Lupine Publishers | A Case Report and Review of Thymic Carcinoma with Adenoid Cystic Carcinoma like Features

Lupine Publishers | Open Access Journal of Oncology and Medicine

Introduction

Adenoid cystic carcinoma (ACC) is also called cylindroma, which is considered as a kind of low-grade malignant tumor and often occurs in head and neck salivary gland tissue. Most of them happened in submandibular gland and minor salivary glands while rarely happened in thymus. There are only 7 cases had already reported before all around the world. Our case is diagnosed as thymic carcinoma with adenoid cystic carcinomalike features by pathology after surgery; it is different with other cases because he had accepted a surgery six years ago because of the mediastinal mass and pleural effusion. Because of the symptom of chest tightness, he came to see doctor again and finally find there was a mediastinal mass and accepted the treatment of surgery. The medical history of our case maybe provides some inspiration of the pathogenic of thymic carcinoma with adenoid cystic carcinoma like features.

Information and history

A 60 years old male came to our hospital because of chest tightness in 2009/10. The enhanced chest CT showed “A large mass measuring 9.2*10.1cm² in the right side of the mediastinal which the average CT value is 9 Hu. The border with the superior vena cava and the right atrial and mediastinum is less clear. The right side of the chest is hydropneumothorax, Hydropericardium. The ultrasonic showed there is a mass of mixed echo in the right chest which had strong echo light and liquid visible mass dark space inside it. The test of pleural effusion by pleural puncture showed that was hematodes exudates without cancer cells. He accepted a surgery to resection of the mass by posterolateral thoracotomy, the pathology showed “Mostly considered as hematoma with organization according to clinical”. After the surgery ,he recovered and discharged from our hospital.

It is said by himself that there was found a mediastinal mass in his chest by CT in the year of 2010(the imaging data has been lost), and he taking chinese traditional medicein(herbal medicine) for tow month. After that he reexamination a chest CT showed the mediastinal mass was disappeared so he didn’t have the follow-up according to the doctor’s advice. 2014/10/13, he had a chest CT examination showed there is a 15*13cm² cystic with solid abnormal density shadow in the right front mediastium; Mediastinal lymph node is enlarged; Density of soft tissue in chest wall which is considered as metastatic. He reexamined a chest CT in 2015/1/4 but did not show significant change. Finally, he came to hospital again because of the intermittent chest pain. Complete the checks after hospitalization, lung function show” FEV1 : 3.94L, FEV1/FVC : 79%”, the enhanced chest CT showed “there is a 15.2*11.6cm² cystic with solid abnormal density shadow in the right front mediastium, the border is smooth and the density inside is uniform, the CT value is 18Hu; Right pulmonary atelectasis, the chest wall and diagram pars maybe have already metastasis tumor”.

a. Anamnesis: The patient with high blood pressure for more than 20 years, he use reserpin and Chinese traditional medicine to ctrl his high blood press by himself, but the effect is poor. His blood pressure was stabled for able 108/90mmHg for all years. Smoking 20 years and quit it for 23 years. We asked his medical history repeatedly, he denied the history of trauma and hemorrhagic disease.

b. Preoperative diagnosis: anterior mediastinum space occupying lesion, malignant tumor is the most possible. The chest wall maybe already metastasized. We suggested him to accept PET/CT to make the tumor’s metabolic strength clear and conform the primary focal; Or accept thoracentesis by fine needle to definite the pathological diagnosis. The patient and his family refused it and screamed for an operation.

So the surgery was planned. The patient was placed in the supine position under general anesthesia. Via median sternotomy. We saw the tumor was located in right anterior mediastinum, 12*12*10cm³, it was dense adhesion with mediastinal pleura, pericardium, diaphragm and right lung. The tumor is invading and partly wrapped around superior vena cava. Cut out part of the tumor tissue and sent to the examination of fast frozen section and the result was benign tumor. Then we completed removal of the tumor and cut one right rib and the tumor on the chest wall, the fast frozen section also report “benign tumor”. The tumor was solid and multicystic hemorrhagic with many sediment sample material. The diagnosis of the frozen section considered that most possible is encapsulated empyema. So we use polyninylpyrrolidone and normal saline to rinse the chest repeatedly and the closed thoracic conventionally.

The result of postoperative pathological: thymic carcinoma with adenoid cystic carcinomalike features with chest wall invasion, the tissue of cystiform is hyperplasia of fibrous tissue and stale hemorrhage. The result of immunohistochemical : CK(+), EMA(-), CK(L)(+), E-Ca(++), ER(+), PR(-), Ki67(10%), CK8/18(+), CD56 Focal(+), NSE(-), Syn(-), CgA(-).After the surgery, we checked the patient’s oral cavity, head and neck region but not found and obvious abnormal. 6 month pasted and we have not found any indication of tumor recurrence. He is still in follow up now.

Discussion

Adenoid cystic carcinoma is salivary gland tumor, but can still be reported in breast [1], lung [2], esophageal [3], postate [4]. Thymic carcinoma with adenoid cystic carcinoma like features is very rare. Only 7 cases have already be reported all around the world before while all cases is not in China.

Thymic carcinomas are defined as thymic epithelial neoplasmas, which are classified into 10 different histological types according to the 2015 update of the WHO classification, i.e.[5]

a. squamous-cell carcinoma

b. basal cell carcinoma

c. mucoepidermoid carcinoma

d. lymphoepithelioma-like carcinoma

e. sarcomatoid carcimoa

f. clear cell carcinoma

g. adenocarcinoma

h. NUT carcinoma

i. unclassified carcinoma

j. other rare thymic carcinoma.

Within the group of adenocarcinoma, four histologic subtypes are known: papillary adenocarcinoma; thymic carcinoma with adenoid cystic carcinomalikefeatures; mucinous adenocarcinoma; adenocarcinoma, non specifically. Compared with the 2004 update of the WHO classification, the name of adenoid cystic carcinoma is changed to thymic carcinoma with adenoid cystic carcinomalike features. It lack the real features of adenoid cystic carcinoma in the character of immunohistochemical because it is generate from the thymus (Table 1) [6-8].

