Safety, Efficacy and Pharcacokinetics of Targeted Therapy with The Liposomal RNA Interference Therapeutic Atu027 Combined with Gemcitabine in Patients with Pancreatic Adenocarcinoma. A Randomized Phase Ib/IIa Study.

BACKGROUND: Atu027 is a liposomally formulated short interfering RNA with anti-metastatic activity, which silences the expression of protein kinase N3 (PKN3) in the vascular endothelium. This trial was designed to assess the safety, pharmacokinetics and efficacy of Atu027 in combination with gemcitabine in advanced pancreatic carcinoma (APC). METHODS: In total, 23 patients (pts) with inoperable APC were randomly assigned to gemcitabine combined with two different Atu027 schedules (0.235 mg/kg once weekly vs. 0.235 mg/kg twice weekly). ClinicalTrials.gov Identifier: NCT01808638. RESULTS: The treatment was well-tolerated. There were Grade 3 adverse events (AEs) in 9/11 pts (arm 1) and 11/12 pts (arm 2), while Grade 4 AEs were reported for two pts in each arm. The AEs were mainly laboratory abnormalities without clinical significance. The median progression-free survival reached statistical significance in patients who had metastatic disease (1.6 vs. 2.9 months, p = 0.025). Disease control during treatment was achieved in 4/11 pts (arm 1) and in 7/12 pts (arm 2). Pts in arm 1 experienced stable global health status while pts in arm 2 reported improvement. CONCLUSIONS: Combining Atu027 with gemcitabine is safe and well tolerated. In pts with metastatic APC, twice-weekly Atu027 is associated with significantly improved outcomes. Our clinical results support the significant involvement of the vascular endothelium in the spread of cancer, and thus the further investigation of its target role.

Neuroendocrine carcinoma of the cervix: a systematic review of the literature.

BACKGROUND: Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer. The prognosis of women with NECC is poor and there is no standardized therapy for this type of malignancy based on controlled trials. METHODS: We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify clinical trials describing the management and outcome of women with NECC. RESULTS: Three thousand five hundred thirty-eight cases of NECC in 112 studies were identified. The pooled proportion of NECC among women with cervical cancer was 2303/163470 (1.41%). Small cell NECC, large cell NECC, and other histological subtypes were identified in 80.4, 12.0, and 7.6% of cases, respectively. Early and late stage disease presentation were evenly distributed with 1463 (50.6%) and 1428 (49.4%) cases, respectively. Tumors expressed synaptophysin (424/538 cases; 79%), neuron-specific enolase (196/285 cases; 69%), chromogranin (323/486 cases; 66%), and CD56 (162/267; 61%). The most common primary treatment was radical surgery combined with chemotherapy either as neoadjuvant or adjuvant chemotherapy, described in 42/48 studies. Radiotherapy-based primary treatment schemes in the form of radiotherapy, radiochemotherapy, or radiotherapy with concomitant or followed by chemotherapy were also commonly used (15/48 studies). There is no standard chemotherapy regimen for NECC, but cisplatin/carboplatin and etoposide (EP) was the most commonly used treatment scheme (24/40 studies). Overall, the prognosis of women with NECC was poor with a mean recurrence-free survival of 16 months and a mean overall survival of 40 months. Immune checkpoint inhibitors and targeted agents were reported as being active in three case reports. CONCLUSION: NECC is a rare variant of cervical cancer with a poor prognosis. Multimodality treatment with radical surgery and neoadjuvant/adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy is the mainstay of treatment for early stage disease while chemotherapy with cisplatin and etoposide or topotecan, paclitaxel, and bevacizumab is appropriate for women with locally advanced or recurrent NECC. Immune checkpoint inhibitors may be beneficial, but controlled evidence for their efficacy is lacking.

Radiogenic angiosarcoma of the breast: case report and systematic review of the literature.

