Assessment of Target Volume Definition for Contemporary Radiotherapeutic Management of Retroperitoneal Sarcoma: An Original Article

Introduction

Soft tissue sarcomas are relatively rare and comprise a heterogeneous group of malignancies. While the most common localization for soft tissue sarcomas includes the limbs, a considerable proportion occur in the retroperitoneum. Soft tissue sarcomas include a variety of histologic subtypes such as liposarcomas, undifferentiated-unclassified tumors, and leiomyosarcomas. Among the group of soft tissue sarcomas, retroperitoneal sarcomas deserve utmost attention since they represent a heterogeneous and relatively rare group of tumors originating from mesenchymal cells with considerably high rates of local recurrence and mortality. Surgery has been the principal mode of management for retroperitoneal sarcomas, however, complete surgical removal may not be achievable particularly in the setting of large tumor sizes and involvement of nearby critical structures. In an attempt to improve therapeutic outcomes, the use of radiation therapy (RT) has been addressed [1-7]. Surgical resection with negative margins may be challenging to achieve in some circumstances and neoadjuvant or adjuvant therapeutic strategies may be considered. RT may be utilized as a local treatment option, however, adverse radiation effects should be considered [1-7]. Critical advances in the millennium era for improved RT outcomes include sophisticated technologies along with state of the art irradiation techniques [8-46]. Accuracy and precision in target volume definition may be considered as a more important aspect of state of the art radiotherapeutic strategies to comply with these contemporary improvements. An overwhelming majority of RT centers currently make use of Computed Tomography (CT) simulation for radiotherapeutic management of retroperitoneal sarcomas. Clearly, CT remains to be a viable imaging modality for this purpose, however, incorporation of other imaging modalities such as Magnetic Resonance Imaging (MRI) may lead to improved target definition. Herein, we evaluate multimodality imaging based RT target definition for radiotherapeutic management of retroperitoneal sarcomas.

Materials and Methods

Herein, we had the purpose of investigating whether any improvement may be achieved through the incorporation of multimodality imaging in the target volume definition process for radiotherapeutic management of retroperitoneal sarcoma. To achieve this goal, a thorough appraisal has been utilized to shed light on this important aspect. We have carried out thorough comparative investigation of RT target volume definition. To be utilized for actual treatment and comparison purposes, a ground truth target volume was outlined individually by board certified radiation oncologists. Patients who have been allocated to RT for retroperitoneal sarcoma were included, and decision making for RT has been performed on a multidisciplinary basis. At the outset, alternative treatment strategies and protocols have been thoroughly discussed. Synergy (Elekta, UK) linear accelerator (LINAC) has been utilized for treatment delivery. Selected patients underwent CT-simulation at the CT-simulator. After the CT-simulation process has been completed, acquired images have been transferred to the contouring workstation. Outlining of structure sets including treatment volumes and critical structures comprised an important aspect of RT planning. Treatment volume determination has been performed by either the CT-simulation images only or by fused CT and MR images. A comparative analysis has been performed for evaluation of treatment volume determination by CT only and with incorporation of CT-MR fusion based imaging.

Results

Patients with retroperitoneal sarcoma referred to Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences were assessed for treatment volume definition by either CT-only imaging or by CT-MR fusion based imaging in this original research article. Lesion size, localization and association with critical structures, and disease extent were among the considered tumor associated characteristics. Also, we individually took into account the patient ages, symptoms, and performance status before radiotherapeutic management of retroperitoneal sarcoma. The reports by American Association of Physicists in Medicine (AAPM) and International Commission on Radiation Units and Measurements (ICRU) have also been considered for improved treatment planning. Radiation physicists played a significant role in generation of optimal RT plans by taking into account the recent informatory guidelines and clinical experience. Considered parameters in RT planning included the critical organ dose limitations, tissue heterogeneity, electron density, CT number and HU values in CT images. Primary aim of treatment planning was to achieve optimal treatment volume coverage while respecting the preset critical organ dose limitations. Modern treatment equipment has been used for irradiation, and we made use of contemporary image guidance strategies such as kilovoltage cone beam CT and electronic digital portal imaging for optimal setup verification. As the primary outcome of this study, the ground truth target volume was observed to be identical with CT-MR fusion based imaging for precise RT of retroperitoneal sarcoma.