Table 1: The character of the cases of thymic carcinoma with adenoid cystic carcinomalike features which are reported so far.

The Character of Clinical

All of the clinical character of the cases which have already been reported is summarized above (chart-1). Thymic carcinoma with adenoid cystic carcinoma like features is very rare, most of them are occurred in elderly and few distant metastases. But it can show the character of aggressive growth and directly invasive chest wall; pericardium and other adjacent tissue. The initial symptoms of the patients are fever; cough; dyspnea; chest pain; the sense of suppression in the chest and the loss of weight [9]. thymic carcinoma with adenoid cystic carcinoma like features is generated in the tissue of thymus which located in the mediastinum, and the size of the most tumor is large. The severity of the clinical symptoms is uncorrelated with the size of the tumor.

Although the size of the tumor is large, the symptoms of patients is not severely even cannot let them go to see doctor. The clinical symptoms is formed because of the oppress by the tumor, there is no obviously symptoms in early stage, with the growth of tumor , the patient will appear the atypical symptoms such as cough; fever; dyspnea; chest pain and so on. Because thymic carcinoma with adenoid cystic carcinomalike features is a low grade malignancy, all cases had the features of gradual onset and grow progress. So only one case that had already metastases to rib was reported that is different whit the character of adenoid cystic carcinoma in salivary. According to the Masaoka stage of thymus tumor, our case is in stage β.

The Character of Pathology

The macroscopic view of the tumor: Most of them are consist of huge gritty and firm cystic solid mass with smooth border. Some of them have complete capsule. The cross-section showed multicystic, necrotic tissue mixed with fibrotic, yellow tissue nodules. Some of them can be observed the papillary hyperplasia and plenty of hemorrhagic effusion.

a. The microscopic view of the tumor: The character of our case is similar as salivary adenoid cystic carcinoma. The cystic and cribriform texture neoplastic nest is consist of basoloid cell carcinoma ,and bloody fluid or granular basophilic myxoid stroma full of the cyst. The microscopic view of the thymic carcinoma with adenoid cystic carcinomalike features can be classified as three types. If the tumor cell is undifferentiated, it will show the solid structure with irregular funicular or dense array by basaloid cells(solid type). If the tumor cell is differentiation to the glandular epithelium, it will show the gland tubular structure consist of the inner layer of columnar epithelium and the outside of the myoepithelial cells with homogeneous eosinophilic mucin full of the cavity of the tubule(tubular type). If the tumor cell is differentiation to the myoepithelial cell, it will show the cribriform structure with homogeneous basophilic cell matrix(cribriform type)[10]. The classify of thymic carcinoma with ACC like features is closely connected with the prognosis, so we infer that the prognosis of solid type is the worst while the prognosis of tubular type and the cribriform type is more better.

b. Immuno histochemistry: CK and CKL all showed positive in our case, they were marked at the epithelium which consist of cribriform structure. E-Ca(++) prompted the tumor has a certain invasive in accordance with the invasion of chest wall. Ki67(10%) prompted the active proliferation. CD56(focal +) is the new character that has not be reported before ER(+) prompted this case may be sensitive to endocrine therapy, but there isn’t any evidence of evidence-based medicine support it so the clinical significance needs to be confirmed.

Summarize other documents , we can get the following conclusion:

i. These marks is contribute to the diagnosis of thymic carcinoma with adenoid cystic carcinomalike features if they are positive: CollagenIV, laminin, P63, CK34betaE12, Ki67(1- 10%)

ii. These marks is contribute to the diagnosis of thymic carcinoma with adenoid cystic carcinomalike features if they are negative: Syn, NSE, CD117, CgA.

The molecular marks research of this disease has not yet been carried out. There are reports that suggested MYB-NFIB fusion gene, NF-κB, MMP-2, survivin is related to adenoid cystic carcinoma [11], and it is helpful to the molecular marks research of thymic carcinoma with adenoid cystic carcinomalike features.

The Differential Diagnosis

PET/CT has great significance to this disease in differential diagnosis, it can estimate whether the mass is primary tumor or metastases. The report suggested the tumor of this disease show high value of SUV max in PET/CT while its metastases can also show unusually high value of SUV max [9]. The retrospective analysis show that have a examination of PET /CT before surgery is correct and meaningful. In the primary thymic carcinoma, this disease should be distinguished with basaloma. In morphology, most of the tumor cell of basaloma is cubic cells with small and deep dyeing nucleus which array form lobulated or funicular [12,13]. The results of Immuno histochemistry can confirm that our case can be diagnosed as thymic carcinoma with adenoid cystic carcinoma like features.

The treatment and prognosis

Surgery is given priority to this disease at present and radiation therapy can according to the situation. The effect of chemotherapy for this disease is poor and if take chemotherapy as a routine treatment is still controversial. Some professional insist of that adenoid cyst carcinoma cannot get enough benefit from chemotherapy, so we should treat chemotherapy as the last treatment [14]. We believe that A case report and review of thymic carcinoma with adenoid cystic carcinoma like features is a low level malignant tumor so the it should have better prognosis after standardized treatment. But we still should be carefully evaluated before surgery and if we suspect the diagnosis as thymic tumor with ACC like carcinoma or huge mediastinal mass, PET/CT will be suggested to confirm the quality of the mass and whether there is metastases or not.

Locally metastasis and the chest wall invasion should not be the absolute contraindications of surgery because as a low level malignant tumor, if we resection the tumor and metastases completely and take some radiation therapy appropriately, nice quality of life will get. In our case a recurrence is appear after the surgery in 2009, but he said itself that the mediastinal mass was once disappeared after the treatment of Chinese traditional medicine. So we guess that Chinese traditional medicine may effective for this disease.

