Molecular analysis of sunitinib resistant renal cell carcinoma cells after sequential treatment with RAD001 (everolimus) or sorafenib

Sequential application of target drugs is standard procedure after renal cell carcinoma (RCC) patients develop resistance. To optimize the sequence, antitumour effects of the mTOR inhibitor RAD001 or the tyrosine kinase inhibitor (TKI) sorafenib on RCC cells with acquired resistance to the TKI sunitinib was evaluated. RCC cells were exposed to 1 μM sunitinib for 24 hrs (as control) and for 8 weeks (to induce resistance) and then switched to RAD001 (5 nM) or sorafenib (5 μM) for a further 8 weeks. Tumour cell growth, cell cycle progression, cell cycle regulating proteins and intracellular signalling were then investigated. Short‐term application of sunitinib (24 hrs) induced cell growth blockade with accumulation in the G2/M phase. RCC cells became resistant to sunitinib after 8 weeks, demonstrated by accelerated cell growth along with enhanced cdk1, cdk2, loss of p27, activation of Akt, Rictor and Raptor. Switching to sorafenib only slightly reduced growth of the sunitinib resistant RCC cells and molecular analysis indicated distinct cross‐resistance. In contrast, full response was achieved when the cancer cells were treated with RAD001. p19 and p27 strongly increased, phosphorylated Akt, Rictor and Raptor decreased and the tumour cells accumulated in G0/G1. It is concluded that an mTOR‐inhibitor for second‐line therapy could be the strategy of choice after first‐line sunitinib failure.     

Serious gastric perforation after second stereotactic body radiotherapy for peripheral lung cancer that recurred after initial stereotactic body radiotherapy: a case report

Background

In recent reports, re-irradiation with stereotactic body radiotherapy for lung tumors in patients previously treated with thoracic radiation therapy resulted in several serious toxicities. Serious non-lung toxicities were observed mostly in patients with central tumors, but we experienced a case of fatal gastric perforation after a second stereotactic body radiotherapy in a patient with a peripheral lung tumor.

Case presentation

An 83-year-old Asian man was diagnosed with T2N0M0 lung cancer in the form of squamous cell carcinoma in the lower lobe of his left lung. He was treated with stereotactic body radiotherapy of 40 Gy in 4 fractions and the tumor decreased in size in partial response. The local tumor recurred 8 months after the first stereotactic body radiotherapy, and he was re-irradiated with a second stereotactic body radiotherapy of 50 Gy in 4 fractions. A Sengstaken–Blakemore tube was inserted below his diaphragm by laparoscopic surgery before the second stereotactic body radiotherapy in order to reduce the stomach dose by keeping his stomach apart from the tumor. Two months after the second stereotactic body radiotherapy, he developed fatal gastric perforation and gastropleural fistula penetrating his diaphragm.

Conclusions

To the best of our knowledge, this is the first report about a gastric perforation after stereotactic body radiotherapy for lung tumors and it warns of serious complication of stereotactic body radiotherapy in not only centrally located but also peripherally located tumors like in this case.

     

Interleukin-6 (IL-6) and C-reactive protein (CRP) concentration prior to total nephrectomy are prognostic factors in localized renal cell carcinoma (RCC)

Background

Radical nephrectomy is the gold standard for treatment of renal cell carcinoma (RCC), but even for localized disease the survival rates are still unsatisfactory. Identification of prognostic factorsl is the basis for future treatment strategies for an individual patient.

Aim

The aim of our study was to assess the usefulness of the concentration of IL-6 and CRP as prognostic factors in patients after nephrectomy due to localized RCC.

Materials and methods

Our prospective study included 89 patients (55 men and 34 women) who had been surgically treated for RCC. The examined group included patients with localized advanced disease (from T1 to T3) with no metastases in lymph nodes (N0), and with no distant metastases (M0). All patients had blood samples drawn three times during the study (one day before surgery, six days after surgery and 6 months after surgery) to evaluate the concentration of CRP and IL-6. In each patient RCC of the kidney was removed during radical nephrectomy. Statistical analysis was conducted using statistica v.7.0.