BACKGROUND: Radiogenic angiosarcoma of the breast (RASB) is a rare late sequela of local irradiation of the breast or chest wall after breast cancer. The prognosis of women with RASB is poor and there is no standardized therapy for this type of malignancy. CASE PRESENTATION: We present the case of a 54 year old woman with RASB (poorly differentiated angiosarcoma of the left breast; pT1, pNX, M0, L0, V0) and a history of invasive-ductal cancer of the left breast (pT1b, G2, pN0, ER positive, PR positive, HER-2/neu negative) treated in July 2012 with breast-conserving surgery, adjuvant chemotherapy with 6 cycles of epirubicin and cyclophosphamide, adjuvant irradiation of the left breast with 50 Gray, and adjuvant endocrine therapy with an aromatase inhibitor. In August 2016, a bilateral salpingo-oophorectomy was performed to remove a tumor of the left ovary, which was diagnosed as breast cancer recurrence. At the same time, a small, purple skin lesion of 1.2 cm in diameter was noted in the inner upper quadrant of the right breast. RASB was diagnosed by punch biopsy and the tumor was excised with clear margins. Imaging studies showed no evidence of further metastases. A systemic chemotherapy with 6 cycles of liposomal doxorubicin was initiated. Five months later, a local recurrence of RASB was diagnosed and mastectomy was performed. Six months later, the patient is alive with no evidence of disease. Three hundred seven cases of RASB were identified. The pooled incidence rate of RASB was 1/3754 women. The most common treatment of RASB was mastectomy in 83% of cases. Adjuvant radiotherapy or chemotherapy were rarely used with 6 and 4%, respectively, whereas in case of recurrence, chemotherapy was the mainstay of treatment, used in 58% of cases. Radiotherapy and repeated surgery were also common with 30 and 33% of cases, respectively. Overall, the prognosis of women with RASB was poor and the recurrence-free survival was short with a mean of 15.9 months. Mean overall survival was 27.4 months. CONCLUSION: RASB is a rare late complication of breast irradiation. The prognosis of women with RASB is poor. Surgery is the mainstay of treatment for localized disease while systemic chemotherapy and re-irradiation are appropriate for women with disseminated or recurrent RASB.

Melanoma of the Vagina: Case Report and Systematic Review of the Literature.

BACKGROUND: Primary melanoma of the vagina (PMV) is a rare entity. The prognosis of women with PMV is poor and there is no standardized therapy for this type of malignancy. We present the case of a 72-year-old woman with PMV (cT2, pN0, M0). CASE REPORT: Imaging studies showed no evidence of regional or distant metastases. Molecular analysis demonstrated wild-type B-Raf proto-oncogene, serine/threonine kinase (BRAF). Staging laparoscopy with pelvic lymphadenectomy and subsequent radiotherapy with 60 Gy delivered as pelvic teletherapy and vaginal brachytherapy was applied. Systematic literature review: A total of 805 cases of PMV were identified. Most lesions were melanotic (65%) and localized (66%), whereas amelanotic (35%) and primary advanced lesions (34%) were only seen in a minority of patients. BRAF mutation was detected in none out of 33 cases, tumor protein 53 (TP53) mutations and mast/stem cell growth factor receptor CD117 (KIT) amplification were identified in one case each. The most common treatment was surgery, reported in 43% of cases. Surgery combined with adjuvant radiotherapy, adjuvant immunotherapy (mostly with interferon-alpha), or adjuvant chemotherapy were given in 35%, 8%, and 3% of cases, respectively. Radiotherapy or chemotherapy as sole treatments were used in 5% and 1% of patients, respectively. Among patients with recurrence, chemotherapy (mostly dacarbazine) alone or in combination with surgery, radiotherapy or immunotherapy was the most common treatment in 61% of cases. The mean durations of recurrence-free and overall survival were 16.4 and 22.2 months, respectively. CONCLUSION: PMV is a rare malignancy with a poor prognosis. Surgery, radiotherapy, and immunotherapy with interferon-alpha are the mainstay of treatment for localized disease, while chemotherapy with dacarbazine is mostly used for unresectable and recurrent disease. No data on the clinical value of immune checkpoint inhibitors in PMV have been published.

Thalidomide and lenalidomide for recurrent ovarian cancer: A systematic review of the literature.

The present review aimed to assess the safety and efficacy of thalidomide and lenalidomide, two immunomodulatory drugs with anti-angiogenic properties, in women with recurrent ovarian, fallopian tube, and primary peritoneal cancer. A systematic review of the literature was conducted whereby Medline and the Cochrane Central Register of Controlled Trials were searched using terms associated with thalidomide, lenalidomide, and recurrent ovarian, fallopian tube and primary peritoneal cancer. Published English language case reports, trials and studies that described the safety and efficacy of thalidomide or lenalidomide alone, or in combination with other drugs were reviewed. A total of 16 clinical studies involving 394 patients treated with thalidomide (n=188), lenalidomide (n=77) and 129 controls were identified, including five case reports (n=6), three case series (n=45), two phase I trials (n=27), four phase II trials (n=109), and two randomized phase III trials (n=207). In a pooled analysis of thalidomide investigated as a single drug, the overall clinical benefit rate was 43% (43/99) with a mean time to progression of 5.6 months. The response rate (complete response + partial response) was 25%. In a phase III trial, the combination of thalidomide and topotecan significantly increased the overall response rate compared with topotecan alone [14/30 (47%) vs. 8/39 (21%)]. In another phase III trial involving women with asymptomatic biochemical recurrence, compared with tamoxifen, thalidomide was not more effective. Lenalidomide was investigated in three phase I trials and in one phase II trial with an overall clinical benefit rate of 52% (34/65), and a mean time to progression of 4.6 months. The response rate (complete response + partial response) was 6%. Systemic toxicity of both drugs was noted in >77% of patients with pneumonitis/pneumonia, fatigue, neuropathy and venous thromboembolism reported as the most common side effects. Thalidomide and lenalidomide are moderately active in recurrent ovarian cancer. Thalidomide possesses synergistic effects with topotecan. The toxicity of both drugs is considerable and there is a greater amount of data available for thalidomide compared to lenalidomide.