The discussion of pathogenesis

A case report and review of thymic carcinoma with adenoid cystic Carcinoma like features is a kind of thymic carcinoma, it is generated from thymic epithelial cells. If the tumor cell is differentiation to the myoepithelial cell, it will show the cribriform structure with homogeneous basophilic cell matrix. The medical history of our case is so specially that he found the mediastinal mass six years ago and experienced the surgery. The pathological report at the time of 2009 showed “hematoma with organization”. Organization means the absorption process by new granulation tissue if necrotic tissue, thrombus, .com or foreign body cannot be dissolved or absorbed or separated or discharged. The granulation tissue contains abundant myocyte and some of them will differentiate to myofibroblast after the stimulate of cytokines.

And these cytokines that can induce differentiation may induce the differentiate thymic epithelial cell to myoepithelium and finally generate to the type of cribriform of thymic carcinoma with adenoid cystic carcinomalike features is a kind of thymic carcinoma. This maybe one of the triggers of this disease although still need to establish by experiments. According to the inference above, we consider coagulate hemothorax and mediastinal hematoram may result thymic carcinoma with adenoid cystic carcinoma like features. In order to avoid the remained thymus tissue be stimulated to differentiate to thymic carcinoma, in the surgery of mediastinal hematoma, thymectomy completely is necessary and fat tissue of mediastinal should be resection completely too.

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Lupine Publishers | Subjection between Breast Cancer and Body Mass Index, the Role of L-Carnitine in Prediction and Outcomes of the Disease

Lupine Publishers | Open Access Journal of Oncology and Medicine

 

Abstract

Increasing the effectiveness of antitumor therapy in breast cancer patients who take L-carnitine during preoperative systemic antitumor therapy compared with patients receiving standard neoadjuvant systemic antitumor therapy served as a prerequisite for studying possible antitumor mechanisms of L-carnitine. The positive effect of L-carnitine is due to the transfer of palm-n-LC through the inner membrane into the mitochondrial matrix, which promotes the formation of a significant number of ATP molecules. It has also been shown that L-carnitine can have a double protective effect, enhancing the energy dynamics of the cell and inhibiting the hyperexcitability of the cell membrane, that making it an ideal nutrient for the prevention and treatment of cancer. This article summarizes the results of epidemiological and clinical studies of the use of L-carnitine in the treatment of breast cancer
Keywords: Body mass index (BMI); Breast cancer (BC); Obesity; Overall survival; L carnitine

Introduction

The incidence of breast cancer in the world in general and in Ukraine in particular is growing. In 2017, in Ukraine the incidence reached 16 percent of female population, for which, the breast cancer ranked first in structure of oncological incidence among women. In analyzing the data of the National Cancer Registry of Ukraine, it should be noted, that in comparison with 2014 year, the prevalence rate of breast cancer in 2016has increased by 5,1%, that indicates importance of improvement diagnostic procedures and methods of treatment it [1]. Studying the scientific literature on this subject, we noticed that there is a strong biological relationship between obesity and a poor outcome of breast cancer. And having analysed the date of Ministry of Health in Ukraine it can be concluded, that about 26% of women in 2017 year had overweight or obesity.
Obesity has a chronic metabolic character, which is the result of the interaction of the endogenous factors, environmental conditions and lifestyle. Endogenous factors could be considered a violation of the genetic and hormonal balance. The external conditions and type of lifestyle include irregular rhythm nutrition, use of substandard products and sedentary lifestyle. Obesity is the first risk factor for metabolic syndrome, diabetes type II, cardiovascular disease and some forms of cancer, including breast cancer. Since overweight is a risk factor for breast cancer, there is reason to believe that among patients with breast cancer the percentage of obese women is higher than in the population. The risk of breast cancer in postmenopausal women by 30%, it is more than in premenopausal, women with obesity-50%. Furthermore it was proven that obesity is associated with poor prognosis in patients with breast cancer, regardless of menopausal status, and effectiveness of systemic medication breast cancer in patients that have over weight is lower than in patients with normal BMI.
Although obesity is associated with a poor outcome in women with breast cancer, it is unclear how weight loss after diagnosis will change its course and results. Recently, complementary and alternative medicine (CAM) is widely accepted among patients with breast cancer, which may provide several beneficial effects including reduction of therapy-associated toxicity, improvement of cancer-related symptoms, fostering of the immune system, and even direct anticancer effects [2]. L-carnitine is a metabolite of C₄ oil LC, which is involved in the transfer of palm-n-LC through the inner membrane into the mitochondrial matrix and is a substrate for the formation of ATP molecules. Carnitine is a trim ethylated amino acid naturally synthesized in the liver, brain and kidneys from protein lysine and methionine. Several factors, such as sex hormones and glucagon, can influence the distribution and level of carnitine in tissues [3,4].
In the absence of L-carnitine, the inner membrane of the mitochondria becomes impermeable to fatty acids, which entails a chain of various metabolic disorders in the human body. Carnitine has a modulating effect on the function of acetylcholine excitatory neurotransmitter, glutamate excitatory amino acid, insulin growth factor-1 (IGF-1) and nitric oxide (NO)[3]. Also proved, that L-carnitine may have a dual protective effect by enhancing the energy dynamics of the cell and inhibiting cell membrane hyper excitability, which make it an ideal nutrient for cancer prevention and treatment [5]. In view of the foregoing, the study of the influence of the body mass index on the effectiveness of systemic treatment of breast cancer is an urgent scientific problem and a promising field of research. This article presents the information of epidemiological and clinical studies of the influence of the body mass index on the effectiveness of breast cancer treatment by individualizing therapeutic measures taking into account the characteristics of patient's metabolism.
Studies on the Effects of BMI on The Course and Outcome of Breast Cancer and the Role of L-Carnitine in the Treatment of Cancer: The effectiveness of the prescribing of L-carnitine for breast cancers' treatment, as well as the effect of BMI on the outcome of the disease is proven in epidemiological and clinical studies.