Discussion

Although relatively rare, retroperitoneal sarcomas comprise a heterogeneous group of tumors originating from the mesenchymal cells. They may be typically associated with high rates of local recurrence and resultant mortality. While the main therapeutic option includes surgical resection to achieve optimal treatment results, complete removal of the tumor may not be achieved in some patients particularly when the tumor is large and in intimate association with surrounding critical structures. Within this context, RT may be considered in selected patients as another local therapeutic approach [1-7]. The primary objective of irradiation is eradication of as many tumor cells as possible without damage to normal tissues. However, achieving an optimal therapeutic ratio by RT may be hampered by critical organ dose constraints and the desired ablative doses of irradiation may sometimes not be administered due to the risk of excessive radiation induced toxicity. Several contemporary RT techniques and strategies have been developed recently to improve the toxicity profile of radiation delivery. Nevertheless, target definition has gained more importance and relevance with the availability of contemporary RT strategies. In this context, target definition for optimal RT planning is an indispensable component of sophisticated RT approaches. Meanwhile, CT-simulation is the most frequently used procedure for RT planning in a plethora of cancer centers. Cross sectional imaging with thin CT slices has clearly improved target and critical organ definition for radiotherapeutic management, however, incorporation of additional imaging with MRI may further refine this critical procedure. Fusion of CT-simulation and MR images may allow for exploiting the advantage of multimodality imaging. Indeed, the addition of MRI to CT images has been demonstrated to improve RT planning for a variety of cancers [47-80]. At this standpoint, we cordially believe that this study may add to the accumulating data on this subject and may have pertinent clinical implications for utilization of multimodality imaging for optimal RT of retroperitoneal sarcoma. We conclude that our study indicates improvement in treatment volume determination for precise RT of retroperitoneal sarcoma by integration of MRI in RT target definition process albeit with the requirement for further supporting evidence.

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Mental Depression©

Pharmaceutical Drugs Can Cause Permanent Harm

A person depressed is immersed in gloom. For them, everything is bad, they see no hope. They are constantly exhausted. Their glass is always half empty and all the traffic lights are at red. They may well blame someone. They drag down all those close to them and can cause mental depression in others. This is a common plight that is not cured by modern pharmaceutical medicine or drug wielding psychiatrists. A doctor will prescribe an anti-depressant drug to help the patient cope. All that does is switch off part of the brain and prolonged consumption causes permanent brain damage. If they stop taking the drug, stress increases and in fear they become more drug dependant. Good business for the pharmaceuticals. There is no known drug that repairs thoughts. The brain is the hardware, in computer terms, and thoughts are the software. Depression is a software problem. Emotions can be chemically stimulated but there is no control. For example, alcohol shifts the mood towards extraversion and caffeine can shift the other way with an inability to relax and that causes harm. Thoughts out of control are dangerous. At one extreme a person can think they are invincible and at the other commit suicide. No doctor should ever consider mood shifting for medical healing.

The only way to manage thoughts is conversation. We used to follow the explanations of Sigmund Freud and snigger at the technique of a patient on the psychiatrist’s couch until the drug makers took over and repaired the brain chemically. If a patient was not helped by one drug, they were given an alternative with the explanation that they were not responding properly, the patient’s fault. This suited the doctors who are called general practitioners with ten minutes to process each patient. A conversation about a person’s troubles could take an hour. The patient, who was helpless, hence their depression, never complained other than to often demand a stronger dose. Long term follow-ups confirmed that the person was now coping. To cope with life was regarded as a cure. Drug dependency had been caused (Figure 1).

Figure 1.