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies.

BACKGROUND: To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). METHODS: Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. RESULTS: Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). CONCLUSIONS: Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

Synchronous Endometrial and Ovarian Cancer in Young Women: Case Report and Review of the Literature.

BACKGROUND: Young women with endometrial cancer (EC) have an increased risk of synchronous ovarian cancer. The prognosis of women with synchronous endometrial and ovarian cancer (SEOC) is good. A high proportion of affected women have hereditary non-polyposis colon cancer syndrome (HNPCC). CASE PRESENTATION: We present the case of a 45-year-old woman with histologically proven endometrioid adenocarcinoma of the endometrium (pT1B, G2, R0 without lymphovascular space invasion). She underwent laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy. Final histology revealed a synchronous bilateral endometrioid ovarian cancer (pT1A, G2, R0). HNPCC analysis by immunohistochemistry showed no microsatellite instability in MSH2, MSH6, MLH1, and PMS2. No adjuvant therapy was administered, clinical follow-up with regular gynecological examinations was recommended. In a systematic literature review, 2,904 cases of women with SEOC were identified with 1,035 (36%) of them being premenopausal or <50 years of age. The proportion of women with SEOC among all reported EC cases was 842/23,498 (3%) and the proportion of young women with SEOC among all reported EC cases was 261/23,498 (1%). In summary, microsatellite instability and subsequent mutations in mismatch repair genes compatible with HNPCC were identified in 6/15 (40%) women analyzed. The mean recurrence-free and overall survival times of young women with SEOC were 1.9 (min 0.2, max 3) and 4.0 (min 0.2, max 22.1) years, respectively. CONCLUSION: Young women with EC have a high risk of synchronous ovarian cancer. Thus, in young women with EC, bilateral salpingo-oophorectomy or careful histological assessment of both ovaries are recommended in order to confirm or rule out SEOC. HNPCC testing should be offered to all women.

What Characterizes Long-term Survivors of Recurrent Ovarian Cancer? Case Report and Review of the Literature.

BACKGROUND: Women with recurrent ovarian cancer have a poor prognosis and short survival. However, some women are long-term survivors and it is unclear whether they share specific common characteristics. CASE REPORT: We present the case of a 63-year-old woman with histologically-proven recurrent ovarian cancer and a survival time of 16 years after the diagnosis of recurrence. She underwent initial debulking surgery in 1994, followed by 6 cycles of adjuvant chemotherapy with cisplatin and paclitaxel. After recurrent disease was diagnosed by re-laparotomy in 2000, she underwent four lines of systemic chemotherapy from 2000 to 2009 (carboplatin/paclitaxel, topotecan, etoposide/treosulfan and liposomal doxorubicin) and four lines of endocrine therapy between 2002 and 2014 (tamoxifen, goserelin, tamoxifen and exemestane). In 2014, she underwent secondary debulking surgery and was tumor-free until 2015. Upon progression, she was then started on the fifth-line of endocrine therapy, fulvestrant, which was changed to the mTOR inhibitor everolimus in June 2016. In a PUBMED literature search, 360 cases of long-term survivors of recurrent ovarian cancer (LTSROC), defined as women with survival >5 years after the diagnosis of recurrence, were identified with a mean post-recurrence survival time of 7.5 years. Comparing the patient and therapy details of these women, we identified common characteristics of LTSROC, i.e. young age and optimal debulking at initial surgery, a long time span between first-line therapy and first recurrence and the combined use of optimal cytoreductive surgery and systemic chemotherapy. CONCLUSION: LTSROC are rare, with 360 cases described in the literature. LTSROC are characterized by young age, low tumor stage, long recurrence-free interval and combined modality treatment with optimal cytoreductive surgery and systemic chemotherapy.

Lymphoma of the Cervix: Case Report and Review of the Literature.

