Comprehensive tumor molecular profile analysis in clinical practice.

BACKGROUND: Tumor molecular profile analysis by Next Generation Sequencing technology is currently widely applied in clinical practice and has enabled the detection of predictive biomarkers of response to targeted treatment. In parallel with targeted therapies, immunotherapies are also evolving, revolutionizing cancer therapy, with Programmed Death-ligand 1 (PD-L1), Microsatellite instability (MSI), and Tumor Mutational Burden (TMB) analysis being the biomarkers employed most commonly. METHODS: In the present study, tumor molecular profile analysis was performed using a 161 gene NGS panel, containing the majority of clinically significant genes for cancer treatment selection. A variety of tumor types have been analyzed, including aggressive and hard to treat cancers such as pancreatic cancer. Besides, the clinical utility of immunotherapy biomarkers (TMB, MSI, PD-L1), was also studied. RESULTS: Molecular profile analysis was conducted in 610 cancer patients, while in 393 of them a at least one biomarker for immunotherapy response was requested. An actionable alteration was detected in 77.87% of the patients. 54.75% of them received information related to on-label or off-label treatment (Tiers 1A.1, 1A.2, 2B, and 2C.1) and 21.31% received a variant that could be used for clinical trial inclusion. The addition to immunotherapy biomarker to targeted biomarkers' analysis in 191 cases increased the number of patients with an on-label treatment recommendation by 22.92%, while an option for on-label or off-label treatment was provided in 71.35% of the cases. CONCLUSIONS: Tumor molecular profile analysis using NGS is a first-tier method for a variety of tumor types and provides important information for decision making in the treatment of cancer patients. Importantly, simultaneous analysis for targeted therapy and immunotherapy biomarkers could lead to better tumor characterization and offer actionable information in the majority of patients. Furthermore, our data suggest that one in two patients may be eligible for on-label ICI treatment based on biomarker analysis. However, appropriate interpretation of results from such analysis is essential for implementation in clinical practice and accurate refinement of treatment strategy.

End-of-study results of Turkish gastric cancer patients from the global REGATE study.

PURPOSE: Registry of Gastric Cancer Treatment Evaluation (REGATE) study was an international, prospective study including over 10000 patients from 22 countries, designed to describe the pattern of care in gastric cancer globally. The aim of this study was to summarize the data of the Turkish arm and compare them with the global results. METHODS: Ten centers from Turkey took part in the REGATE registry. Between 2004 and 2008, 395 patients (median age, 60 years; range, 18-91, 67.6% men) with newly diagnosed primary adenocarcinoma of the stomach were followed at initial visit and 8-10 months later, at the time of treatment completion. Data on patient demographics, medical history, histopathology, cancer stage, planned and realized treatments was prospectively collected. Data processing and analysis were conducted centrally. RESULTS: In Turkey, the majority of patients were diagnosed at an advanced stage, while the rate of surgery was lesser compared with the rest of the world. Realized treatment included more palliative-only therapy than initially planned (63.3%), while no therapy was recommended in 21.8%. Surgery involved total gastrectomy (46.3%) or distal subtotal gastrectomy (51.9%), with 87% R0 resection, 51.0% D1 and 44.9% D2 lymph node dissection. Combination chemotherapy was administered in more than half of the patients receiving palliative therapy (57.9%). Chemoradiotherapy was used in 66.7% of the cases receiving adjuvant therapy. Radiotherapy was applied to 32% of the cases receiving palliative therapy. CONCLUSION: Advanced stage gastric cancer is highly prevalent in Turkey. Increasing public awareness and implementing screening programs in high risk groups may help identify gastric cancer at earlier stages.

An investigation of the effects of FGFR2 and B7-H4 polymorphisms in breast cancer.

INTRODUCTION: Polymorphisms in FGFR2 are important markers for breast cancer susceptibility in the general population. CHEK2 and FGFR2 polymorphisms with known susceptibility alleles of BRCA1, BRCA2, PTEN, and TP53, can be investigated as potential modifiers of high penetrant risk alleles. Although the B7-H4 gene is highly expressed in many different tumors, there is one published study showing the association of polymorphisms with breast cancer. We aimed to investigate FGFR2 and B7-H4 polymorphisms in breast cancer in the Turkish community. MATERIALS AND METHODS: In a group of 31 cases diagnosed with breast cancer and 30 healthy women with matched ages, the single-nucleotide polymorphisms (SNPs) rs1219648, rs2981582 in FGFR2 gene were identified by sequence analysis and the SNPs rs10754339, rs10801935, and rs3738414 in the B7-H4 gene were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Statistical analysis was performed using SPSS. RESULTS: Although statistically not significant, the frequency of FGFR2 heterozygous polymorphisms in the group with breast cancer was detected to be higher. In the B7-H4 SNP rs10801935, polymorphic AA, and AG genotype distributions were found in higher frequencies in the breast cancer patients. In contrast to the results of a published study, the present study shows that B7-H4 rs3738414 polymorphism GG genotype was found in higher frequency in the control group than the breast cancer group and the result was statistically significant (P=0.018). CONCLUSION: Larger scale studies are necessary to determine the prevalence of these polymorphisms and association with breast cancer in Turkish community, as this study is the first study performed.

