The Trailing Fecundation Epithelioid Trophoblastic Tumour

Preface

The World Health Organization (WHO) classifies Epithelioid Trophoblastic Tumour (ETT) as a category of Gestational Trophoblastic Neoplasia (GTN). Initially scripted by Shih and Kurman in 1998, the exceptional epithelioid trophoblastic tumour emerges as a derivative of neoplastic, chorionic- type, intermediate trophoblastic tissue and is associated with a variable clinical representation [1]. Epithelioid trophoblastic tumour may frequently coexist with placental-site trophoblastic tumour and the entities necessitate appropriate segregation. Nevertheless, a comprehensive, universally accepted protocol of tumour discernment, appropriate therapeutic regimen and duration of therapy for epithelioid trophoblastic tumour remains obscure.

Disease Characteristics

Epithelioid trophoblastic tumour commonly occurs within the reproductive age group and is usually discerned following a gestational event such as a full-term delivery, molar pregnancy or spontaneous abortion. Tumefaction is exceptionally delineated within postmenopausal women [2,3]. Epithelioid trophoblastic tumour appears to be associated with a preceding gestational trophoblastic neoplasm, preceding normal pregnancy or preceding spontaneous abortion [2,3]. Epithelioid trophoblastic tumour follows antecedent pregnancy by several months or years Generally, the neoplasm may follow a previous gestational event beyond > 6 years [2,3]. Serum beta Human Chorionic Gonadotropin (β-HCG) levels appear elevated [2,3]. Epithelioid trophoblastic tumour configures up to 2% of gestational trophoblastic neoplasia (GTN) and is associated with proportionate mortality of nearly 24%. Incidence of epithelioid trophoblastic tumour following a term pregnancy is nearly 1 in 150,000 pregnancies. The neoplasm exhibits pertinent ethnic variation [2,3]. Commonly, tumefaction may be situated within the uterine fundus, lower uterine segment or endo-cervix. Infrequently, pulmonary parenchyma or abdominal wall exhibit the lesion in the absence of a uterine neoplasm. Non metastatic neoplasms confined to the uterus are associated with comprehensive (~100%) disease- associated survival although metastatic tumours demonstrate around 60% proportionate survival [2,3].

Clinical Elucidation

The neoplasm is commonly discerned upon locations such as uterus or lower uterine segment, cervix or pulmonary parenchyma. Sites such as vagina, broad ligament, fallopian tubes or associated pelvic organs are infrequently implicated [4,5]. The gradually progressive neoplasm remains confined within the uterus for an extended duration. Thus, vaginal bleeding or amenorrhea is a commonly discerned clinical symptom [4,5]. Incriminated subjects depict irregular, variable vaginal bleeding, Abnormal Uterine Bleeding (AUB) or mild vaginal discharge. Preceding gestational event followed by abnormal uterine bleeding may indicate the occurrence of gestational trophoblastic neoplasia as epithelioid trophoblastic tumour [4,5]. The neoplasm may manifest as a nodule confined to a Caesarean scar or follow a spontaneous abortion with retained Products of Conception (POCs) [4,5]. Generally, the lower uterine segment exhibits a painful tumefaction of variable magnitude and vaginal bleeding along with mildly elevated serum beta Human Chorionic Gonadotropin (β-HCG) levels [4,5]. Majority of neoplasms are devoid of a Y chromosome complement [4,5].

