All stages and classification of bladder cancer according to the TNM system

A malignant tumor in the bladder is a fairly serious and life-threatening disease. In medicine, there are 4 stages of bladder cancer, each of which is characterized by special manifestations. There is also a classification of bladder cancer according to the TNM system, with which doctors determine what stage the cancer is at and the characteristic signs of deviation. Treatment measures are prescribed after determining the stage of the disease.

General information

Bladder cancer accounts for 3% of all cancer sites. People whose bodies are exposed to aromatic amines, as well as those suffering from chronic cystitis, are at risk.

More than half of bladder cancer cases among men are associated with smoking (about a third in women)[1]. Researchers argue that there is a direct link between smoking and risk, while stopping smoking reduces risk[2].

The most common form of bladder cancer is transitional cell carcinoma.

(developing from the transitional epithelium of the urinary tract), squamous cell carcinoma and adenocarcinoma (a tumor originating and built from the glandular epithelium) are more rare.
The disease can manifest itself as papillary growths (non-linear mural inclusions) with malignancy or a solid, ulcerated, invasive tumor. There are bladder cancer in situ
, superficial cancer (T1-2) and cancer invading the muscle layer and surrounding tissues (T3-4).

The main focus of papillary bladder cancer often produces multiple metastases. Superficial bladder cancer forms metastases much less frequently. As the disease progresses, the pelvic (N1-2), retroperitoneal lymph nodes (N3-4) are affected, and metastasis occurs to the lungs, liver, and bones.

Malignant tumors

Bladder cancer (abbreviated as bladder cancer) is the most common oncology of the urinary system. In men, bladder cancer (BC) is in seventh place, in women - in 17th place.

The average age of detection of this pathology in men is 65.7 years, in women – 69.2 years. The incidence ratio in men and women is 4-5:1.

The incidence of bladder cancer depends on race and geography: among African Americans and Indians, the incidence is 2 and 8 times lower, respectively, compared to white Americans. The incidence in the CIS countries is approximately 20.8: 10,000 men and 5.0: 10,000 women.

Predisposing factors are:

1. 1The cause of bladder cancer is often the influence of carcinogens excreted from the body in the urine.
2. 2 Occupational hazards (the risk of pathology is higher among workers in rubber, oil, aluminum, textile enterprises, as well as enterprises that use resins, plastics, and paints and varnishes). In most cases, the main carcinogens are derivatives of aromatic amines.
3. 3Consumption of water with a high concentration of arsenic (South America, Taiwan), or chlorinated water can cause cancer (with systematic consumption of chlorinated water, the risk increases by 1.8 times in men, 1.6 times in women).
4. 4Taking certain medications (cyclophosphamide, an alkaloid used in chemotherapy, increases the likelihood of developing bladder cancer by 4.5 times).
5. 5 Smoking (in smokers, the likelihood of bladder carcinoma increases by 2-3 times). A long history of smoking, smoking cigarettes without a filter, and consuming black tobacco lead to an increased risk of this oncology. The duration of smoking cessation leads to a proportional reduction in the likelihood of disease.
6. 6Radiation (radiation therapy to the pelvic area is accompanied by an increase in the likelihood of bladder cancer by 1.5-4 times). The greatest risk is observed in patients who underwent radiation five to ten years ago. In patients with thyroid cancer who have undergone radioactive iodine therapy, the risk of cancer increases by 3 times.
7. 7 Urogenital schistosomiasis. The disease is characterized by endemicity (Southeast Asia, North Africa). In men, the likelihood of cancer increases by 3.9 times, in women – by 5.7 times. Schistosomiasis often causes squamous cell carcinoma.
8. 8Chronic inflammation of the bladder mucosa, urolithiasis, and urostasis phenomena can also cause bladder cancer.

Symptoms

One of the first signs of bladder cancer is hematuria (blood in the urine), although it can be caused by other causes. Blood clotting in the bladder cavity can lead to the development of acute urinary retention.

Another common symptom of the disease is frequent, painful urination. Pain above the womb is also possible. Compression of the ureteric orifices by the tumor leads to disruption of the outflow of urine from the kidneys, as a result of which pyelonephritis or chronic renal failure can develop.

There is a known case of weekly priapism, which, as it later turned out, was a symptom of the disease [3].