Erythropoietin against cisplatin-induced peripheral neurotoxicity in rats.

Cisplatin (CDDP) is a potent anticancer drug, and neurotoxicity is one of its most important dose-limiting toxicities. In this study we investigated the role of recombinant human erythropoietin (rhuEPO) for protection against CDDP-induced neurotoxicity. All experiments were conducted on female Wistar-albino rats. Animals were randomly assigned to three groups. Group A received only CDDP, group B received CDDP plus rhuEPO, and group C received only rhuEPO. Electroneurography (ENG) was done in the beginning and at the end of 7 wk, then the rats were sacrificed and the sciatic nerve was removed for histopathological examination. The mean initial latency was 2.7438 ms in group A, 2.4875 ms in group B, and 2.62 ms in group C. After 7 wk of treatment, the latency was 2.4938, 2.6313, and 2.3900 ms, respectively. The difference in latencies was not statistically significant. The amplitude of compound muscle action potential (CMAP) was 12.8125 mV, 14.3875 mV, and 14.5600 mV before the treatment and 8.4875, 12.8250, and, 13.0800 mV after treatment, respectively. Amplitude of CMAP was significantly greater in rhuEPO-treated groups (groups B and C) compared to cisplatin only Group A. The mean area of CMAP was 12.2625, 12.3500, and, 12.2800 mV s before the treatment and 5.7125, 10.6463, and 9.1600 mV s after the treatment, respectively. The area of CMAP was significantly larger in rhuEPO-treated groups. In histopathological studies thick, thin, and total number of nerve fibers were 4053, 5050, and 9103, in group A, 5100, 8231, and 13331, in group B, and 5264, 6010, and 11274, in group C respectively. In the microscopic examination active myelinization process was observed in rhuEPO-treated groups. We concluded that at the given dose and schedule CDDP-induced motor neuropathy and rhuEPO prevented this neuropathy by sparing the number of normal nerve fibers and by protecting the amplitude and area of CMAP. We concluded that rhuEPO may also play a role in active myelinization and it is an active agent in protection against CDDP-induced peripheral neuropathy, warranting further clinical studies.

Protection against cisplatin-induced nephrotoxicity by recombinant human erythropoietin.

Cisplatin (CDDP) is a potent nephrotoxin, and nephrotoxicity is its most important dose-limiting toxicity. In this study, we aimed to investigate the role of recombinant human erythropoietin (rhEPO) in the protection of cisplatin-induced nephrotoxicity and compare its efficacy with the cell-protective agent amifostine. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to four groups, each including six rats. Group A received only CDDP, group B received CDDP plus rhEPO, group C received CDDP plus amifostine, and group D received only rhEPO. At the end of 7 wk, hemoglobin (Hgb), hematocrite (Htc), blood urea nitrogen (BUN), and creatinine (Cr) levels were determined and kidneys of the rats were removed. The weights of the kidneys were measured and sent for histopathological examination. Proximal tubules from four areas of the kidney (outer cortex, inner cortex, the medullary ray, and outer stripe of outer medulla [OSOM]) were evaluated. There were statistically significant differences among the groups in terms of tubular scores, including overall renal tubular score, cortex, inner cortex, OSOM, and medullary ray tubular scores, and Htc levels. Group A rats had the worse tubular scores in all categories when compared to group D rats. When the results of groups B and C were compared, there were no differences in terms of BUN, Cr levels, and tubular scores, but the Htc level was significantly higher in group B. Group B rats had better overall and OSOM tubular scores when compared to group A. Group C also had better overall and OSOM tubular scores compared to group A. The present study showed for the first time that rhEPO plays an important role in the prevention of cisplatin-induced nephrotoxicity and it is as effective as amifostine.

Protective effect of amifostine against cisplatin-induced motor neuropathy in rat.

Cisplatin (CDDP) is a potent anticancer drug. Neurotoxicity is one of the most important dose-limiting toxicity of CDDP. We investigated the role of amifostine in the protection against CDDP-induced neurotoxicity especially on the motor nerves. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to two groups, each including six rats. Group A received CDDP plus amifostine and Group B received CDDP only. Electroneurography (ENG) was carried out in the beginning and at the end of 7 wk; then, the rats were sacrificed and the sciatic nerve was removed for histopathological examination. The mean initial latency was 2.4667 msn for group A and 2.44833 msn for group B. After 7 wk of treatment, the latency was 2.9167 for group A and 2.6333 for group B. The difference in latencies was not statistically significant. The amplitude was 11.7853 mV and 13.533 mV for groups A and B, respectively. After 7 wk of treatment, the amplitude was 9.400 mV and 9.000 mV, respectively. The decrease of amplitude in compound muscle action potential (CMAP) was 20% in the amifostine group and the decrease was 33% in the untreated group. The mean area of the CMAP in group A was 9.400 mVsn initially and 9.666 mVsn at the end of the treatment; there was a 0.3% increase despite CDDP treatment. In group B, the mean area of the CMAP was 13.816 mVsn initially and 11.857 mVsn at the end of the treatment; this corresponded to a statistically significant 14% decrease as a result of CDDP treatment. The ENG and histopathological studies showed that at the given dose and schedule CDDP-induced motor neuropathy and amifostine reduced this neuropathy both by protection of the amplitude and area of the CMAP in ENG studies and by sparing a larger number of nerve fibers.