Histological Elucidation

Macroscopically, discrete tumour nodules or a cystic or haemorrhagic tumour mass exhibits deep-seated infiltration within circumscribing soft tissue. Cut surface is whitish, tan or brown and depicts focal haemorrhage and tumour- induced necrosis. Focal ulceration and configuration of a fistula is frequently observed [6,7]. Grossly, a well-defined, pearly white, friable tumefaction with a fascicular external surface and magnitude of up to 5 centimeters appears to invade the uterine serosa and incriminates in excess of > 50% of myometrium. Usually, the neoplasm emerges as a solid, well circumscribed lesion confined to the cervix or as an extrauterine, localized tumefaction. Besides, the neoplasm may manifest as a discrete, solitary, nodule with a well circumscribed perimeter [6,7]. Cut surface is solid, tan or brown with focal haemorrhage and necrosis. Frequently, the neoplasm configures nodules or tumour masses and depicts an expansive growth pattern [6,7]. Upon microscopy, tumefaction is composed of solid cellular zones, elongated articulations and tumour cell nests. The well-defined, nested growth pattern is configured of miniature tumour cells with minimal nuclear pleomorphism and lack of intercellular bridges. A “ pushing” tumour perimeter is exemplified by the neoplasm [6,7]. The nodular, well circumscribed neoplasm exhibits focal, peripheral tumour infiltration. Mononuclear, uniform tumour cells are configured in nests and cords. Tumour cell nests are admixed with an eosinophilic, fibrillary, hyaline-like substance composed of type IV collagen along with onco-foetal and adult subtypes of fibronectin [6,7]. Cells of chorionic- type, intermediate trophoblastic tissue exhibit moderate, eosinophilic to clear cytoplasm imbued with glycogen, spherical nuclei, miniature, distinctive nucleoli and distinct cellular membranes. Tumour calcification is frequent [6,7]. Circumscribing stromal cells appear decidua-like. Exceptionally, focal regions resembling placental- site nodule, placental-site trophoblastic tumour or choriocarcinoma can be discerned [6,7]. The neoplasm can simulate mature stratified squamous epithelium and appears to re-epithelialize endometrial surface or endocervix. Fragments of endocervical tissue may be admixed with clusters of intermediate trophoblastic cells [6,7]. Mean tumour mitotic count appears at an estimated 2 per 10 high power fields although up to 20 mitosis per 10 high power fields may be discerned. Atypical mitotic figures can be delineated. Tumefaction enunciates extensive or “geographic” necrosis [6,7]. Tumour is composed of intermediate trophoblastic cells imbued with abundant eosinophilic cytoplasm and vesicular nuclei. Tumour cell aggregates are surrounded by a fibrous tissue stroma whereas tumour cells may circumscribe and replace walls of medium-sized vascular articulations and spaces [6,7]. Uterine serosa abutting the neoplasm may depict zonal rupture with tumour cell infiltration and focal necrosis. Soft tissue perimeter may be devoid of discernible tumour cell infiltration. Adjacent pelvic lymph nodes are preserved and lack tumour metastases [6,7].

Immunohistochemistry

Tumour cells are intensely, diffusely immune reactive to Cytokeratin Cocktail (CK) AE1/AE3, cytokeratin 18, Cyclin E, Cyclin D1, CD10, Epithelial Membrane Antigen (EMA), inhibin-α, E-cadherin, prolyl 4-hydroxylase, Human Leucocyte Antigen G(HLA-G), hydroxy-delta-5-steroid dehydrogenase 3 beta and steroid delta- isomerase 1 (HSD3B1), GATA3 and p63. Focal immune reactivity to Human Placental Lactogen (HPL), Human Chorionic Gonadotrophin (HCG) and CD146 (Mel-CAM) is observed [8,9]. Ki-67 nuclear labelling index exceeds > 10%. The neoplasm may display immune staining with PD-L1, thus corroborating beneficial therapeutic outcomes with employment of immune checkpoint inhibitors [8,9]. Tumour cells are immune non-reactive to smooth muscle actin (SMA), desmin and CD117 [8,9] (Figures 1-8) [10-16].

Figure 1: Epithelioid trophoblastic tumour exemplifying nests and cords of intermediate trophoblastic cells with abundant, eosinophilic cytoplasm and vesicular nuclei [10].

Figure 2: Epithelioid trophoblastic tumour exhibiting nests and cords of intermediate trophoblastic cells with eosinophilic cytoplasm and vesicular nuclei and a circumscribing stroma with tumour cells replacing vascular articulations [10].

Figure 3: Epithelioid trophoblastic tumour enunciating cords and aggregates of intermediate trophoblastic cells admixed with foci of necrosis [11].

Figure 4: Epithelioid trophoblastic tumour depicting aggregates of intermediate trophoblastic cells surrounding zones of geographic necrosis [12].

Figure 5: Epithelioid trophoblastic tumour delineating a layering of intermediate trophoblastic cells with eosinophilic cytoplasm and focal necrosis [13].

Figure 6: Epithelioid trophoblastic tumour demonstrating intermediate trophoblastic cells invading vascular elastic tissue and circumscribing vascular lumen [14].