The Spectrum of Emotions

Below is a diagram of the spectrum of emotions. I used this first in an article about The Life Switch. When the mood is below normal, there is no healing. A depressed person is not just unhappy, they are ill. Aches and pains get worse. The immune system does not work. Add drugs to the helpless body and the immune system completely packs in (Figure 2). I observe, watch and listen to patients treated by Calsonic. A few weeks ago, a hunch that Cell Sonic is anti-depressant was confirmed. I visited St James Clinic in Birmingham to meet two lady professors from Poland when were interested in our technology. https://stjamesxh-clinic.com/. Here we are outside. I am the old man in a bow tie (standard garb for a professor) (Figure 3). The directors of St James are Hieu Tran standing between the ladies and Syed Ahmed on my left. The visiting professors are from Rzeszów University. Agnieszka Banas-Ząbczyk is on the left in the picture and Marta Kopańska is in the middle of the group. Both ladies were treated twice by the machine which at St James is called CS1. I explained what the machine does and how we understand it works on the body. The discussion then centred on the CS1 (Cell Sonic) making the patient feel happy. Hieu told of a miserable man who never smiled being seen after a treatment to be smiling. He told his friends it was the machine that did it.

Agnieszka said the same. She felt lifted, relaxed and welcomed more treatments. Marta agreed. Agnieszka said that neurons were being sent into the brain. Here is the machine (Figure 4). St James [1] have developed a standard procedure to treat the spine regardless of what the patient came to the clinic for. In the photo below, Hieu is showing the lady what to do. She is in the process of buying a machine for her own clinic (Figure 5). The protocol is 1,000 pulses at energy level 4.The treatment takes about five minutes with the machine banging at four a second. It can be felt but is not painful. Indeed, the patient enjoys the treatment. Three forces are emitted by the shock head (called a wand in America): pressure, electrical field and light. The spine is connected to the brain and all the organs (Figure 6). By treating the spine with Cell Sonic all the organs receive an electrical boost from the electrical field. There is no direct contact with an electrical charge from the machine (Figure 7). Credit and thanks are given to Dr Jerry Tennant for these illustrations [2]. His book and lectures on “Healing is Voltage” are first class (Figure 8-12). The frequencies needed to stimulate the cells and the related emotions are fully served by Cell Sonic because every pulse is a bang covering a full range of frequencies from high to low.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

Figure 11.

Figure 12.

The very high frequencies are attained by the short rise time of a Cell Sonic pulse lasting a billionth of a second, the time taken for electricity to travel 1 mm as it shorts across the gap in the electrode of the shock head. The resulting sound and flash of lightning is the same as a thunderstorm but smaller. Here below is an explanation of shockwaves taken from HMT, a Swiss company I represented in Britain before they went out of business twenty years ago. Their problem was that doctors demanded endless clinical trials costing the company more than they could afford until they ran out of money. I then formed Cell Sonic and have avoided the pitfalls that beset HMT. The electrohydraulic system is far superior to other methods. Also important is the means of switching the high voltage passing through the electrode. Cell Sonic uses the fastest possible. Slower methods such as a cascade of thyristors cannot achieve the high frequencies needed to restore body cells. Breaking kidney stones is one thing. Generating cell restoration is another and only Cell Sonic has the frequency range needed [3,4].

Conclusion

The discovery that Cell Sonic reduces and helps remove mental depression is a valuable addition to the medical tool kit. Drugs are not used so there are no side effects. The effects have been observed for ten years and reported to me from different continents. In some cases, patients with brain disease are being treated with pulses aimed directly into the brain. Whether this is better than sending the neurons to the brain through the spinal cord remains to be seen. The brain is surrounded by bone as is the spinal cord, so the pressure and light parts of the pulse have little effect. That leaves the electrical field and in bursts of a billionth of a second at low energy levels, no side effects are detected. The mental improvements are accumulative. When the person grows new brain tissue or other parts of the brain take over from the parts damaged by drugs, the person is lifted into the upper half of the emotional spectrum where the immune system becomes active and thus starts the upward spiral of feeling better because the body is healing. When pain is stopped, proper sleep allows the immune system to work and the person is lifted out of gloom into a bright, smiling day.

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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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