Results

Statistically significant relationships were found between the concentration of CRP before the operation and OS (p = 0.0001). CRP concentration at baseline was statistically significantly correlated with CSS (p = 0.0004). The level of IL-6 assessed before the surgery was significantly correlated with survival times such as OS (p = 0.0096) and CSS (p = 0.0002). The concentration of IL-6 and CRP measured 6 days after surgery and 6 months after surgery were not statistically significantly correlated with survival times.

Conclusions

Results of our study showed that elevated levels of IL-6 and CRP in peripheral blood before surgery of RCC were correlated with worse OS and CSS.     

Langerhans cell sarcoma: Response to radiotherapy

We present the case of a patient with progressive Langerhans cell sarcoma whose cutaneous lesions and nodal masses were treated with palliative radiotherapy. Response to relatively low doses of radiotherapy was both good and sustained. We recommend a dose of 15–30 Gy depending on treatment intention and volume of the lesions.     

Napromienianie dwa razy dziennie podwyższoną dawką frakcyjną chorych z przerzutami nowotworów złośliwych do mózgu. Wyniki końcowe prospektywnego badania klinicznego w nierandomizowanej grupie chorych

AimTo evaluate the morbidity and effectivness of twice a day hypofractionation in patients with brain metastases.Material / methodsBetween 1992 and 2000, 116 patients with brain metastases have been treated with whole brain radiotherapy alone and only in 33 patients radiotherapy was applied as adjuvant treatment after surgery. Radiotherapy was given in two of 3 Gy fractions daily with minimum 6 hours intervals between fractions to total dose of 39 Gy. Mean age of treated patients was 55 years. All patients were in general performance status evaluated according to the Karnofsky Performance Scale of at least 50.ResultsEarly tolerance of treatment was acceptable. Of 116 patients only 20 patients were treated with supportive treatment (anti-oedema drugs). Improvement of the neurological status was obtained in 26 patients (22%). The one-year overall survival was 21%. The one–year survival without clinical progression of disease was observed in 10% of all treated patients. Patients with solitary brain metastases treated with surgery and radiotherapy showed the best results.ConclusionsOur results showed that twice a day hypo-fractionation radiotherapy for patients with brain metastases is well tolerated and may provides benefit.     

Clinical Impact of Pancreatic Metastases from Renal Cell Carcinoma: A Multicenter Retrospective Analysis

Pancreatic metastases from renal cell carcinoma are uncommon and their prognostic significance is not well defined. In this analysis we evaluated the outcome of patients with pancreatic metastases treated with either targeted therapies or local treatment to the pancreas. Patients with pancreatic metastases from renal cell carcinoma treated between 1993 and 2014 were identified from 11 European centers. Clinical records were retrospectively reviewed. Kaplan-Meier method and log-rank test were used to evaluate progression-free survival and overall survival. Cox’s proportional hazard models were used for survival analysis. In total, 276 PM patients were evaluated, including 77 (28%) patients treated by either surgery or radiotherapy to the pancreas, and 256 (93%) who received systemic therapy. Median time from nephrectomy to diagnosis of pancreatic metastases was 91 months (IQR 54–142). Disease control rate after first-line TTs was 84%, with a median progression-free survival of 12 months (95% CI 10–14). Median overall survival was 73 months (95% CI 61–86) with a 5-year OS of 58%. Median OS of patients treated with local treatment was 106 months (95% CI 78–204) with a 5-year overall survival of 75%. On multivariable analysis, nephrectomy (HR 5.31; 95%CI 2.36–11.92; p<0.0001), Memorial Sloan Kettering/International Metastatic RCC Database Consortium prognostic score (HR 1.45, 95% CI 0.94–2.23 for intermediate vs good vs risk; HR 2.76 95%, CI 1.43–5.35 for poor vs good risk p = 0.0099) and pancreatic local treatment (HR 0.48; 95%CI 0.30–0.78 p = 0.0029) were associated with overall survival. Difference in median OS between patients with PM and that reported in a matched-control group of mRCC patients with extrapancreatic metastases was statistically significant (p < .0001). Pancreatic metastases from renal cell carcinoma usually occur years after nephrectomy, are associated with an indolent behavior and a prolonged survival. Targeted therapies and locoregional approaches are active and achieve high disease control rate.     