Figure 7: Epithelioid trophoblastic tumour displaying strands of intermediate trophoblastic cells admixed with enlarged foci of geographic necrosis [15].

Figure 8: Epithelioid trophoblastic tumour with intermediate trophoblastic cells immune reactive to p63 [16].

Differential Diagnosis

Epithelioid trophoblastic tumour requires a segregation from conditions such as

a) A typical placental site nodule which is discovered incidentally and characteristically displays moderate to severe cytological atypia of the trophoblastic tissue. A borderline Ki-67 nuclear labelling index of up to 10% is observed [17,18].

b) Keratinizing squamous cell carcinoma of the cervix is composed of tumour cells which configure and infiltrate surrounding stroma as irregular, anastomosing tumour cell nests or singular cells. Enveloping stroma can be desmoplastic or invaded by inflammatory cells. Foci of stromal dehiscence or desmoplastic reaction can be observed [17,18]. Superficial stromal invasion or lymphoid and vascular invasion may be delineated. Tumour grading is contingent to features such as nuclear pleomorphism, nucleolar magnitude, mitotic activity and tumour cell necrosis. Keratin pearls, abundant keratohyaline granules and intercellular bridges may be exemplified. Tumour cells depict enlarged, hyperchromatic nuclei, coarse chromatin and inconspicuous nucleoli. The neoplasm is immune reactive to cytokeratin 5, cytokeratin 6 and p16. Tumefaction is immune non reactive to cytokeratin 18 [17,18].

c) Placental site nodule is a lesion discovered incidentally upon microscopy. The minimally cellular lesion exhibits trophoblastic cells imbued with bland nuclei. Extensive hyalinization and an absence of calcification or necrosis is observed. Mitotic activity is minimal and a decimated K-i67 nuclear labelling index of below < 8% is delineated [17,18].

d) Placental- site trophoblastic tumour exhibits an infiltrative pattern of tumour expansion. Disseminated, multinucleated, intermediate trophoblastic cells accumulated upon the implantation site are common. Frequently, tumour cells appear aggregated into confluent sheets [17,18]. Peripheral neoplastic fragments exhibit singularly disseminated cells, cords or nests of trophoblastic cells. Characteristically, tumour cells segregate individual fibres or group of muscle fibres and infiltrate the myometrium. Vascular invasion is common wherein tumour cells infiltrate and replace walls of myometrial vascular articulations. Tumour cells are incorporated with an abundant amphophilic, eosinophilic or clear cytoplasm, pleomorphic, enlarged, convoluted or hyperchromatic nuclei associated with significant nuclear atypia. Majority of neoplasms depict a minimal mitotic count. Focal calcification or necrosis is absent. The neoplasm is diffusely immune reactive to Mel-CAM and Human Placental Lactogen (HPL). Ki-67 nuclear labelling index is elevated to up to 30% [17,18].

Investigative Assay

Upon ultrasonography, a tumefaction of variable magnitude may be discerned within the lower uterine segment or region of Caesarean scar. Sonography depicts a sharply defined tumefaction along with a hypoechoic halo situated upon the site of a preceding surgical procedure [19,20]. Upon ultrasonography, epithelioid trophoblastic tumour may manifest as a neoplasm with a well circumscribed perimeter and a hypo-echogenic halo [19,20]. Intraoperative inspection may depict a scar associated dehiscence situated upon the site of preceding surgery. Adjoining viscera may be uninvolved [19,20]. Computerized tomography of the thoracic, abdominal and pelvic cavity may exhibit tumour metastasis [19,20]. Colour Doppler may exemplify a specific “peripheral” pattern of vascular outflow. Colour Doppler of tumefaction associated with dehiscence of surgical scar appears devoid of central or peripheral vascular perfusion. Serum beta Human Chorionic Gonadotropin (Β-HCG) levels are elevated whereas Human Placental Lactogen (HPL) values appear normal and are non indicative of disease activity or prognostic outcomes [19,20].

