On-Target Side Effects of Targeted Therapeutics of Cancer.

The concept of precision medicine is based on the identification of hallmarks of cancer to exploit them as drug targets. The basic idea was that in this way the therapeutic modalities will be more effective and the side effects will be less. Since the majority of these novel modalities are not specific for a cancer-related biological process or a cancer-specific (mutant) target protein, it is not a surprise that we had to learn new type of side effects, because these therapeutics also affect physiological or pathological processes. Even more, in cases of some of these novel therapies we were able to discover new molecular mechanisms of physiological and pathological processes. Identification of the on-target side effects of targeted drugs can help to prevent the development of them or better manage the patients when emerge during cancer therapy.

Prognostic factors and mitotane treatment of adrenocortical cancer. Two decades of experience from an institutional case series.

Objectives: This study aimed to characterise the clinicopathological features and prognostic factors of a large cohort of Hungarian patients with adrenocortical cancer diagnosed between 2000-2021. Patients and methods: This retrospective study included seventy-four patients (27 men and 47 women) with histologically confirmed adrenocortical cancer in a single tertiary referral endocrine centre. Descriptive statistics were performed, providing summaries of selected clinical and pathological parameters. Clinicopathological factors contributing to overall survival were analysed. Results: The median age of patients was 48,5 years (17-84 years) at diagnosis. The majority of cases were diagnosed at ENSAT stage II (39,2%) and stage IV (33,8%). At diagnosis, the median tumour size was 9,0 cm (4,5-20 cm). In 47 patients (71,6%), the tumour was hormonally active. The median overall survival and the 5-year survival rate were 23,5 months (95% CI, 17-30,5 months) and 18,3%, respectively. Primary tumour resection was performed in 68 patients (91,8%); R0 surgical resection was achieved in 30 patients. In univariate Cox regression model, tumours with stages III and IV, high proliferative activity (Ki67-index > 10%), R1-R2 surgical resection state and hormonal activity were associated with poorer survival. Cortisol excess, both isolated and combined with androgen production, was associated with poorer survival. Fifty-five patients were treated with mitotane. The overall survival of patients achieving therapeutic mitotane plasma concentration was significantly better compared to those who never reached it [27.0 (2-175) months vs 18.0 (2-83) months; p<0.05)]. The median age, the distribution of gender, ENSAT stage, resection state and Ki67-index did not differ between these two groups. The time needed to reach the therapeutic range of serum mitotane was 96.5 days (95% CI, 75-133 days). Conclusion: Our results confirm previous data that disease stage, mitotic activity, the resection state and the mitotane treatment achieving therapeutic concentration are the most critical parameters influencing the prognosis of adrenocortical cancer. Our data suggest that hormonal activity may be more frequent than described previously, and it is a strong and independent prognostic factor of overall survival. To our knowledge, this is the first single-centre study confirming the prognostic importance of achieving therapeutic mitotane concentration.

[EGFR protein is a negative prognostic and predictive factor in wild-type RAS colorectal cancer]. / Az EGFR-protein-expresszió negatív prognosztikus és prediktív marker vad RAS típusú vastagbélrákban.

Negative predictive markers of the anti-EGFR antibody therapies are RAS or BRAF mutations, while left sidedness can be considered as a positive predictor. Here we analyzed 97 wild type RAS metastatic colorectal cancers looking for the prognostic and predictive roles of EGFR protein expression. We found that right-sided colorectal cancers are characterized by significantly higher EGFR protein expression as compared to left-sided ones, irrespective of the primary or metastatic tissue analysis. Furthermore, tumors with multiple organ involvement are characterized by significantly higher EGFR protein expression as compared to single organ ones. In the homogenous cetuximab treated cohort (n=90) we have found that lower than the applied EGFR protein expression cut-off was associated with favorable survival. In the multivariate analysis only sidedness proved to be a strong independent predictor, however sidedness is an EGFR-dependent predictor of anti-EGFR therapy.