Epidemiological and Clinical Studies

DSM Chan and co-authors [6] reported that women who have BMI> 30 course and outcomes of breast cancer are significantly worse than women with BMI <30. They proved, that women with BMI> 30 have the overall relative risk of total mortality 1.41, women with BMI of 25> 30 - 1.07. At the same time, for every 5 kg / m² of the increase BMI, the risk of both total mortality and mortality from breast cancer increased, namely by 18% and 14%, respectively M. Protani and co-authors [7] have shown that women with breast cancer, who are suffering in obesity, have lower survival rate than women with breast cancer without obesity. Recently published data of randomized clinical researches by ML Neuhouser and coauthors [8] demonstrated, that for women> 50 years old, with 2 and 3 stages of obesity (BMI> 35) is typically the development of GR+ breast cancer.
Similarly, B. Pajares et al. [9] who found significantly worse results for patients with BMI >35 compared with patients with BMI <25, stated that the magnitude of the effect depended on the cancer subtype (estrogen receptor (ER) / progesterone (PR) positive and HER2 negative, HER2 positive, triple negative). An analysis of the pooled data of the three adjuvant studies of the Eastern Cooperative Cancer Group showed significantly worse results for patients with obesity (BMI > 30) than for patients with normal BMI with a hormonal receptor-positive disease. And it was noted absence of negative effect of obesity on survival in patients with other breast cancer subtypes. C Fontanella et al. [10] studied the effect of BMI on different molecular subtypes of breast cancer and concluded that in women with ER / PR-positive and HER2-negative breast cancer, as well as with TNBC, the risk of death is significantly higher than in other subtypes of cancer.
It is proved that even the highest BMI figures are not a risk factor for death for patients with luminal A-like subtype of breast cancer. The reason for this is that fatty tissue produces an excessive amount of estrogen, a high level of which is associated with an increased risk of developing breast, endometrial, ovarian and some other cancers. It has also been proven that the level of adipokine, that promotes cell proliferation, increases in the blood with increasing of level of fat in organism. And adiponectin, which people with obesity have less than people with normal BMI, can have anti proliferative effects. Such data can serve as evidence of the effect of BMI on the course and outcome of breast cancer. Yet another proof of influence developing metabolic syndrome on the course and outcome of breast cancer was proposed by R. Bhandari et al. [11]. They proved that that the presence of metabolic disorders (that is, the metabolic syndrome) is associated with an increased risk of breast cancer in adult women.
The above data led to the need to investigate medicines that contribute to fat burning, such as L-carnitine. Based on the data provided by Rania M. Khalil and co-authors [12], we can prove the positive effect of this medicine on the course and outcome of breast cancer. The study showed that patients who received Tamoxifen with L-carnitine had significant decrease of Her-2 / neu and IGF-1 level (P <0.05) in the serum compared with patients who received only Tamoxifen. Using of L-carnitine led to significant decrease Her- 2 / neu level in the serum (P <0.05) compared to each of the control patients, namely, 59.5%. The effect of tamoxifen on IGF-1 (P <0.05) -decrease its level by 5.4% [13].However, it has been proved that using of L-carnitine in the treatment of ER+ breast cancer does not significantly reduce the level of estradiol, but leads to decrease both tumor markers CEA and CA15.3 (P <0.05,% decrease by 80.9% and 67, 8%, respectively) [13].
Using of L-carnitine in patients with breast cancer and obesity improves the metabolism of fatty acids in mitochondria, restores normal mitochondrial function and, thus, improves the general condition and quality of patients’ life [14]. Carnitine may alsomimic some of the biological activities of glucocorticoids, particularly immunomodulation, via suppressing TNF-a and IL-12 release from monocytes (5). L-carnitine as adjuvant therapy in cisplatin-treated cancer patients proved a beneficial effect in reducing the cisplatin- induced organ toxicity [15]. It is possible that, the extremely lipophilic nature of carnitine may be responsible for the decrease in EGFbinding [16]. Carnitine may insert in the cell membrane and/or interact with one of the many cellular enzymes having lipid substrates or cofactors. In addition, carnitine may interact directly with the EGFR [17].
Experimental evidence is available showing that ROS may induce the light and independent phosphorylation of the EGFR activating Her-2/neu. Moreover, the expression of the receptor is induced in conditions of oxidative stress [18]. L-carnitine, via its free radical scavenging and antioxidant properties, may inhibit ROS-mediated EGFR phosphorylation. It has been found that palmitoyl-carnitine can inhibit the activity of heart and brain protein kinase C in a competitive manner and subsequent phosphorylation of the EGFR [19]. Although the tumor markers and IGF-1 showed no significant difference in TAM-treated patients before and after administration of L-CAR, there was a tendency to decline after L-CAR supplementation [13]. The results of the above studies became a prerequisite for conducting clinical studies aimed at establishing the role of L-carnitine in the treatment of breast cancer.
To date, the search in the online clinical research registration system ClinicalTrials.gov using key words L-carnitine + breast cancer has revealed several studies evaluating the efficacy and safety of L-carnitine in the treatment of breast cancer patients. Analyzing the obtained results, we can conclude that L-carnitine was the drug of choice for neuropathies, as a consequence of chemotherapy, in patients with breast cancer.

Conclusion

L-carnitine is widely used in clinical practice. However, recently this medicine causes growing interest among oncologists. In a number of studies, L-carnitine has proven itself as a medicine that capable, during the preoperative systemic antitumor therapy, to increase its effectiveness compared with standard neoadjuvant systemic antitumor therapy. And also, taking L-carnitine with neoadjuvant systemic antitumor therapy helps to increase the number of cases of complete morphological regression (V degree of therapeutic pathomorphosis). To date, there are several clinical studies that are researching using L-carnitine in various malignant tumors, the results of which are the basis for further in-depth study of the effect of the medicine in the treatment of malignant neoplasms.