Types of bladder cancer - medical classification of malignant tumors

Today in medical science there is the following classification of bladder cancer:

Depending on the morphological component

• Transitional cell carcinoma

Today it is the most common type of cancer of the organ in question. It is formed by the cells of the inner wall of the bladder. Due to certain factors, they begin to change and grow.

The neoplasm is covered with short thick villi. The destructive process may involve the mucous membrane, submucosal membrane, and in rare cases, the muscular membrane of the bladder. The mucous membrane changes its shape: it becomes swollen and hyperemic.

At the zero and first stages, this type of tumor does not manifest itself in any way.

As the disease progresses and depending on its location, the following symptoms may be observed:

1. The presence of blood in the urine, which provokes iron deficiency anemia. In some cases, urination is accompanied by the release of blood clots, but more often patients complain of pink urine.
2. Expanding pain in the lower abdomen when urinating, which radiates to the anus. A similar phenomenon occurs when the tumor is located in the area of ​​the bladder neck. Patients may also complain of frequent urge to go to the toilet.
3. Pain in the lumbar area , chills, difficulty urinating indicate the appearance of a tumor directly in the ureter. Damage to the two ureters is accompanied by disruptions in the functioning of the gastrointestinal tract, weakness, and itching.
4. Pain after the outflow of urine and a false urge to urinate are signs that the tumor is located inside the bladder.

• Squamous cell carcinoma

It is based on epithelial cells, which during reproduction can affect all the membranes of the bladder, including nearby lymph nodes.

This type of cancer is diagnosed mainly in men after they reach 60 years of age. This disease is provoked by long-term inflammatory processes in the genitourinary system.

Symptoms of squamous cell carcinoma of the bladder become varied as the tumor grows and intensifies when the bladder is full:

1. Pain when urinating.
2. Frequent urge to go to the toilet.
3. Pain in the pubic area, sacrum, groin.

If this type of malignant neoplasm is located near the ureter, serious disruptions in the functioning of the kidneys will occur in the future (up to uremia ).

In the initial stages, squamous cell carcinoma will manifest itself as idiopathic hematuria (the presence of blood in the urine).

• Adenocarcinoma

This type of cancer develops due to a mutation in the cells that make up the bladder glands. A similar situation may arise due to the fact that the secretions of the glands constantly stagnate in the mucous membrane of the bladder.

Symptoms of adenocarcinoma are similar to those of transitional cell and squamous cell carcinoma.

In addition, against the background of disorders associated with lymph outflow, patients may complain of severe swelling of the lower extremities.

Depending on the form of manifestation of the disease

• Papillary cancer

It is represented by papillary growths, which over time transform into malignant formations.

Most often, the tumor is localized in the bottom of the bladder and in the area of ​​its neck.

Outwardly, such a tumor resembles cauliflower, and during histological testing, signs of necrosis and cell mutation can be observed.

• Solid cancer

It can appear in two forms:

1. Exophytic tumor. It is characterized by the presence of hilly neoplasms that protrude into the cavity of the bladder. Against the background of progressive ulcers, the tumor undergoes purulent melting. This negatively affects the mucous membrane: it changes its color to bluish, swells, and is often covered with tiny tumor-like neoplasms. This tumor is capable of growing through the entire thickness of the bladder wall and spreading to neighboring organs.
2. Endophytic tumor. It grows very quickly due to which it often has a flat structure. The free space inside the bladder quickly fills, which is externally manifested by a frequent urge to urinate and pain in the lower abdomen. An endophytic tumor does not grow inside the ureters or urinary canal, but as it grows, it can put pressure on them, thereby causing urinary difficulties.

Based on the depth of damage to the lining of the bladder by cancer cells

• Superficial (non-invasive) cancer

The zone of influence of malignant cells is limited to the mucous and submucosal layers of the bladder.

This type of cancer does not provoke metastases. Transitional cell carcinoma is often superficial, which has a positive effect on the quality of treatment of the disease.

• Invasive cancer

It affects the inner layers of the bladder, often metastasizes to neighboring organs (lungs, liver), and often spreads to the pelvic/retroperitoneal lymph nodes.

Adenocarcinoma and squamous cell carcinoma are most often invasive cancers.

Depending on the degree of deformation of the malignant neoplasm

• Well differentiated cancer

The mutation of the cellular structures of this type of cancer is clearly pronounced.

With such tumors, the disease occurs in an aggressive form and is very dangerous.

• Poorly differentiated cancer

The malignant formation of the type of cancer in question is endowed with less aggressiveness.

