, preferably with an oxygen tank. In empyemas, direct daily instillation of 50,000 units of penicillin dissolved in 50 cc. saline into the pleural cavity may be curative. Streptomycin is the drug of choice in gram-negative infections of the lung. It is highly specific for pneumonias and pulmonary infections due to Friedlander's bacillus, B. tularensis, B. pestis, hemophilus influenzae and E. coli. It is best given by intramuscular injection of ½ gram every six hours until the infection is under control. In suppurative diseases of the lungs and bronchiectasis, aerosol streptomycin in conjunction with penicillin should be used. Aureomycin is the drug of choice in atypical pneumonia, ornithotic pneumonia, tularemic pneumonia, Rocky Mountain spotted fever, Q fever infections and brucellosis. The drug is given orally, using 1 gram every six hours for several days, and then ½ gram every six hours. Bacterial pneumonias not responding to penicillin and streptomycin may respond to aureomycin. Chloromycetin is the drug of choice in pulmonary infections due to typhus, salmonella group, E. coli and brucella organisms. The drug is given by mouth, using 1 gram every four to six hours until improvement takes place, then ½ gram every six hours. Combined Therapy : In pulmonary infections of unknown etiology, it is often invaluable to use both penicillin and streptomycin at once, and if in a short time improvement does not occur, aureomycin and/or streptomycin should be added. Other Antibiotics : Several of the newer antibiotics show great promise in the treatment of hitherto incurable lesions, such as fungus and viral infections. Most of these are still toxic to animals, but it is very likely that with further refinements in preparation, they will soon prove to be effective in a still wider range of pulmonary infections.

THE ABUSE OF DRUGS.

All drugs which are potent for good contain the possibilities of evil. This statement applies with equal truth to most, if not all, of those natural agencies which we employ—not as generally as we should, perhaps—in our struggle with disease. A superabundance of food, indigestible or illy prepared viands, create digestive disorders which are liable to eventuate in chronic and incurable lesions. Excessive exercise in the form of athletics may lay the foundation of organic heart disease. We must study minutely the proper methods of applying electricity if we would derive the benefits inherent in that powerful agent. In the same manner might be pointed out the reverse side of the influence of every drug or agency employed in medicine. Nothing is more distinctive of modern methods of teaching therapeutics than the preliminary attention given to the physiologic action of drugs. We seek to understand the action of medicaments on