Regular chromogranin A monitoring facilitated the early detection of a gastrointestinal neuroendocrine tumour in a patient with type 1 diabetes.

Not required for Clinical Vignette.

[Therapeutic aspects of inherited colorectal cancer syndromes]. / Az örökletes vastagbélrákok kezelése.

Inherited colorectal cancer syndromes account for 6-10% of all cases. The diagnosis of the polypoid forms is easier due to their phenotypes, compared to the non-polypoid cases. The evaluation of the MSI/MMR status of the already developed colorectal cancer cases could help in the recognition and screening of the latter forms. This screening method is much more sensitive than that solely based on family anamnestic data. The MSI/MMR status of the tumor also could help in adjuvant or palliative treatment planning, therefore it is recommended in all colorectal cancer cases. Here we review the available information regarding the inherited colorectal cancer syndromes, and the role of MSI/MMR status in the management of colorectal cancers.

EGFR Protein Expression in KRAS Wild-Type Metastatic Colorectal Cancer Is Another Negative Predictive Factor of the Cetuximab Therapy.

The selection of colorectal cancer patients for anti-epidermal growth factor receptor (EGFR) antibody therapy is based on the determination of their RAS mutation status-a strongly negative predictive factor-since the protein target, EGFR, is not a reliable predictor of therapeutic response. In this study, we revisited the EGFR protein issue using a cohort of 90 patients with KRAS exon2 wild-type colorectal cancer who have been treated with cetuximab therapy. Twenty-nine of these patients had metastatic tissue available for analysis. The level of EGFR protein expression in the patients was determined by immunohistochemistry and evaluated by H-score (HS) methodology. Progression-free survival (PFS) and overall survival (OS) of the patients were determined according to the EGFR-HS ranges of both the primary and metastatic tissues using Kaplan-Meyer statistics. In the case of primary tumors, EGFR scores lower than HS = 200 were associated with significantly longer OS. In the case of metastatic tissues, all levels lower than the EGFR-HS range chosen were associated with significantly longer OS. These results are explained by the fact that metastatic tissues rarely maintained the expression levels of the primary tumors. On the other hand, high EGFR expression levels in either primary tumors or metastatic tissues were associated with multiple metastatic disease. This suggests a negative prognostic role of EGFR expression. However, in a multivariate analysis, one-sidedness remained a strong independent predictive factor of survival. Previous studies demonstrated that the EGFR expression level depends on sidedness. Therefore, a subgroup analysis of the left- and right-sided cases was performed on both primary and metastatic tissues. In the case of metastic tissues, an analysis confirmed a better OS in low EGFR protein-expressing cases than in high EGFR protein-expressing cases. Collectively, these data suggest that EGFR protein expression is another negative predictive factor of the efficacy of cetuximab therapy of KRAS exon2 wild-type colorectal cancer.

First Line Sorafenib Treatment for Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis.

BACKGROUND: Medullary thyroid cancer (MTC) is a rare disease, the prognosis of advanced and metastatic disease is poor and few therapeutic options are available in this setting. Based on the results of phase II and III studies with sorafenib in differentiated thyroid cancer and the lack of availability of registered tyrosine kinase inhibitors, vandetabin and cabozantinib in Hungary, we designed a uncontrolled, prospective efficacy and safety study of patients with metastatic MTC treated with first-line sorafenib in five Hungarian oncology centers. METHODS: Ten consecutive patients with progressive or symptomatic metastatic MTC were included and started sorafenib 400  mg twice a day between June 2012 and March 2016. The primary end point was median progression-free survival (mPFS). Secondary endpoints included disease control rate, biochemical response, symptomatic response and toxicity. RESULTS: Four patients achieved partial remission (40%) according to RECIST 1.1 evaluation. Five patients had stable disease beyond 12 months (50%) and one patient had progressive disease (10%). Median PFS was 19.1 months. The disease control rate was 90%. Association between radiologic response and biochemical or symptomatic response was inconsistent. Most common side effects were Grade 1-2 fatigue (60%), palmar-plantar erythrodysesthesia, rash/dermatitis 50-50%, alopecia 40%. CONCLUSIONS: In our prospective case series in patients with MTC first-line sorafenib showed at least similar efficacy as in other small phase II trials and case reports. Based on comparable efficacy with registered tyrosine kinase inhibitors and it's manageable toxicity profile, we believe that sorafenib has role in the sequential treatment of MTC.