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Lupine Publishers | Somatic Mutations in Cancer-Free Individuals: A Liquid Biopsy Connection

Lupine Publishers | Open Access Journal of Oncology and Medicine

 

Abstract

Somatic mutations have been perceived as the causal event in the origin of the vast majority of cancers. Advanced massively parallel, highthroughput DNA sequencing have enabled the comprehensive characterization of somatic mutations in a large number of tumor samples for precision and personalized therapy. Understanding how these observed genetic alterations give rise to specific cancer phenotypes represents an ultimate goal of cancer genomics. However, somatic mutations are also commonly found in healthy individuals, which interfere with the effectiveness for cancer diagnostics.
Keywords: Somatic mutation; Germline; Cell-free DNA; Liquid biopsy; Next-generation sequencing
Abbreviations: NGS: Next-Generation Sequencing ; cfDNA: Cell-free DNA; MAF: Mutant Allele Frequency

Introduction

Mutations in healthy individuals are not all germline
Over the course of our lifetime, there are many millions of cell divisions in the body. By chance alone, mutations will definitely occur. Indeed, spontaneous somatic mutations constantly occur in individual cells. These background mutations arise either from replication errors or from DNA damage that is repaired incorrectly or left unrepaired, and have been detected in healthy tissues, including blood, skin, liver, colon, and small intestine [1-3]. Deepsequencing studies in normal tissues also surprisingly identified cancer-driving mutations, e.g., in blood, driver mutations can be detected in ~10%of individuals older than 65 years of age and resemble patterns seen in leukemia patients. Individuals carrying these driver mutations have an elevated future risk of blood cancers [4-6], suggesting that these are genuine precancerous clones. Further, a detailed analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies revealed that the majority, if not all, of aberrations that were observed in the cancer-associated cohort were also seen in cancer-free subjects, albeit at lower frequency [7,8].
Somatic mutations in healthy individuals are very prevalent, with an average mutation number of around 2–6 mutations/1 M bases [9,10]. The baseline somatic mutation spectrum in healthy population not only can help fill the gaps for the establishing early cancer diagnosis strategies, but also argues against the idea of using normal cells as germline control to make somatic mutation calls in sequencing tests. Moreover, the same driver mutation could exist in both tumor and normal cells yet with distinct biological effects, we should not simply define the threshold of mutation detection by removing the background mutations found in a healthy population. Taken together, we need to incorporate and carefully calibrate the background somatic mutations in healthy individuals; the fact is they are not all germline mutations.
Somatic driver mutations found in healthy population by liquid biopsy
With the dramatically decreased cost of next-generation sequencing (NGS) in recent years, it is now practical to screen a large number of individuals at ultra-deep sequencing depths to identify cancer-related mutations. Cell-free DNA (cfDNA) in the blood circulation of cancer patients (as liquid biopsy) have emerged as key biomarkers for cancer monitoring and treatment decisionmaking [11]. Both academic research groups and industry players are chasing the pan-cancer screening by a simple blood draw. However, the reliable and accurate application of cfDNA detection requires better understanding of background somatic information in healthy individuals.
We performed ultra-deep target sequencing on 50 cancerassociated genes for plasma cfDNA from a cohort of 129 apparently healthy cancer-free subjects. To increase the confidence of the called mutations, we here defined the mutation as the variant allele frequency greater than 1% and the average depth more than 5,000 xs for demonstration. Our data revealed an age-independent mutation spectrum with average 3.12 somatic mutations per subject (Figure 1). The most frequently mutated genes are TP53 (42%), KIT (6%), KDR (5.5%), PIK3CA (5.5%), EGFR (5%) and PTEN (3.7%). These results highlighted the prevalence of some cancer-associated driver mutations in healthy individuals as background mutations. We also demonstrated the concordance between our results and a recent study for revealing the real somatic mutation in healthy population.
Figure 1: Distribution plots of somatic mutation detected in a cohort of 129 healthy subjects.
The study by Xia et al. [12] examined the background somatic mutations in white blood cells and cfDNA in healthy controls based on sequencing data from 821 non-cancer individuals with the aim of understanding the baseline profile of somatic mutations detected in cfDNA. The data comparison was summarized in Figure 2. Although there are differences in study cohort composition, sample volume, extraction methodology and analytical platform, the end results are remarkably similar, i.e., average 3 mutations per subject with an almost identical list of frequently mutated genes. Although varying mutation spectra in cancers have often been attributed to cancerspecific processes, our data suggest that at least a subset of these mutations actually reflect normal tissue-specific processes. This concept is consistent with the idea that a substantial fraction of the mutations found in cancers occur in normal stem cells [13,14].
Figure 2: Comparison of somatic mutation detection in healthy population from two studies.
Normal tissue as a germline control not justified
There is evidence for the presence of tumor-derived cfDNA in early cancers [15]. However, the real fraction of cfDNA that shed by tumor rather than the background somatic mutations is not well illustrated. For clinical application, the low level of tumor mutation as well as the heterogeneity of background mutation present in the circulation needs to be clearly addressed and differentiated to achieve accuracy. Unfortunately, this goal can’t be achieved by pushing detection limit of current advanced technology to below 0.01% mutant allele frequency (MAF). Contrarily, the higher sensitivity will guarantee higher chance to pick up background somatic mutations. Also, the clinical relevance of those lowpercentage tumor mutations is still debatable in terms of treatment decision or regimen change. Each human individual is unique. Every cancer patient is different. No two tumors are the same even resides within the same patient; to distinguish the definitive cancer-specific mutations from background signals observable in plasma is extremely daunting. Evaluation of specificity in plasma cfDNA profiles from large numbers of healthy individuals as representative controls for the cancer population seems farfetched with uncertainty, especially when standardized protocol and optimized technology are still lacking.
Unlike tissue genomic DNA, circulating cfDNA is so diluted and dynamic with a relatively short half-life, making single-point measurement not suitable for clinical application. We reason that cfDNA in circulation is truly under a continuous selection pressure to select for highly aggressive/proliferative clones, as disease progressing the low-abundant tumor clones will either evolve and dominate or vanish by the immune clean-up processes, therefore longitudinal clinical follow-up should be performed to identify the best time and target for precision therapy, meanwhile to filter out contaminating background mutations. To achieve high clinical specificity, a cfDNA-based test must be capable of distinguishing between the background signals originating from non-cancer or pre-cancerous processes and the invasive malignancy of clinical interest. It is still possible that mutational signatures in cfDNA could distinguish basic biological processes from malignant and pathological processes.
Figure 3: A representative mutational trending curve after filtering out background mutations.
Here we propose a combined approach based on the tumor evolutional principle of “survival and domination of the fittest” in circulation that is to perform multiple time-point monitoring, filter out potential background mutations (e.g., <1% MAF), reduce sample input volume and interrogate multiple databases. A representative mutational trending curve following our approaches was shown (Figure 3). Our findings underscore the importance of an assessment of the landscape of somatic mutations in cancerfree population, and associated mutation signatures. Somatic mutations and mosaicism in healthy individuals have implications not only for early detection, diagnosis and treatment of cancer using liquid biopsy but also emerging technologies in healthcare. We recommend caution while extending the mutation conclusions to cancer patients by employing matched normal tissue as germline control. To increase sample input and push liquid biopsy sensitivity toward <1% may not serve the interest of detecting low-frequency mutant allele, but only to increase the chance of background mutation contamination. Application of artificial intelligence, machine-learning on big database to create an algorithm for highrisk population screening of cancer is a good idea for preventive medicine, yet the outcome is uncertain given the uniqueness of every patient, each tumor - one size can’t fit all.