Therapeutic Options

Comprehensive surgical excision of the neoplasm is recommended and an optimal therapeutic strategy. Total abdominal hysterectomy along with or the absence of bilateral salpingo-oophorectomy or adnexal eradication is contemplated as a cogent treatment modality for epithelioid trophoblastic tumour. Alternatively, an exploratory laparotomy may be performed [19,20]. A haematoma may accompany the neoplasm confined to isthmus or diverse uterine segments. Morphologically, circumscribing pelvic viscera appear intact and uninvolved. Reconstruction of the uterus may be required [19,20]. Adjuvant chemotherapy is usually unnecessary and the neoplasm appears resistant to chemotherapy. Stage I disease can be appropriately managed with total abdominal hysterectomy [19,20]. Prognostic factors indicating unfavourable outcomes are designated as

a) Duration from antecedent pregnancy exceeding > 48 months

b) Elevated mitotic count exceeding > 6 mitosis per 10 high power fields

c) Cellular and nuclear atypia

d) Vascular invasion

e) Myometrial invasion beyond inner one third of uterine myometrium

f) Diffuse, multifocal uterine disease

g) Stage III or stage IV disease as per International Federation of Obstetrics and Gynaecology (FIGO) anatomical staging. Pertinent staging is a significant prognostic factor [19,20]. Tumefaction following antecedent pregnancy beyond > 48 months in the absence of adverse factors can be subjected to surgical procedures as total abdominal hysterectomy with bilateral salpingectomy wherein adjuvant chemotherapy remains unnecessary, especially in individuals wishing to preserve fertility. Oophorectomy may be circumvented in macroscopically unremarkable ovaries [19,20]. Neoplasms associated with metastasis are suitably managed with surgical resection and adjuvant chemotherapy [19,20]. A combination of complex surgical manoeuvers along with adjuvant chemotherapy is recommended in females with elevated serum beta human chorionic gonadotropin (β-HCG) levels and metastatic disease. Commonly, an antecedent gestational event exceeding > 48 months and advanced disease stage are cogent indicators of an inferior prognostic outcome [19,20].

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Diabetic Ketoacidosis: Precipitating Factors, Pathophysiology, and Management

Introduction

Diabetes mellitus can be described as a chronic disease occurred due to elevated blood sugar level because of the body cannot produce insulin at all or secrets insufficient insulin hormone or not use it effectively. The nonexistence of insulin or the cell is not sensitive to use insulin leads to enhanced blood glucose level which is the hallmark of diabetes mellitus. Diabetes mellitus affects more than 422 million people around the world. By the year 2040, the number of people with diabetes is expected to rise to 642 million, most of who are going to reside in low- or middle-income countries. Diabetes mellitus is a growing public health problem affecting people worldwide, with a rapidly elevating prevalence in both advancing and advanced countries [1]. The World Health Organization observed that high blood sugar level due to diabetes is the third highest risk factor for premature mortality after high blood pressure and tobacco use [2]. T1DM can be a common autoimmune condition that often presents in childhood and perhaps complicated by episodes of diabetic ketoacidosis [3]. One of the alarming life-threatening complications of type 1 diabetes mellitus is diabetic ketoacidosis [4]. The definition of diabetic ketoacidosis is biochemically expressed as venous potential hydrogen 200mg/ dL (11mmol/L) together with ketonemia, glucosuria, and ketonuria. DKA may be rarely occurring with normal circulating glucose concentrations; if there has been partial management or with pregnancy. The severity of DKA is determined by the degree of acidosis such as mild; when venous pH >7.2 and <7.3, bicarbonate <15 mmol/L; moderate; when venous pH >7.1 and <7.2, bicarbonate <10 mmol/L; severe when venous pH <7.1, bicarbonate <5 mmol/L [5]. Diabetic ketoacidosis is a life threatening emergency manifesting with hyperglycemia when random blood sugar >200 mg/dL, high anion gap metabolic acidosis (pH-3) [6].

Precipitating Factors of DKA

Patients with diabetes mellitus who are admitted with diabetic ketoacidosis should be counselled about the precipitating cause and early warning symptoms. Failure to do so is a missed educational opportunity. Things to consider include the following

i. Identification of precipitating factors such as infection or omission of insulin injections;

ii. Education to prevent recurrence; for example, provision of written sick day rules;

iii. Warning about potential insulin ineffectiveness; for example, the patient’s insulin may be expired or denatured;

iv. Provision of hand-held ketone meters with education on management of ketonaemia [7-11]. Several conditions can lead to the advancement of DKA such as infections; new diagnosis of diabetes; poor adherence to, or inadequate doses of, insulin; myocardial infarction; stroke; acute pancreatitis; trauma; burns; surgery; medications such as glucocorticoids, beta blockers, thiazides and atypical antipsychotics; psychological factors including depression and eating disorders and illicit substance use [7,12].