Diagnostics

The main methods for diagnosing bladder cancer are cystoscopy with biopsy.

Additional diagnostic methods - excretory urography, computed tomography, ultrasound, etc.

Bimanual palpation is always necessary, but small tumors growing inside the bladder are usually not palpable. A palpable formation indicates a widespread penetrating lesion of the bladder.

To clarify the degree of infiltration of the bladder wall and its transition to surrounding tissues, sometimes they resort to x-ray examination under double contrast conditions, in which oxygen is injected into the bladder and into the surrounding tissue. Against the background of gas, you can see a thickening of the bladder wall and areas where the tumor extends beyond its boundaries.

To determine or exclude metastases to the lungs, a chest x-ray is performed. If bone metastases are suspected, bone x-rays are performed.

Specifics of the 1973 and 2004 WHO histopathological gradings.

Most clinical studies on bladder tumors in modern oncology are carried out using the 1973 WHO classification criteria. The degree of differentiation of the primary tumor, which is directly related to histopathology, according to this classification is divided as follows: GX - differentiation of abnormal structures cannot be established, G 1 - high , G 2 – moderate, G 3 – low, G 4 – undifferentiated oncological tumor.

Urothelial cancer of grades G3 and G4 is combined by practicing urological oncologists in some clinical cases and noted in medical documents as “G3-4 (poorly differentiated or undifferentiated bladder cancer.”

In 2004, WHO proposed and adopted a new histopathological gradation, the main achievement of which was a detailed morphological description of all structural differences in cancer tumors. To more accurately determine the criteria included in it, the results of histological studies are used.

In accordance with this classification, the following types of cancer of the urinary storage organ are distinguished:

• Papilloma. Pathological epithelial formation growing into the cavity of the bladder and covered with normal epithelium.
• A papillary urothelial structure that has a reduced potential for malignancy. This type of neoplasm is characterized by the presence of a superficial layer of overgrown transitional cell epithelium, a fairly low risk of progression and a pronounced tendency to frequent relapses.
• An epithelial cancerous neoplasm with an average degree of malignancy, classified according to the classification adopted in 1973 as G1, and in some cases, when cytological (intracellular) changes become noticeable under high microscope magnification, and G2 degrees.

This gradation of malignant neoplasms of the urinary storage organ allows for oncological tumors to standardize the diagnosis and distinguish between tumor structures localized in the urinary bladder in accordance with their risk potential.

Genetic markers

The genetic apparatus of the cells of the human body has a complex system for controlling cell division, growth and differentiation. Currently, a number of signaling pathways have been identified that are involved in the regulation of the cell cycle and, if disrupted, lead to oncogenesis or progression of bladder cancer, as well as molecular genetic markers of such disorders. The changes in the cell cycle that occur during bladder cancer have been the most studied. Here among the genetic markers it is necessary to highlight[4]:

• tumor suppressor gene TP53
  , located in the p13.1 locus of the 17th chromosome and encoding the p53 transcription factor (the loss of this locus leads to the loss of the suppressive function of the p53 protein and to the progression of bladder cancer);
• CDKN1A
  gene , localized in the p21.1 locus on chromosome 6 and encoding an inhibitor of the cyclin-dependent kinase
  p21
  (the latter is regulated by the p53 protein);
• MDM2
  gene , located in the q14.3-q15 locus of the 12th chromosome and encoding the MDM2 protein - a natural inhibitor of p53 (an increase in the number of copies of this gene was found in breast cancer);
• INK4a
  gene , located in the p21 locus of the 9th chromosome and encoding simultaneously two non-homologous nuclear proteins - P16INK4a and P14ARF (products of alternative reading frames; the second of them is capable of stabilizing and activating the p53 protein, so that the normal operation of this gene ensures the suppression of oncogenesis).

Causes and factors for the development of pathology

The formation of a tumor is based on the breakdown of genes. As a result, cells with altered characteristics are formed. A malignant neoplasm, regardless of location, has a number of universal features:

• rapid reproduction - the rate of growth and reproduction of tumor cells is several times higher than normal;
• invasive type of growth - a malignant tumor is capable of germinating virtually all surrounding tissues and organs;
• autonomy - tumor cells do not obey any regulatory signals from the body and exist according to their own laws; they take from the bloodstream most of the nutrients from which new cells are built;
• excellent blood supply - tumor cells force the body to form new vessels in this area to supply nutrients;
• formation of secondary foci (metastases) - tumor cells penetrate through the blood and lymphatic vessels into the lymph nodes and distant organs, and each malignant cell becomes the founder of a new pathological formation.