Central nervous system metastasis from osteosarcoma: Case report and literature review

Osteosarcoma is the most common primary malignancy of bone in children and young adults, the highest incidence peak is during adolescence and doesn’t have any gender predominance. The main site of metastasis are the lungs and extrapulmonary cases are occasional. The incidence of metastasis in the Central Nervous System (CNS) is 2–6.5%, increase to 10–15% in patients with pulmonary metastases. Therefore, metastatic disease of the CNS is rare and the information on such patients is limited. Here, we describe a case of a 20-year old patient diagnosed with osteosarcoma in the left distal femur stage IIB, he developed pulmonary disease, during palliative chemotherapy experienced relapse to the brain classified as recursive partitioning analysis (RPA) class II, and was treated with external radiotherapy (30?Gy in 10 fractions) and later he had a poor evolution and died.     

Treatment with sorafenib in advanced thyroid cancer - a case report

Papillary thyroid cancer (PTC) usually has a good prognosis. The treatment, including total thyroidectomy and complementary radioiodine (RAI) therapy, gives complete remission in 90% of patients. However, in 10% of subjects with metastatic disease, the prognosis is poor. In the group of patients with disease progression and no 131I uptake, searching for new therapeutic modalities before all tyrosine kinase inhibitors and other antiangiogenic agents is necessary. The study presents the case of a 55-year-old male with advanced PTC /pT3mNxMo/ diagnosed in 1993. Primary treatment by total thyroidectomy and 131I ablation led to complete remission. In 2000 local as well as lymph node recurrence was diagnosed and successively treated by surgery. In 2006 an increasing serum thyroglobulin level was noted and a single lung metastasis was diagnosed and operated on. In 2007 new foci in CNS and vertebral column with no 131I uptake were stated. Further progression (bones, CNS, and pterygoid muscle) was confirmed by PET-CT. The patient underwent neurosurgical metastasectomy twice and palliative CNS and vertebra's radiotherapy. Liver metastases were diagnosed in 2009. Treatment with increasing doses of thalidomide (up to 800 mg/d) was administered for 3 months with a good tolerance; however, the therapy was withdrawn due to cancer progression. Next, sorafenib (800 mg/d) was given for 16 weeks. Radiological examination performed after 16 weeks confirmed stable disease, whereas 2 months later, after sorafenib withdrawal due to lack of treatment possibility, further progression was observed. Metronomic chemotherapy with Adriamycin was instituted which gave disease stabilization for 6 months. The patient died with advanced disseminated disease due to pulmonary embolism. We present this case to document no adverse effects of therapy with sorafenib in a patient with brain DTC metastases. Sorafenib therapy was only short-term, but no progression occurred in this time.     

Factors affecting survival after palliative radiotherapy in patients with lung cancer

BackgroundLung cancer is the most common cancer worldwide. It is estimated that 60% of patients with NSCLC at time of diagnosis have advanced disease. The aim of this study was to identify factors that play a major role in the survival of lung cancer patients treated with palliative radiotherapy.Materials and methodsWe retrospectively reviewed data of 280 lung cancer patients treated with palliative radiotherapy from January 2013 to December 2017. A multivariate analysis using the proportional hazards model of Cox was conducted. Also, Kaplan Meier curves were used to describe the distribution of survival times of the patients. The level of significance was set at 0.05.ResultsThe mean age at diagnosis was 65.6 years. About 77.5% of patients were male and 22.5% were female. In our cohort > 95% had stage 4 lung cancer. Most cases were adenocarcinomas (72.5%) and ECOG-PS 0–1 (80.4%). Different sites were submitted to palliative treatment: 120 brain metastases, 96 bone metastases, 53 lung tumour, 8 lymph nodes and 3 lung metastases. Brain as first site of palliative radiotherapy (HR: 1.553, 95% CI: 1.167–2.067, p = 0.003) and ECOG-PS 2–3 compared with ECOG-PS 0–1 (HR: 2.253, 95% CI: 1.546–3.283, p ≤ 0.001) were associated with increased likelihood of lung cancer death. Patients who received biological therapy had 70.7% (p ≤ 0.001) reduction in lung cancer death risk.ConclusionBrain as the first metastatic site treated with radiotherapy and ECOG-PS 2–3 are associated with increased lung cancer death. Biological therapy was associated with decreased death risk.     