Pathophysiology of DKA

Figure 1: Pathophysiology of diabetic ketoacidosis.

DKA is the result of a critical relative or absolute deficiency of insulin, resulting in intracellular starvation of insulin-dependent tissues (muscle, liver, adipose), stimulating the release of the counter-regulatory hormones glucagon, catecholamines, cortisol, and growth hormone. The counter-regulatory hormonal responses may also be the result of stress-induced proinflammatory cytokines [5]. Hyperglycemia and ketosis in diabetic ketoacidosis are the result of insulin deficiency and elevate in the counterregulatory hormones glucagon, catecholamines, cortisol, and growth hormone. Three processes are mainly responsible for hyperglycemia such as elevated gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues [13]. Insulin deficiency, elevated insulin counter-regulatory hormones (cortisol, glucagon, growth hormone, and catecholamines), and peripheral insulin resistance lead to hyperglycemia, dehydration, ketosis, and electrolyte imbalance, is the underlie pathophysiology of DKA. Due to elevated lipolysis and decreased lipogenesis, abundant free fatty acids are converted to ketone bodies including β-hydroxybutyrate (β-OHB) and acetoacetate. Hyperglycemia-induced osmotic diuresis, if not accompanied by sufficient oral fluid uptake, leads to dehydration, hyperosmolarity, electrolyte loss, and subsequent lower in glomerular filtration rate. With decline in a renal function, glycosuria diminishes and hyperglycemia worsens. With impaired insulin action and hyperosmolar hyperglycemia, potassium uptake by skeletal muscle is markedly diminished; also hyperosmolarity can cause efflux of potassium from cells. This results in intracellular potassium depletion and subsequent loss of potassium via osmotic diuresis, causing reduction of total body potassium averaging 3-5mmol/kg of body weight. A “normal” plasma potassium concentration still indicates that total body potassium stores are severely diminished, and the institution of insulin therapy and correction of hyperglycemia will result in hypokalemia [14,15] (Figure 1).

Treatment of DKA

The intentions of management of DKA with fluid and insulin is to restore perfusion, which will elevate glucose uptake in the periphery, elevate glomerular filtration, and reverse the progressive acidosis; arrest ketogenesis with insulin administration, which reverses proteolysis and lipolysis while stimulating glucose intake and processing, thereby normalizing blood glucose concentration; replace electrolyte losses [5]. Several significant steps should be followed in the early stages of DKA management are

1) Collect blood for metabolic profile before initiation of intravenous fluids;

2) Infuse 1L of 0.9% sodium chloride over hr after drawing initial blood samples;

3) Ensure potassium level of 3.3 mEq/L before initiation of insulin therapy;

4) Initiate insulin therapy only when steps 1-3 are executed [14]. Management of DKA consists of fluid and electrolyte replacement, insulin administration, and careful ongoing monitoring of clinical and laboratory factors.

Fluid and Electrolyte Replacement: The osmotic diuresis generated by glucosuria results in large water and electrolyte losses, exacerbated by compromised uptake due to nausea and vomiting. Initial fluid resuscitation begins with 10mL/kg of isotonic fluid, either 0.9% saline or lactated ringer solution, administered over 1hr. For more critically ill pediatric, for whom there is concern over impending cardiovascular collapse, additional resuscitation fluid should be administered more quickly. After the initial fluid resuscitation, the remainder of the fluid deficiency is replaced evenly over 48hrs. Most patients who have DKA are approximately 6% dehydrated and 10% for 2 yrs pediatric. For patients presenting with more severe DKA (serum glucose 600 to 800 mg/dL (33.3 to 44.4mmol/L) and pH 7.1)), fluid losses are approximately 9% of body weight and 15% for 2yrs pediatric. The 0.9% saline (with added potassium) is continued as the hydration fluid until the blood sugar value declines to less than 300mg/dL (16.7mmol/L) and at that time, our practice is to change the fluid to D5 0.45% saline (with added potassium). The American Diabetes Association recommendation is that deficit replacement fluids contain at least 0.45% saline with added potassium. If the blood glucose concentration declines below 150mg/dL (8.3mmol/L) the dextrose content may need to be elevated to 10% or even 12.5%. Both insulin managements of DKA and correction of the acidosis cause potassium to move intracellularly. Unless the patient exhibits hyperkalemia or anuria, potassium should be added to the intravenous fluids at the beginning of the second hr of treatment. If the patient presents with hypokalemia, potassium replacement is initiated immediately. Most patients require 30 to 40mEq/L of potassium in the replacement fluids, with adjustment based on serum potassium concentrations that are measured every 1 to 2hrs. DKA results in significant phosphate depletion, and serum phosphate values decrease during treatment.