  
  Malignant cells are formed as a result of damage to genetic material

The immune system plays an important role in the oncological process. It is she who is entrusted with the main task in the body - recognizing friends and foes. The latter also include one’s own cells with genetic damage. Normally, all of them should be eliminated by the immune system. However, in cancer, tumor cells escape such influence.

A number of factors play an important role in the development of bladder cancer:

• work in hazardous working conditions - printing, foundry, metallurgical, paint and varnish production;
• contact with special chemicals that cause gene mutations (carcinogens) - phenols, indole, skatole;
• urinary retention for various urological reasons (narrowing of the urethra, prostate adenoma);
• smoking, which triples the risk of developing a malignant tumor;
• ionizing radiation - work with sources of radioactivity, radiation therapy;
• taking certain medications - painkillers, antitumor agents;
• parasitic disease of the bladder - schistosomiasis (pathology is common in hot countries of Africa and Asia);

  
  Schistosomiasis is a parasitic disease common in tropical regions.

• unfavorable environmental conditions.

Video: Bladder cancer you can catch

Classification according to the TNM system

This classification (European Association of Urology, 2009) uses numerical designations of different categories to indicate the extent of the tumor and the presence or absence of local and distant metastases.

T - from lat. tumor 'tumor'. Describes and classifies the main tumor site.

Ta - non-invasive papillary carcinoma

Tis - carcinoma in situ

(flat tumor)

T1 - tumor extends to subepithelial connective tissue

T2 - tumor invasion of the muscle layer

T2a - tumor invasion of the superficial muscle layer (inner half)

T2b - tumor invasion of the deep muscle layer (outer half)

T3 - tumor extends to paravesical tissue

T3a - microscopically

T3b - macroscopically (extravesical conglomerate)

T4 - tumor invasion of any of the following organs: prostate, uterus, vagina, pelvic wall, abdominal wall

T4a – tumor has spread to the prostate or uterus or vagina

T4b - tumor invasion of the pelvic wall or abdominal wall

N - from lat. nodulus 'knot'. Describes and characterizes the presence of regional metastases, that is, metastases to regional lymph nodes.

Nx—regional lymph nodes cannot be assessed

N0 - no metastases in regional lymph nodes

N1 - metastasis in one regional lymph node (internal iliac, obturator, external iliac, presacral)

N2 - multiple metastases in regional lymph nodes (internal iliac, obturator, external iliac, presacral)

N3 - metastases in the common iliac lymph nodes

M - from lat. metastasis 'metastasis'. Characteristics of the presence of distant metastases, that is, metastases to distant lymph nodes, other organs, tissues (excluding tumor germination).

Mx - distant metastases cannot be assessed

M0 - no distant metastases

M1 - distant metastases

P, G

For some organs or systems, additional parameters are used (P or G, depending on the organ system), characterizing the degree of differentiation of its cells.

Histopathological differentiation

Together with staging, clinical and morphological classifications, which are mandatory before starting a therapeutic course against cancer, the MPRS proposed the use of pathohistological grading of oncological tumors. It is based on the results obtained after examination under a microscope of the biopsy material obtained during TUR, that is, the basis for this systematization of malignant tumors of the bladder is the degree of maturity of abnormal cells.

This histological classification for bladder cancer allows practicing urological oncologists to correctly assess the aggressiveness of the tumor structure removed from the urinary storage organ, and, if necessary, make adjustments to the treatment protocol.

Depending on how the cellular structures look under a microscope, malignant neoplasms are conventionally divided by specialists into the following types:

• Highly differentiated bladder cancer. There are no significant cellular and tissue atypical changes observed in the biomaterial under study. Most of these structures retained normal features and were practically indistinguishable from healthy ones. Germination into the submucosal and muscular layers, as well as damage to regional lymph nodes, is not observed.
• Moderately differentiated bladder cancer. When performing histology, the oncologist notes the presence of a large number of cells with an altered structure - multiple nuclei of different sizes and scant cytoplasm. Their shape and size also become significantly different. Such a mutation is found not only in the superficial layer, but also in the muscle layer, as well as in one or more regional lymph nodes, which indicates a significant increase in the aggression of the oncological tumor.
• Poorly differentiated bladder cancer. In the biomaterial under study, there were practically no cells left that retained their normal structure. Atypical changes are found in the organs surrounding the bladder, and clinical signs of damage to secondary malignant foci, grown from cells with low differentiation, in distant areas of the body are also noted.
• Undifferentiated bladder cancer. The histological picture of the biopsy material taken during TUR shows such strong differences in the cellular structure that the specialist does not see in it any connection with normal cells of the urinary storage organ. This indicates a very high degree of aggression of the oncological tumor and transfers it to the category of incurable.