Sorafenib Neoadjuvant Therapy in the Treatment of High Risk Renal Cell Carcinoma

ObjectiveTo evaluate the clinical efficacy of sorafenib as preoperative neoadjuvant therapy in patients with high risk renal cell carcinoma (RCC).ResultsAmong the 18 patients there were 13 male and 5 female, with a median age of 54.6 years. The objective response rate (ORR) of the operation on the selected patients is very high (94.4%), including 4 cases (22.2%) of partial response (PR) and 13 cases (72.2%) of stable disease (SD). After preoperative sorafenib treatment, the average tumor size of the 18 patients decreased from 7.8 cm (ranging from 3.6 to 19.2 cm) to 6.2 cm (ranging from 2.4 to 16.8 cm), and the median value of average tumor CT value decreased from 61HU to 52 HU. Among the 5 patients who had IVC tumor thrombi, the grades of tumor thrombi in 2 patients who were grade II before sorafenib treatment became grade I and grade 0 respectively, 2 patients of grade III both became grade II.ConclusionPreoperative neoadjuvant therapy with sorafenib for high risk RCC patients can significantly decrease primary tumor volume as well as tumor thrombus, which could help the nephron-sparing surgery (NSS) or radical nephrectomy to be done successfully.     

Nasopharyngeal mucoepidermoid carcinoma: A case report and review of literature

Background

Salivary gland-type tumors originating in the nasopharynx are rare, and only a few articles about mucoepidermoid carcinomas (MEC) in this location have been reported. We describe one case of nasopharyngeal MEC and, based on a review of the literature, discuss different therapeutic approaches that can be taken regarding the result of histological findings, radiological tests and extent of disease.

Case presentation

A 47-year-old woman diagnosed with mucoepidermoid carcinoma of nasopharynx, T1 N3 M0 (stage IV-B) was treated in 2007 with a combination of radiotherapy and chemotherapy to a maximum dose of 70 Gy and concomitant Cisplatin during the radiation. One year later, with the head and neck disease under control, mediastinal nodes relapse appeared which were treated with exclusive radiotherapy to a maximum dose of 65 Gy. One year after the first relapse, a second relapse was detected in the right lung, next to the previously treated mediastinal regions, and the patient initiated a treatment with exclusive chemotherapy based on TPF scheme.

Conclusion

For limited or resectable MEC, combined surgery with radiotherapy, or radiochemotherapy, should be considered the main treatment policy. On the other hand, in poorly differentiated, unresectable tumors or nasopharyngeal MEC, radiochemotherapy could be currently the main treatment approach.     

Incidence of hospitalization in patients receiving short course palliative cranial radiotherapy on outpatient basis in a limited resource setting – Experience from a regional cancer center in India

AimTo investigate incidence of toxicity and related hospitalization among patients treated at our institute by a short course of palliative cranial radiotherapy against a longer, widely established schedule.BackgroundShorter schedule palliative cranial radiotherapy is more convenient for patients and reduce waiting times. Although many studies have established safety of short schedules, the need for hospitalization due to acute treatment toxicity remains under-explored. Hospital admissions are an economic burden both for the patient and healthcare system in a limited resource setting. Delivery of treatment on an outpatient basis and within shorter times is preferred by patients, caregivers and healthcare staff.Materials and methodsThis was a prospective study on 68 patients treated with palliative whole brain radiotherapy between November 2010 and October 2012. One group received 20 Gy in 5 fractions over 1 week and the other group, 30 Gy in 10 fractions over 2 weeks. Treatment toxicity due to cranial radiotherapy was assessed as per RTOG acute and late toxicity criteria. Need for hospitalization owing to acute toxicity was also noted. Significant differences in the study parameters between the two groups were calculated by Fisher's t-test.ResultsRequirement for hospital stay due to acute toxicity was not significantly different between the two groups. Patients in both groups experienced similar toxicity both during and after treatment.ConclusionsThe shorter course entailed no significant increase in toxicity related admissions, suitable for limited resource settings where patient transport is difficult, there are financial constraints, and the healthcare system is overburdened.     