[Laparoscopic resection of a liver metastasis from segment VII. Case report]. / A máj VII-es szegmentumában igazolt áttéti daganat laparoszkópos reszekciója.

The technique and clinical results of liver surgery are constantly evolving in recent years, and this development felt most intensely in the field of laparoscopic liver surgery. Based on the results of comparative studies reported to date, laparoscopic surgery is not inferior to open surgery. Although a very small percentage of liver resections are performed with laparoscopic technique, clearly it has a role in oncological surgery. The minor, major, anatomical, or even multi-stage liver resections can be performed with laparoscopy. The previously general recommendation, that lesions in the front segments of the liver are recommended for the minimally invasive technique is currently outdated. The authors present the history of a 70-year-old female, who underwent complex oncosurgical treatment of a locally advanced rectum carcinoma and a pure laparoscopic resection of a solitary hepatic metastasis of segment VII. With this case report the authors want to underline that malignant lesions in the posterior segments of the liver can be removed safely with laparoscopy.

[Treatment of metastatic midgut neuroendocrine tumour associated with carcinoid syndrome]. / Carcinoid szindrómával társuló metasztatikus középbél-eredetu neuroendokrin tumor kezelése.

Although the incidence of neuroendocrine tumours is low, their prevalence is high due to the usually slow course of the disease. Between July 1, 2008 and July 1, 2013 the authors evaluated 56 patients with well-differentiated or moderately differentiated neuroendocrine tumours; 36 patients with metastatic disease underwent treatment while 17 patients who had tumour resection were followed without additional treatment. All patients with metastatic disease received long acting octreotide, and additional therapy was based on the site of origin, grade of differentiation, Ki67 index, and focal labelling of the tumours during somatostatin-receptor or metaiodo-benzyl-guanidine scintigraphy. The authors present a detailed case history of a patient with carcinoid syndrome due to a metastatic midgut neuroendocrine tumour, who received long acting octreotide and peptide receptor radionuclide treatment. In this patient an objective tumour response was reached in addition to the resolution of symptoms of carcinoid syndrome. The authors conclude that the case history confirms previous observations showing that long acting octreotide combined with peptide receptor radionuclide treatment may provide long survival with good quality of life in a patient with metastatic midgut neuroendocrine tumour accompanied with carcinoid syndrome. Orv. Hetil., 2014, 155(5), 194-198.

[Diagnosis and treatment options of neuroendocrine tumours]. / A neuroendokrin daganatok kórisméje és kezelésének irányelvei.

Neuroendocrine neoplasms belong to the group of rare tumours. Their clinical importance may be highlighted by their high prevalence despite low incidence. Since survival rate is similar to other progressive neoplastic diseases in metastatic cases, early recognition and appropriate therapy of these neoplasms are equally important. Classification of neuroendocrine tumours is based on their pathologic characteristics according to the 2010 WHO recommendation. Non-functioning tumours cause local symptoms due to their mass effect, while functioning tumours produce well-defined endocrine syndromes. Among laboratory tests, serum chromogranin-A is considered the most important biomarker of both non-functioning and functioning neuroendocrine tumours. Localization of these tumours includes the use of conventional diagnostic imaging, endoscopic examinations, and functional imaging studies. With respect to treatment, elimination of the primary tumour remains one of the most important issues. In advanced cases of the disease metastasectomy, interventional radiologic methods, medical treatment and endoradiotherapy can be used. The aim of this review is to summarize briefly the symptoms, diagnostic methods and treatment options of neuroendocrine tumours.