Hypophosphatemia may cause metabolic disturbances. Phosphate replacement should be given if the values of phosphate decrease below 1mg/dL. In the absence of severe hypophosphatemia, provide phosphate in intravenous fluids, typically by giving half of the potassium replacement as potassium phosphate. Administration of potassium acetate to provide the other half of the potassium replacement further decreases the chloride load. The serum calcium concentration must be monitored if phosphorus is given, due to the risk of hypocalcemia. If hypocalcemia develops, phosphate administration should be stopped. During the treatment of DKA, the patient can produce substantial bicarbonate as insulin stimulates the generation of bicarbonate from the metabolism of ketones. Potential risks of bicarbonate treatment involve paradoxic central nervous system acidosis and exacerbation of hypokalemia. Bicarbonate management also has been correlated with cerebral edema, the most frequent cause of mortality for children who have DKA. Therefore, bicarbonate treatment should be considered only in cases of extreme acidosis, such as for the patient whose pH is 6.9, when the acidosis may impair cardiovascular stability, or as management of life-threatening hyperkalemia. If bicarbonate administration is believed to be necessary, 1 to 2mmol/kg (added to 0.45% saline) should be provided over 1 to 2hrs [15].

Insulin Therapy: Insulin should be started after initial fluid expansion and provides a more realistic starting glucose level 0.1U/kg/hr is given as a continuous infusion, using a pump. 50Us of regular insulin are diluted in 50mL normal saline to provide 1unit/ mL. The administration of 0.1unit/kg subcutaneously every hr perhaps preferable and can be adjusted to maintain blood glucose concentrations at approximately 180-200mg/dL (10-11mmol/L). Fluid expansion alone will have a dilutional effect, lowering high blood glucose levels by as much as 180-270mg/dL (10-15mmol/L). With insulin infusion the rate of glucose decline should be 50- 150mg/dL (2.8-8.3mmol/L/hr), but not >200mg/dL (11mmol/L/ hr). If the blood sugar concentration falls below 150mg/dL (8.3mmol/L) 10% dextrose solution should be given and the insulin dose reduced to 0.05 U/kg/hour if a glucose concentration is not sustained by the 10% dextrose solution. Insulin should not be stopped; a continuous supply of insulin is needed to inhibit ketosis and permit continued anabolism. If the individuals demonstrate marked sensitivity to insulin, the dose may be lowered to 0.05units/ kg/hour, or less, provided that metabolic acidosis continues to resolve [5,16-18].

The Two-Bag System: Once the patient is receiving fluids and then insulin, the blood glucose will fall, usually quite rapidly. The objective of two bag system is to maintain the blood glucose in the 10 to 15mmol/L range over the first day or so, to provide a buffer against the advancement of hypoglycemia. Two bags of intravenous fluids, similar in their electrolyte composition and differing only in their dextrose concentration, are run in parallel through the same cannula. The total fluid rate from these two bags determined by the protocol will be constant, and the final concentration of dextrose can be altered simply by juggling the rates of the two bags. The two-bag system is easy to institute, uses commercially available solutions, and has been revealed to reduce the time needed to make an alter in IV rates, to lower the number of IV bags used during an admission, and to reduce the cost of IV solutions used [19,20] (Figure 2).

Figure 2: Schematic illustration of the two bag system.