Use of 5-fluorouracil, bleomycetin and platidiam in combined treatment of localized cancer of the larynx]

Preliminary results of chemoradiotherapy in 30 patients with the larynx cancer T3T4N0M0 are presented. Two treatment schemes were applied. According to scheme I, the treatment was started with chemotherapy with 5-fluorouracil in doses of 1000 mg on days 1, 2 and 3, bleomycetin in doses of 15 mg on days 1, 2 and 3 and platidiam in doses of 120 mg/m2 on day 4 followed by radiotherapy to the total dose of 66 to 70 Gy. Scheme II included two analogous courses of the chemotherapy, one prior to the radiotherapy and the other after irradiation in a dose of 38 to 40 Gy, after a two-week interval the radiotherapy was continued to doses of 66 to 70 Gy. 15 patients were treated in accordance with each scheme. Complete resorption of the tumor was observed in 66.6 and 83.3 per cent of the patients treated according to schemes I and II, respectively. The results showed that the use of 5-fluorouracil, bleomycetin and platidiam in combination with radiotherapy was promising in treatment of patients with local cancer of the larynx.     

TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC

TOPK/PBK (T-LAK Cell-Originated Protein Kinase) is a serine/threonine kinase that is highly expressed in a variety of human tumors and is associated with poor prognosis in many types of human malignancies. Its activation mechanism is not yet fully understood. A bidirectional signal transduced between TOPK and ERK2 (extracellular signal-regulated kinase 2) has been reported, with ERK2 able to phosphorylate TOPK at the Thr9 residue. However, mutated TOPK at Thr9 cannot repress cellular transformation. In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2. Phospho-TOPK (S32) was found to be involved in the resistance of renal cell carcinoma (RCC) to sorafenib. Herein, combined a TOPK inhibitor with sorafenib could promoted the apoptosis of sorafenib-resistant RCC. High expression of HGF/c-met contributes to activation of p-TOPK (S32) during the development of sorafenib resistance in RCC. The current research presents a possible mechanism of sorafenib resistance in RCC and identifies a potential diagnostic marker for predicting sorafenib resistance in RCC, providing a valuable supplement for the clinically targeted treatment of advanced RCC.Subject terms: Predictive markers, Renal cancer     

Muscle-invasive bladder cancer treated with TURB followed by concomitant boost with small reduction of radiotherapy field with or without of chemotherapy

Aim

To evaluate the clinical outcome and toxicity of the treatment of muscle-invasive bladder cancer (MIBC) that combined transurethral resection of bladder tumor (TURB) with “concomitant boost” radiotherapy delivered over a shortened overall treatment time of 5 weeks, with or without concurrent chemotherapy.

Background

Local control of MIBC by bladder-sparing approach is unsatisfactory. In order to improve the effectiveness of radiotherapy, we have designed a protocol that combines TURB with a non-conventionally fractionated radiotherapy “concomitant boost”.

Materials and methods

Between 2004 and 2010, 73 patients with MIBC cT2-4aN0M0, were treated with “concomitant boost” radiotherapy. The whole bladder with a 2–3 cm margin was irradiated with fractions of 1.8 Gy to a dose of 45 Gy, with a “concomitant boost” to the bladder with 1–1.5 cm margin, during the last two weeks of treatment, as a second fraction of 1.5 Gy, to a total dose of 60 Gy. Radiochemotherapy using mostly cisplatin was delivered in 42/73(58%) patients, 31/73(42%) patients received radiotherapy alone.