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Lupine Publishers| Immunotherapy in Some Types of Tumors

Lupine Publishers| Open Access Journal of Oncology and Medicine

Charasteristics

a) Immunotherapy exerts its antitumor action by stimulating the response immune response of patients to cancer, unlike classic treatments, which directly attack the tumor
b) Previously immunotherapy was limited to patients in whom the conventional treatment, usually with chemotherapy, but currently in patients with some types of tumors, such as melanoma or some lung cancers, is already considered the treatment of first choice
c) Immunotherapy is able to control some types of malignant tumors prognosis very long, even for several years
d) Immunotherapy exerts its antitumor action by stimulating the immune response of patients against cancer, unlike classic treatments, which attack directly to the tumor. This implies a series of advantages and characteristics of this novelty strategy.
e) Its main advantage is its ability to control the tumor for very long periods of time in a certain percentage of patients, which varies according to the type of cancer. In some patients with tumors that were previously considered incurable, at this time they are getting very long survivals, even years.
f) Currently, immunotherapy with antibodies that block PD-1 receptors or action on these PD-L1 protein receptors has shown efficacy against a large number of tumors, including among others melanoma, cancers of the lung, kidney, bladder, these treatments are usually administered intravenously and their toxicity is usually lower than conventional treatments, such as chemotherapy
g) However, between a 5-15% of patients can develop relevant toxicities, which are usually due to the activation of the immune system against the patient’s own organism. The organs most frequently affected by these reactions are: the lung (“pneumonitis”), which manifests in the form of cough and shortness of breath; and the digestive tract (“colitis”), which presents as diarrhea. When they are used as unique drugs,
which is the most usual Now a days, toxicity is not usually a major problem. However, when they use in combination, their frequency and severity is greater. New immunotherapy strategies Despite these results, there is still a long way to go, given that today Only 40-60% of melanoma patients benefit from these treatments between 10 and 30% of patients with other types of tumors.
Some of the main ones Developing strategies to improve the effectiveness of immunotherapy are:

a) Combination Immunotherapy: During the development of a tumor it is they can alter several phases of the immune response. Therefore, the use simultaneous treatment of two or more immunotherapy treatments is one of the strategies more used to increase antitumor efficacy. The combinations of immunotherapy have shown significant activity in patients with melanoma and renal cancer. The main mechanisms of action of drugs which are used for these combinations are: directly activate the answer immunological; unlock the inhibition of the immune response produced by many tumors; or provide fundamental elements to trigger the immune response, as antigens or cells of the immune system New vaccines: antitumor vaccines consist of administering patient tumor antigens (small fragments of it, usually proteins), for the immune system to recognize them and thus put in place the antitumor immune response. Modern molecular biology techniques have allowed to advance a lot in the processes of selection of antigens with greater possibilities of triggering these responses and, therefore, this is one of the most hopeful ways for the development of new treatments of immunotherapy. Currently there is an anti-cancer vaccine against cancer prostate whose use in patients is approved in the USA. (Sipuleucel). In addition, some vaccines against infectious diseases can confer a high degree of protection against tumors associated with them (for example: human papilloma virus, associated with cervical cancer, or hepatitis B virus, associated with hepatocarcinoma).Vaccination against these viral infections dramatically reduces the incidence of associated tumors.

b) CAR-T Cells (Chimeric Antigen Receptor, or Antigenic Receptor Chimeric): It consists of extracting the patient’s immune cells; process them in the laboratory to express an antigen that specifically recognizes to tumor cells; and readminister them to the patient, to attack the tumor. This strategy is having considerable efficacy in patients with some types of leukemia, although its use in patients with solid tumors It seems more complicated. In addition, it is associated with relevant toxicities, although the Most can be controlled with specialized medical care. As we have already seen, the small advances, taken together, are relevant. From here our motto from SEOM: In Oncology, each advance is written in capital letters. These small advances, considered each of them in isolation, could have have been considered of little relevance, but accumulated among themselves have led to change in many cases in a remarkable way the prognosis and the quality of life of many patients. In oncology, each advance is written with capital letters (madrid, february 19, 2018).

c) CAR-T cells (Chimeric Antigen Receptor, or Antigen Receptorchimeric): it consists of extracting the patient’s immune cells; process them in the laboratory to express an antigen that specifically recognizes to tumor cells; and readminister them to the patient, to attack the tumor. This strategy is having considerable efficacy in patients with some types of leukemia, although its use in patients with solid tumors. It seems more complicated.