Thrombotic thrombocytopenic purpura associated with ticlopidine.

Thrombotic thrombocytopenic purpura is a syndrome characterized by hemolytic anemia, thrombocytopenia, neurological symptoms, fever and renal dysfunction. Although the syndrome is usually associated with various infections, vasculitis and pregnancy, rarely can it be associated with certain neoplasms and drugs such as ticlopidine. A 63-year-old woman, who had undergone coronary angioplasty and had been started on ticlopidine, was admitted to our clinic with a history of vomiting, fatigue, hematuria and deterioration in her cognitive abilities. Thrombotic thrombocytopenic purpura was diagnosed on the basis of neurological changes, an increase in LDH, urea, creatinine, indirect bilirubin levels, anemia and peripheral smear findings. Treatment was initiated with daily plasmapheresis and complete clinical and laboratory recovery developed. The patient was discharged after 14 days.

Comparison of radiation-induced oral mucositis scoring systems.

BACKGROUND: A number of oral toxicity scoring systems have been described, but their direct comparison has rarely been undertaken and little data exists. An impediment to mucositis research has been the lack of an accepted, validated scoring system. The objective of this study was to design a test and validation of scoring systems. MATERIALS AND METHODS: Forty-three patients with head and neck malignancies who had been irradiated were evaluated. Five different mucositis scoring systems (World Health Organization, Radiation Therapy Oncology Group, "Hickey", "Van der Schueren" and "Makkonen") were compared with each other. RESULTS: Daily mucositis scores demonstrated a high correlation among scoring systems (P < 0.05 and coefficient of correlation kappa and r = 0.5-0.95). Objective mucositis scores demonstrated a strong correlation with symptoms. CONCLUSIONS: All scoring systems were equally valid. The exact grading of mucositis is achieved by combining clinical information about pain and nutritional status with oral mucosal reactions.

Muscle metastasis as initial manifestation of epidermoid carcinoma of the lung.

Typical sites of squamous cell carcinoma of lung metastases include liver, brain, bones, pulmonary and adrenal glands. In advanced dissemination it can rarely involve the skeletal muscle. The patient in this case report was a 46-year-old man, with no significant medical history. He was admitted to hospital because of a large swelling on his left thigh. Investigations resulted in a diagnosis of primary squamous cell carcinoma of the lung. Biopsy of the left great adductor muscle produced similar pathology to that of the lung primary. This case report describes a skeletal muscle metastasis as the first sign of metastatic disease.

Acute myeloblastic leukemia achieving complete remission with amifostine alone.

Amifostine, a phosphorylated thiol-amine, is known as a cytoprotective agent especially for cisplatin containing chemotherapies. Apart from the cytoprotective role, Amifostine could also be used in the treatment of hematologic malignancies such as myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML), as a treatment option or for potentiating the effects of cytotoxic agents. We tried to use Amifostine in a patient with AML, which did not respond to conventional cytotoxic chemotherapy and aimed to publish the results. The patient was a 77-year-old male patient, he was diagnosed as AML by peripheral blood smear and bone marrow aspiration. Treatment commenced with low dose cytosine arabinoside (Ara-C) but the therapy should have ceased due to patient intolerance. The patient refused further therapy and he was offered to have Amifostine treatment. Amifostine was administered 200 mg/m2 three times a week, with ciprofloxacin, pentoxifyllin and dexamethasone. Dramatic response was obtained after 8 weeks of administration. Blast rate was reduced from 35 to 7% in bone marrow aspiration; pancytopenia was restored to normal levels. This remission was maintained through 8 more weeks. Amifostine treatment was restarted after he relapsed but this time he did not respond to the treatment and died of gastrointestinal bleeding on the 8th week of treatment.

A Case Report: Large Granular Cell Leukemia/Lymphoma (LGL).

We presented a 64-year-old male patient with T-large granular cell leukemia/lymphoma with an agressive clinical course. Large granular lymphocytes were noted on peripheral blood smear. The phenotyping of the cells was typical T-cell lineage [CD2 (+), CD3 (+), CD5 (+)]. Clonal rearrangement of the T-cell receptor gene (TCR) was demonstrated by DNA hybridization technique. Large granular cell leukemia/lymphoma is a distinct entity with spesific clinicobiological aspects. The clinical spectrum is wide and immunophenotyping and genotyping studies need to make a diagnosis.