Intravenous Glucose Infusion: Management of DKA should be aimed on clearing ketones as well as normalizing blood sugar. Introduction of 10% glucose is recommended when the blood glucose falls below 14mmol ⁄ l in order to avoid hypoglycemia, while continuing the fixed-rate intravenous insulin infusion to prevent ketogenesis. It is significant to continue 0.9% sodium chloride solution coincidently to correct circulatory volume if the fluid deficit has not been corrected. Glucose should not be discontinued until the patient is eating and drinking normally [21].

Potassium Therapy: Adults with DKA have total body potassium deficits of the order of 3-6mmol/kg. The major loss of potassium is from the intracellular pool as a result of hypertonicity, insulin deficiency, and buffering of hydrogen ions within the cell. Serum potassium levels at the time of presentation may be normal, elevated or lowered hypokalemia at presentation perhaps related to prolonged duration of disease, whereas hyperkaliemia primarily results from lowered renal function. Administration of insulin and the correction of acidosis will drive potassium back into the cells, lowering serum levels [22].

Bicarbonate Therapy: Alkali therapy in DKA has not been routinely recommended, as metabolic derangements tend to correct with insulin therapy and fluids as hypovolemia, tissue perfusion and renal function improve. As a consequence of the elevated severity of metabolic acidosis with pH less than 7.0, bicarbonate may empirically be given as an isotonic solution with an initial dose of 50mmol intravenous bicarbonate (one ampoule of 7.5 % NaHCO3 solution in 250ml sterile water) with 15mEq of KCL for each ampoule of bicarbonate administered if serum potassium 5.5mEq/L. Alternatively, if the pH is 6.9, 100mmol (100mEq) administered in 400mL sterile water may be infused at 200mL/h with frequent re-dosing every 2hrs until pH exceeds 7 [23-26].

Phosphate Therapy: Whole-body phosphate depletion is a hallmark of poorly controlled diabetes mellitus. Hyperglycemia and hyperosmolarity cause an intracellular to extracellular shift of serum phosphate; due to this reason, serum phosphate levels may be normal or increased at the onset of DKA. Insulin therapy in the setting of DKA perhaps show hypophosphatemia as insulin drives phosphate back into cells. Potassium or sodium phosphate supplementation (20-30mEq/L) may be added to replacement fluids over several hrs with close monitoring of serum calcium and phosphate levels. Alternatively, in patient tolerating oral intake with mild deficits, oral phosphate (2.5-3.5 g/day in 2-3 divided doses may be administered [23,27,28].

Conclusion

Diabetic ketoacidosis is a life threatening emergency manifesting with hyperglycemia when random blood sugar >200mg/dL, high anion gap metabolic acidosis (pH-3). Several conditions can lead to the advancement of DKA such as infections; new diagnosis of diabetes; poor adherence to, or inadequate doses of, insulin; myocardial infarction; stroke; acute pancreatitis; trauma; burns; surgery; medications such as glucocorticoids, beta blockers, thiazides and atypical antipsychotics; psychological factors including depression and eating disorders and illicit substance use. The counter-regulatory hormonal responses may also be the result of stress-induced proinflammatory cytokines. Therapy of diabetic ketoacidosis consists of fluid and electrolyte replacement, insulin administration, and careful ongoing monitoring of clinical and laboratory factors.

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Trends in Organ Printing Technologies-A Patent Study

Introduction

Biological sciences development embarks very promising technologies such as restriction endonuclease, monoclonal antibodies, nude mice, dolly sheep, and so on. Artificial pacemakers, the use of bolts and plates in ortho surgery, prosthetic limbs, and so on helped human society to battle with unfortunate body damages. Further development where body organ transplant from donor to a receiver, in this domain is the practice of today with various challenges including graft rejection and so on. All these techniques and developments involved scientists, doctors, and associated service providers. However, considering the current population and demand for organs, tissue probably some new solutions are required to handle current challenges. Hence now scientists started thinking about the use of 3D printing for developing artificial organs. In this paper, we tried to understand this trend at a global level. We mainly focused on patent data related to this technology. The objective of the study is to understand the overall current development in this domain. The second objective is to know who are the leaders in this technology development. We hope that this data analysis may help researchers, practitioners, and policy makers working in this domain.