In the case when the primary focus of malignancy contains cells with varying degrees of differentiation, it is classified according to the least favorable and, accordingly, the most aggressive course of therapy is prescribed. The histopathological classification of cancerous tumors, proposed by WHO in 1973 and edited with major amendments in 2004, is based on data from histological examination.

Worth knowing! Practicing oncologists and pathologists use both gradations in their work, since both have confirmed their prognostic value in practice. But due to the fact that their criteria have significant differences, and each classification has its own advantages and disadvantages, in order to make a more correct diagnosis and prescribe a course of treatment, specialists must know all the nuances of these gradations.

Treatment

Treatment includes various options for surgery, radiation and drug therapy. For bladder cancer in situ

and superficial cancer of stage T1, transurethral resection of the bladder is used, and in stage T2 - partial resection of the bladder. For an invasive tumor of significant size (TZ), cystectomy[en] (removal of the bladder) with or without pelvic lymphadenectomy (unavailable link) is recommended. Sometimes chemotherapy and radiation therapy are preferred to such an operation, and then, if necessary, surgery is performed. For stage T4 bladder cancer, involvement of the retroperitoneal lymph nodes (LN), and distant metastases, chemotherapy is of primary importance.

Often, intravesical chemotherapy is also advisable in the early stages of the disease in cases of multicentrically growing cancer, and it is advisable to carry out chemotherapy after surgery.

Chemotherapy includes intravesical or systemic administration of cytotoxic drugs. One of the following drugs is administered intravesically (in 100 ml of isotonic sodium chloride solution for 1 hour) (cisplatin 60 mg or adriamycin 80 mg once a month; thiophosphamide 60 mg once a week, 3 doses; mitomycin C 40 mg once a month 2 months).

The daVinci robot allows for surgery to remove the bladder and then reconstruct it using patient tissue. This device was used, in particular, in the clinic named after. Meshalkin in Novosibirsk[5].

Polybia paulista , has a potential anti-cancer effect against bladder tumors.

. As preclinical studies show, the peptide is capable of forming large pores (holes) in the wall of cancer cells, thereby damaging them and leading to cell death[6][7].

All types of benign bladder tumors in women and men - symptoms of pathology

According to its morphological characteristics, the disease in question is divided into two types:

1. Malignant neoplasms
2. Benign neoplasms. This type of bladder tumor tends to grow and, if not treated promptly, can transform into cancer.

Benign epithelial neoplasms of the bladder include:

• Polyps

They are a defective proliferation of connective tissue cells that are attached to the mucous membrane of the bladder with the help of a thin stalk.

Externally, in their shape, they resemble a mushroom, the stem of which is directed into the cavity of the bladder. They have a smooth surface, soft in structure and quite fragile.

This pathology is often discovered accidentally during a routine ultrasound: polyps in the early stages of development usually do not manifest themselves in any way. The exception is those cases when the neoplasm is localized in the area of ​​the ureter or urethra: over time, urinary retention may occur, and during the process of emptying the stream splashes and changes its direction. Indications for installation of a cystostomy

If the polyps are located directly in the bladder area without accompanying exacerbations, the disease will be asymptomatic.

However, if the integrity of the tissues of the pathological formation is violated; When complications arise, as well as when education parameters increase, the following complaints from the patient will occur:

1. Urine color is pink/red. Indicates the destruction of the walls of the polyp and the opening of bleeding.
2. Painful sensations when urinating. It is a sign of tissue death of the specified neoplasm. Similar symptoms are present with inflammatory phenomena.

• Papillomas

They are mature formations that have a rough surface, soft structure and a pinkish tint. They can be single or multiple, and their main feature is their tendency to relapse. At the same time, re-growing into the mucous membrane of the bladder, they often change.

Atypical papillomas are considered the initial stage of cancer .

Like polyps, this type of epithelial benign formation practically does not manifest itself in any way at the initial stage.