[Small bowel stromal tumors diagnosed by capsule endoscopy]. / Vékonybél-stromatumorok diagnózisa kapszulás endoszkópiával.

UNLABELLED: Small intestinal stromal tumors account for approximately 35% of all gastrointestinal stromal tumors. Gastrointestinal bleeding is considered as one of the main clinical symptoms for SISTs. Capsule endoscopy has brought revolution in small bowel diagnostics, as it is considered the best method of visualisation of the entire small intestine. Besides, it is well tolerated by patients and is accompanied by a low number of complications. It is also indicated as the first diagnostic method in gastrointestinal bleeding of obscure origin, following negative upper endoscopy and colonoscopy. CASE REPORT: 2 patients (a male and a female, aged 58 and 69, respectively) presented with obscure gastrointestinal bleeding have been examined by capsule endoscopy after negative upper endoscopy and colonoscopy. Videorecords have been assessed in both cases by two independent experts. The capsule reached the Bauchin-valve in both cases during the 8 hours of the testing time and the entire small bowel was clearly visible. - Based on the capsule endoscopic images, for one of the two cases a tumor has been reported as the background of the small intestinal bleeding. In the other case we could mark the location of the bleeding, while we were unable to ascertain the type of the actively bleeding lesion during the test. In order to determine the accurate bleeding source double-balloon enteroscopy was performed in the second case. After surgery the histological and immunohistochemical tests have justified the presence of spindle cell GISTs. Taking into consideration the Fletcher-classification, for the tumor size and the mitotic index, both cases can be classified as a GIST of low malignant potential. CONCLUSIONS: An early diagnosis and application of a definitive therapy become possible by using capsule endoscopy, therefore the chance of survival of the patients might be increased.

[Evaluation of diagnostic yield and clinical impact of capsule endoscopy in patients with obscure gastrointestinal bleeding]. / A kapszulás endoszkópia diagnosztikus értékének és klinikai kihatásának vizsgálata tisztázatlan eredetu gasztrointesztinális vérzésekben.

BACKGROUND AND AIMS: The major indication of small bowel capsule endoscopy is the diagnostics of obscure gastrointestinal bleeding. The present retrospective study was aimed to analyze the diagnostic yield, positive and negative predictive values and clinical impact of capsule endoscopy in patients with obscure gastrointestinal bleeding. PATIENTS AND METHODS: During a 36 month period at two workplaces 66 capsule endoscopy studies were performed in 62 patients with gastrointestinal bleeding who had undergone non-diagnostic upper endoscopy and colonoscopy. Capsule video recordings were evaluated by two investigators at both workplaces. Capsule endoscopy findings were divided into 3 groups according to the bleeding source: definitive bleeding source (48 patients), uncertain bleeding potential (5 patients), and negative finding (8 patient). Patients after capsule endoscopy were followed-up until a mean of 20 (1-41) months. RESULTS: A definitive small bowel bleeding source was detected in 78.7% of the cases studied by capsule endoscopy. Definitive bleeding sources included angiodysplasia (28 cases), small bowel Crohn's disease (5 cases), small bowel tumor (5 cases), small bowel stenosis (2 cases), NSAID therapy related ulcer (1 case), non-specific inflammation (1 case) and helminthiasis (1 case) respectively. The positive and negative predictive values of capsule endoscopy studies were 95.8% and 84.6% respectively. In cases with definitive bleeding sources 72% of patients received therapy in accordance with capsule endoscopy findings (surgery in 18 patients, medical treatment modification in 16 patients, chemoembolisation in 1 patient). During the follow-up period 17.7% of the patients had rebleeding. CONCLUSIONS: Capsule endoscopy is a useful and effective diagnostic method in cases with obscure gastrointestinal bleeding. Effective therapy may be introduced in accordance with the majority of positive capsule endoscopy results.