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Lupine Publishers | Central Nervous System Manifestation of Multiple Myeloma: A Case Report

Lupine Publishers | Open Access Journal of Oncology and Medicine

Abstract

Multiple myeloma accounts for <1% of all malignancies and Central nervous system (CNS) manifestation of multiple myeloma (MM) is rare. Multiple myelomais characterized by malignant transformation of plasma cells that produces immunoglobulin chains. The accumulation of plasma cells in bone marrow results in clinical features like anaemia, osteolytic lesions, hypocalcaemia, renal failure and immunodeficiency [1,2]. The involvement of central nervous system is very uncommon in multiple myeloma and it may present early or late during the course of disease. The neurological symptoms can be diffuse headache, persistent vomiting, vertigo, weakness in limbs, urinary incontinence etc. Symptoms can be attributed to spinal cord or nerve root compression, peripheral neuropathies, and uremia [3,4]. Likely risk factors of CNS manifestation are unfavourable cytogenetics, high tumour load, low marrow involvement. In this report we describe a patient with CNS involvement after receiving systemic chemotherapy and symptomatic treatment.
Keywords: Central nervous system, Multiple myeloma

Case Report

A 52 years pleasant lady presented with complaint of pain in left leg with lower backache and tingling sensations for 10 days. Subsequently she developed pain in right leg followed by urine incontinence. MRI Lumbosacral Spine was done which reported ill defined lesions at L3-L4 vertebra (with associated periosseous fluid collections) and multiple focal lesions in the L4 vertebra, bilateral sacral ala and both iliac bones along with indentations upon the thecal sac by spondyliticridges, secondary spinal canal stenosis and neural foraminal narrowing at multiple levels and left exiting nerve root compression at L3-L4, L5-S1 levels (Table 1). She underwent L1-L5 stabilization, L3 decompression with laminectomy, biopsy, posterolateral fusion with local autograft. Histopathology reported plasma cell dyscrasia at L3-L4 level. Immunohistochemistry reported tumor cells are focally positive for CD-138 and kappa light chain and negative for lambda light chain. On further evaluation bone marrow biopsy reported plasma cells approximately 50% of total nucleated cells suggestive of plasma cell myeloma. Bone marrow aspiration shows plasmacytosis approximately 24% of total nucleated cells which confirmed the diagnosis. She received 15 cycles of Bortezomib and Thalidomide.

Table 1:

Table 2:

In view of persistent pain in legs MRI dorsal spine was done which reported well defined altered intensity expansile lesion in L3 vertebra extending into epidural space. She received palliative external beam radiotherapy to L3 vertebra 30Gy/10 fractions. She remained asymptomatic for a month. Then she presented with complaint of lower limbs weakness and nausea, loss of appetite, constipation, weight loss (Table 2). USG whole abdomen was done which reported multiple hypoechoic masses in epigastric region. Whole body PET CT reported metabolically active soft mass lesion in gastro hepatic region measuring 9.7x5.5 cm SUV max 20.3, recto uterine pouch measuring 9.2 x 7.8cm SUV 20.9, left iliac fossa measuring 7.2x4.0cm- ?mitotic, metabolically active mesenteric nodes measuring upto 2.2cm-? mitotic and metabolically active lytic lesion involving L3 vertebra with paravertebral soft tissue component infiltrating left psoas muscles.

Table 3:

Table 4:

To confirm the diagnosis CT guided core needle biopsy from supraumbilical mass was done which was compatible with multiple myeloma. She then received 1st cycle of Bortezomib, cyclophosphamide and dexamethasone. After few days, she developed headache, giddiness and syncopal attacks. On evaluation CEMRI brain reported diffuse leptomeningeal enhancement involving both cerebral as well as cerebellar hemispheres. Mild enhancement of basal cistern with associated marginal dilation of ventricular system (Figure 1). In view of above mentioned complaints, cerebrospinal fluid study was done (Table 3) (Figure 2). CEMRI spine was done which reported no abnormal enhancement in vertebra, cord or thecal sac (Figures 3 & 4). She received 7 fractions (14 Gy) out of 12 planned fractions (24Gy) of whole brain radiotherapy and two intra thecal injection of methotrexate. MRI upper abdomen with MRCP reported large mass replacing entire head and body region of pancreas. Mass encases and compresses CBD with mild bilobar intra hepatic biliary radical dilation. There is also encasement of second part of duodenum with possible infiltrartion of adjacent hepatic parenchyma as well. Features are suggestive of aggressive pancreatic malignanacy, possibility of pancreatic lymphoma. Thickening and edema of gall bladder wall was seen which was suggestive of concomitant cholecystitis. She was advised for ERCP with SEMS placement which was refused by attendants (Figure 5). In view of her deranged liver function test, both radiotherapy and methotrexate were discontinued and she was maintained on supportive care (Table 4).