Over time, cystitis and urinary retention may develop. A urine test will determine the presence of blood in it.

Nonepithelial tumors of the bladder are rare in practice.

They come in several types:

1. Fibroma . Characterized by small sizes. Outwardly it resembles a ball or ellipse of light pink color. With significant magnification, it can change color. Formed due to uncontrolled cell proliferation. This neoplasm does not manifest itself, and its removal from the walls of the bladder is a fairly simple surgical procedure.
2. Myoma . It has a smooth surface and can grow to large sizes. Its structure is mixed and consists of connective and fibrous tissue cells.
3. Fibromyxoma . It is a spherical, non-solid formation on a stalk.
4. Hemangioma . A type of vascular tumor of a red-blue color. Often this pathology is a congenital anomaly that is prone to rapid progression. A distinctive feature of hemangioma is bleeding from the urethra.
5. Neuroma. It is a spherical, oval or irregularly shaped formation with a bumpy surface, which is formed from auxiliary cells of the nervous tissue.

Nonepithelial tumors of the bladder practically do not manifest themselves. In cases where the tumor begins to actively increase in size, similar symptoms appear as with polyps and papillomas.

Prevention

In a ten-year study of nearly 49,000 people, it was found that those who drank at least one and a half liters of water (6-8 glasses) per day had a significantly lower incidence of cancer compared to those who drank less. It was also found that the risk of bladder cancer decreased by 7% for every 240 milliliters of fluid added[8].

Prevention of bladder cancer consists of measures to eliminate occupational hazards from chemical production: first of all, direct contact of workers with chemicals is eliminated, and medical examination is also strictly carried out. All benign papillomas of the bladder are subject to radical treatment using electrocoagulation or surgical removal. Timely treatment of inflammatory diseases is also necessary.

Recent studies have revealed a direct connection between bladder cancer and smoking, so quitting smoking is often considered a necessary preventive measure to prevent various cancers, including bladder cancer.

Features of the structure of the bladder

The bladder is the most important component of the human genitourinary system. About one and a half to two liters of urine are produced per day. It contains many waste chemicals that must be eliminated from the body.

The primary formation of urine occurs in the kidneys. From the pelvis it goes to the ureters, from where it goes directly to the bladder. This organ is located in the pelvic area and is closely adjacent to the rectum, prostate in men, uterus and vagina in women.

The purpose of the bladder is to accumulate and temporarily store urine. It is excreted through the urethra.

The bladder is located in the pelvic area

The bladder is a hollow organ. Its wall consists of three layers:

• the internal mucosa, in direct contact with urine, is represented by a single layer of cells called the urothelium;
• middle muscle, consisting of several layers of smooth muscle cells, it provides the ability to contract and relax the organ, accumulate and excrete urine;
• external adventitia covering the bladder, this layer consists of connective tissue.

  
  The wall of the bladder consists of three layers, which allow the organ to stretch and contract depending on its filling.

Notes

1. Zeegers MP (2000). "The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies." Cancer 89
   (3):630–9. DOI:10.1002/1097-0142(20000801)89:3<630::AID-CNCR19>3.0.CO;2-Q. PMID 10931463.
2. Boffetta P (2008). “Tobacco smoking and risk of bladder cancer.” Scand J Urol Nephrol Suppl 42
   (S218):45–54. DOI:10.1080/03008880802283664. PMID 18815916.
3. Man, 52, endured a WEEK-LONG erection that felt like it was 'about to explode' and had to have his member amputated after doctors discovered it was caused by cancer
4. Izmailov A. A.
   Molecular genetic prognostic markers of bladder cancer (literature review) // Siberian Medical Journal. - 2011. - T. 26, issue. 4-1. - pp. 24-28.
5. Novosibirsk doctors performed a unique operation using the Da Vinci robot. NEWS Novosibirsk. Retrieved March 2, 2020.
6. Leite NB et al. PE and PS Lipids Synergistically Enhance Membrane Poration by a Peptide with Anticancer Properties //Biophysical journal. - 2020. - T. 109. - No. 5. - pp. 936-947.
7. Wasp venom destroys cancer cells. Retrieved September 19, 2015.
8. Valtin H (November 2002). ""Drink at least eight glasses of water a day." Really? Is there scientific evidence for “8 × 8”?” American Journal of Physiology 283
   (5):R993-R1004. DOI:10.1152/ajpregu.00365.2002. PMID 12376390.