Literature Review

The field of tissue engineering is rapidly growing these days [1]. Traditional tissue engineering technologies had limited success in fabricating complicated 3D structures and in-vivo organ regeneration [2,3]. As a result, it is logistically and economically unsuitable for clinical use. In this regard, 3D bioprinting has been quite successful [4]. This is an extended application of additive manufacturing and involves a top-down approach of layer-by-layer building of complex tissue by deposition of matter in a controlled manner-resulting in anatomically accurate 3D models of the tissue mimicking the model generated by computer graphics [5,6]. There have been numerous number of patent applications filed in the field of bioprinting and organ printing. Studying a patent landscape of a technology gives an overall approach of country’s invention policies [7,8]. A patent analytics is always crucial for ensuring that the business or research is on the right track and offers future funding directions.

Research Methodology

Generally, an analysis of patent data over the last five years gives an overall idea about the technology trend. Therefore, the search has been restricted from January 1st, 2017 to the present date. The patent data has been downloaded from the LENS database on May 27th, 2020. The database has been last updated on May 19, 2022. LENS is an online patent search and analysis platform provided by an independent, international non-profit organization Cambia dedicated to democratizing innovation [9]. It has a collection of over 123.5 M patent records over 105 jurisdictions and 67.5 M patent families. The query string used is Patents (300) = Title: (3d AND (print* AND organ)) OR (Abstract: (3d AND (print* AND organ)) OR Claims: (3d AND (print* AND organ))). A total of 400 patents/ patent applications has been retrieved. After grouping down the patent families, the size collapsed to 301 documents.

Results and Discussion

Figure 1 shows the number of patent applications filed, published and granted since 2015. As can be seen, published and granted patent follow similar trend. This is logical, as the published patent applications are further going through examination and getting grants. The difference between the number of patent applications published and granted are around 40. Figure 2 shows that most of the documents used in the analysis are patent applications. However, there are around 50 granted patent also. (Figures 3-5) show the top applicant, owner, and inventors in this field. There are two main types of patent classifications—International patent classification by WIPO and Cooperative Patent Classification jointly developed by European Patent Office and US Patent and Trademark Office. Patent classifications help patent examiners and researchers to apply filter and select certain relevant patent applications/ patent in a particular technical field. Figure 6 shows the top IPC codes used to file patent applications for 3d organ printing technologies. As can be seen, B33Y is the major class. A search has been carried out in WIPO’s IPC database to understand what the code B33Y represents [10]. It is to be noted that B33 is for additive manufacturing technologies, and the subgroup B33Y includes “additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3d printing, stereolithography or selective laser sintering”. Next, we delve into the cited scholarly works from the patent documents studied in this section. Figure 7 shows how scholarly works are published over the years. Interestingly, the cited documents date way back in 1980s. As expected, most of the cited documents are journal articles. The first cited book is from 2009. Most of the works are going on in the USA, next in line is China. Then, we can see what are the top publishers where articles for 3D organ printing technologies are published and are cited in the patent/patent applications (Figure 8). As can be seen, Elsevier turned out to be the most popular publisher among the researchers in this area. The journal Biomaterials have published most of the articles submitted under the Elsevier umbrella.

Figure 1: Patent filed, published, and granted over the past few years.

Figure 2: Document types in the study.

Figure 3: Top applicant in organ printing.

Figure 4: Top owner currently owning organ printing patents.

Figure 5: Top inventors.

Figure 6: Top International Patent Classification.

Figure 7: Scholarly works published over years.

Figure 8: Top publishers of scholarly works.

Conclusion

The present study provided an analysis of patent and nonpatent data on 3D organ printing technologies for the last 5 years. Our analysis shows that most of the promising works are going on in the USA, while next in line is China. Cellink Ab, Prellis biologicals INC, Lego AS, 3D system inc, and Jerez Roberto Velozzi are top applicants. Cellink Ab, Prellis biologicals INC, and Axial medical printing ltd are leading in ownership of organ printing patents. Gatenholm Erik, Gatenholm Paul, Jerez Roberto Velozzi and Matheu Melanie P are the top inventors and interestingly Jerez Roberto Velozzi is applicant and inventor. According to IPC, B33Y is the major class with reference to this technology. It shows that the concept of 3D printing was proposed long back in literature. Since 1980, publications related to this domain are available. There are books, journal articles, conference publications focused on this domain. In 2010, we can see that lot of work is published. Considering this development probably in the near future organ transplantation domain will see a new shift.

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