Figure 1:

Figure 2:

Figure 3:

Figure 4:

Figure 5:

Discussion

Central nervous system is a rare location of involvement in MM, however it should be considered if a patient with MM presents with neurologic symptoms. Patients with MM often have neurological complications, either due to metabolic disorders such as hypocalcaemia, uraemia and hyper viscosity or due to peripheral neuropathy, spinal cord compression and cranial nerve infiltration [1,2]. The most common cause is spinal cord compression and cranial nerve infiltration [3,4]. The patient may present as a known case of MM with CNS features or as a new case with CNS symptoms. The clinical presentation depends on degree and site of infiltration. The symptoms and signs are headache, memory loss, behavioural changes, convulsions, nausea, vomiting, vertigo, urinary incontinence, backache, and limb weakness [3,4]. These symptoms can be attributed to spinal cord or nerve root compression, raised intracranial tension, meningeal inflammation [5]. In our case she presented with the complaint of headache, giddiness and syncopal attacks. This can be explained by CEMRI brain imaging which reported diffuse leptomeningeal enhancement involving both cerebral as well as cerebellar hemispheres. CSF study was done to reported to be negative. She received 7 fractions out of 12 fractions planned for whole brain radiotherapy and two injections of intrathecal Methotrexate injections [6]. In view of deranged LFT, radiotherapy and IT chemotherapy was stopped and was managed conservatively. She passed away after 2 weeks due to sepsis with LRTI with MM as underlying cause.

Conclusion

In conclusion this patient had an aggressive disease in view of abdominal deposits and unresponsiveness to multiple lines of systemic disease. CNS involvement in cases of MM portends extremely poor prognosis and median overall survival of <6 months. While in this case there was CSF infiltration which would portend even poorer prognosis but she succumbed to sepsis due to Lower respiratory tract infection. CNS disease in MM can be effectively palliated especially because of relative radio sensitivity of MM due to which early responses are seen at lesser doses and an early diagnosis can improve quality of life effectively.

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Lupine publishers | Head Cancer and Metastasic Neck. What Have We Advanced in the Last Years?

Lupine Publishers | Open Access Journal of Oncology and Medicine

Abstract

In 2012, 5.210 new cases of head and neck tumors were estimated in the USA, with an increasing incidence due to tobacco and alcohol habits in the population. A large percentage of the cases debut as a locally advanced disease, so control of the disease is key and we look for the best therapeutic strategy to achieve good survival rates while maintaining quality of life. We present the case of a 60-year-old patient in which our objectives to be presented are the assessment of comorbidity, toxicity and survival.

Clinical Case

A 60-year-old man without medical illnesses to be highlighted. He came to the emergency room in July 2016 due to injury at the cervical level of 1 month of evolution, with progressive growth and breathness, with also difficulty for eating. Also asthenia, anorexia and loss of weight not quantified in the last month.
Physical Examination: Weight 42 kg Head and Neck: mass of hard consistency of approximately 10 cm in diameter in the cervical left region that seems to deflect trachea. Pulmonary auscultation: generalized hypoventilation with some expiratory wheeze.

Additional Tests

a. Fibroscopy (August 2016) ulcerated lesion from right vallecula to mouth of Killian. Paresis of both vocal cords.
b. PET-CT (August 2016): Extensive tumor in pharynxlarynx- esophagus (> 6 cm) Lymph nodes in left IB-II spaces (> 6 cm). If confirmed, carcinoma would correspond to T3 N3 (stage IVB) (Figure 1).
c. Laryngeal Biopsy: Moderately differentiated and keratinizing squamous cell carcinoma.

Figure 1: PET-CT August 2016: Pathological adenopathies> 6 cm in left IB-II spaces

So, confirmed Squamous cell carcinoma stage cT4N3 Mx.The case is presented in the Tumor Committee, deciding treatment with Chemoradiotherapy and 1 cycle of Docetaxel+ Cisplatin (60% dose reduction because of frailty/ malnutrition) previous to induction due to the large tumor volume and waiting for start radiotherapy. Tracheotomy is performed prior to starting because of the risk of airway obstruction and also gastrostomy is placed for nutritional support.
On 31th August 2016 the patient starts on RT concomitantly to Cisplain ( receiving 2 cycles on 12.09.2016 and 10.10.2016 and 70 Gy) During the treatment, he achieves a good general condition until January 2017, when he goes to Otolaryngology Clinics referring dysphagia again although he maintains weight in 51 kg. PET-CT is performed: disease progression with soft tissue increase in the pharyngoesophageal junction despite the good response of cervical adenopathies and the partial response of the primary tumor. New bilateral subpleural pulmonary nodules suggestive of metastasis. Figure 2 Due to progression, he restarts treatment with chemotherapy (palliative intention) with ERBITAX scheme (Paclitaxel 80 mg / m2 weekly (3 / 4s) + Cetuximab 400 mg / m2 followed by 250 mg / m2) with good tolerance,only highlighting secondary rash to cetuximab (predictive factor). After 3 cycles he presents significant partial response (Figure 3) and continues until 6 cycles. After 10 cycles it is considered whether to stop paclitaxel and follow on with cetuximab, but given the good tolerance they remain both of them. However, in January 2018, he presented a new pulmonary progression, so we decided to start a new strategy with inmunotherapy (Nivolumab), receiving 2 cycles to date.

Figure 2: PET-TC January 2017: locoregional tumor progression.

Figure 3: TC March 2017: Partial response of left adenopathy

Discussion

a. The concept of fragility is evaluated incorrectly through the Performance Status (PS). The ACE scale 27 assesses comorbidities and compares survival to having an advanced stage, so that is a fact to take into account more than the ECOG at the time of choosing the treatment.
b. When a patient progress to chemoradiotherapy, we have two good “palliative chemo” options: phase III EXTREME study(5-FU + Cisplatin + Cetuximab) or phase II of Hitt (Paclitaxel-Cetuximab) with fewer side effects, which is an alternative to cisplatin, achieving good response rates (20.43%) [1].
c. After 6 cycles of Paclitaxel + Cetuximab can be considered to keep Cetuximab as monotherapy, continue both or suspension until progression.
d. If pulmonary metastatic disease is controlled for> 1 year, we can consider surgical intervention.
e. Support treatment improves tolerance to chemotherapy. The indication of prophylactic enteral nutrition is a controversial issue, so we have to individualize.
f. We need predictive factors for each tumor type that we can know about before hand the prognosis and guide the treatment according to it. We must raise multidisciplinary strategies with the aim of achieving the best treatment sequence to improve survival in a population with few therapeutic options [2]

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