Results

Acute genitourinary toxicity of G3 was scored in 3/73(4%) patients. Late gastrointestinal toxicity higher than G2 and genitourinary higher than G3 were not reported. Complete remission was achieved in 48/73(66%), partial remission in 17/73(23%), and stabilization disease in 8/73(11%) patients. Three- and five-year overall, disease specific and invasive locoregional disease-free survival rates were 65% and 52%, 70% and 59%, 52% and 43%, respectively.

Conclusions

An organ-sparing approach using TURB followed by radio(chemo)therapy with “concomitant boost” in patients with MIBC allows to obtain long-term survival with acceptable toxicity.     

The role of radiotherapy in the prevention of recurrence and central nervous system metastases in childhood medulloblastoma

PURPOSE: To present the postoperative radiotherapy technique in children with medulloblastoma, and analyse the effectiveness of radiotherapy and the survival data. MATERIALS AND METHODS: 66 consecutive children (45 male and 21 female) received postoperative chemotherapy and radiotherapy between 1986 and 1998. The mean age was 8.3 years. The radiotherapy was performed with linear accelerator 9MV X-ray irradiation. The high risk patients received 36 Gy craniospinal irradiation, the low risk patients recived 30 Gy. The boost irradiation to the posterior fossa was 20 Gy in both patient groups. The patients received multi-drug chemotherapy immediately after the tumor resection. The radiotherapy started 6-8 weeks after the operation. RESULTS: All 66 patients were evaluated. The mean follow-up time was 45.4 months. The chance of cure is higher at age 8 or more, and less favorable under age 8. After 60 months 68.6% of children under age 8 and 75.9% older than 8 are alive. 20 children (64.5%) are alive after radical tumorectomy and 11 died. The 5 year overall survival was 71%. Recurrence was observed in 23/66 cases, it was the most frequent cause of death. Local failure was in posterior fossa in 15 patients (68.2%). CONCLUSION: The radicality of operation had no significant influence to the overall survival. The tumor stage, age of patients, risk group and metastases are important prognostic factors.     

Radiotherapy alone as a method of treatment for sinonasal mucosal melanoma: A report based on six cases and a review of current opinion

Objectives

Radiotherapy in patients with sinonasal mucosal melanoma (SNMM) was given as alternative treatment to surgery in cases with advanced, inoperable tumors or those not eligible for surgery. We presented the outcomes for patients with SNMM treated with radiotherapy alone.

A case report of an ampullary tumor presenting with spontaneous perforation of an aberrant bile duct and treated with totally laparoscopic pancreaticoduodenectomy

ABSTRACT: BACKGROUND: This case report discusses a patient who presented with bile peritonitis due to spontaneous perforation of an aberrant bile duct that originated in the triangular ligament of the liver. It was associated with an ampullary tumor and treated with total laparoscopic pancreaticoduodenectomy (TLPD). Case report A 58-year-old male patient was admitted to the emergency department of Medical Park Gaziantep Hospital in September 2009 with acute abdominal findings. He underwent an urgent laparoscopy, and, interestingly, bile peritonitis due to the rupture of an aberrant bile duct in the triangular ligament was noted. After laparoscopic treatment of the acute conditions, the follow-up examinations of the patient showed the finding of obstructive jaundice. Endoscopic retrograde cholangio-pancreatography revealed a 1-cm polypoid mass located at the ampulla of Vater (duodenal papilla) with possible extension to the ampullary sphincter. A stent was inserted for temporary biliary drainage, and subsequent endoscopic biopsy showed the pathological finding of adenocarcinoma. After waiting for a 1-month period for the peritonitis to heal, the patient underwent pyloruspreserving TLPD and was discharged without any major complications on postoperative day 7. CONCLUSION: In patients with bile peritonitis, it should be considered that the localization of the perforation may be in an aberrant bile duct localized at the triangular ligament and the etiology may be associated with an obstructing periampullary tumor. Laparoscopic pancreaticoduodenectomy is a feasible operative procedure in carefully selected patients. This technique can achieve adequate margins and follows oncological principles. Randomized comparative studies are needed to establish the superiority of minimally invasive surgery over traditional open surgery.