BACKGROUND: Lymphoma of the uterine cervix (LUCX) is rare and may occur as a primary or secondary manifestation of this disease. Clinical and cytological presentations of LUCX vary and establishing diagnosis is often difficult. Surgery followed by radiation or chemotherapy is the mainstay of treatment. CASE REPORT: We present the case of a 73-year-old woman with recurrent pathological PAP smears of the cervix and a history of chronic lymphatic leukemia 15 years ago. Colposcopy of the cervix showed no acetowhite lesion and a conization was performed. Histology revealed endocervical lymphoid cells, specified as low-malignant B-Non-Hodgkin lymphoma of the cervix based on the expression of CD5, CD20, and CD23, whilst CD10 and cyclin D1 were negative. The diagnosis was confirmed by flow cytometry of peripheral blood. Staging revealed enlarged iliacal, para-aortic, mediastinal, cervical, subclavicular, and inguinal lymph nodes and hepatosplenomegaly. Bone marrow analysis confirmed lymphoid infiltration consistent with B-cell lymphoma. The patient was scheduled for a combined immuno-chemotherapy with obinutuzumab and chlorambucil. In a MEDLINE literature search, 246 cases of LUCX were identified. One hundred and eighty-five cases were primary and 61 cases were secondary manifestations of LUCX. With a mean follow-up time of 38 months, overall survival was 81%. Data in the literature including clinical and histological characteristics of LUCX as well as the clinical management and prognosis are discussed herein. CONCLUSION: LUCX is rare and has distinct clinical and histological features. LUCX is usually treated with local surgical excision followed by radiotherapy or chemotherapy.

Primary malignant melanoma of the breast: case report and review of the literature.

BACKGROUND: Melanoma of the breast is a rare disease and may present as a metastatic manifestation of primary cutaneous melanoma or as primary malignant melanoma of the breast (PMMB). Clinical presentations of PMMB vary and surgery is the mainstay of treatment. CASE REPORT: We present the case of a 54-year-old woman with a primary malignant melanoma of the left breast. She was treated with mastectomy, axillary sentinel lymph node excision and primary reconstruction with a tissue expander. Final histology revealed a malignant melanoma with 10 cm in the largest diameter. Molecular characterization by DNA-sequencing showed B-RAF, N-RAS and c-kit wild types. Immunohistochemical characterization demonstrated weak expression of S100 and melan-A and strong expression of polyclonal S100. HMB45, tyrosine kinase and the cytokeratins AE1/AE3 and MNF 116 were not expressed. Lymphoma-specific markers (CD30, CD3, CD20) and sarcoma-specific markers (desmin, actin, CD34) were also negative. The tumor proliferation rate according to Mib1-staining was 90%. Staging of the abdomen, chest, head and bones showed no evidence of metastases. A dermatological examination showed no primary melanoma of the skin. Interferon-alpha was suggested as adjuvant therapy but declined by the patient. With a follow-up of 6 months, the patient is still alive with no evidence of disease. CONCLUSION: PMMB is rare and may be successfully treated with surgical excision. Locally advanced PMMB may occur without regional and distant metastases.

First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors.

PURPOSE: Atu027 is a novel liposomal RNA interference therapeutic that includes a short-interfering RNA (siRNA), which silences expression of protein kinase N3 in the vascular endothelium. Atu027 has previously been shown to inhibit local tumor invasion as well as lymph node and pulmonary metastasis in mouse cancer models. This first-in-human study aimed to assess the safety, tolerability, and pharmacokinetics of Atu027 while evaluating therapeutic effects on both primary tumors and metastatic lesions. PATIENTS AND METHODS: Thirty-four patients with advanced solid tumors received 10 escalating doses of Atu027 without premedication, as one single followed by eight intravenous infusions twice per week during a 28-day cycle. Response was monitored by computed tomography/magnetic resonance imaging at baseline, at the end of treatment (EoT), and at final follow-up (EoS), and was assessed according to RECIST. RESULTS: Atu027 was well tolerated up to dose levels of 0.336 mg/kg; most adverse events (AEs) were low-grade toxicities (grade 1 or 2). No maximum tolerated dose was reached. Plasma levels of siRNA strands and lipids were dose proportional, peaking during 4-hour infusion. Disease stabilization was achieved in 41% of patients at EoT (n = 14 of 34 treated patients); eight patients had stable disease at EoS, and some experienced complete or partial regression of metastases. sFLT1 (soluble variant of vascular endothelial growth factor receptor-1) decreased from pretreatment levels in most patients after dose levels 04 to 10. CONCLUSION: Atu027 was safe in patients with advanced solid tumors, with 41% of patients having stable disease for at least 8 weeks. In view of these results, further clinical trials have been initiated, and sFLT1 will be investigated as a potential biomarker.

Atypical cell populations associated with acquired resistance to cytostatics and cancer stem cell features: the role of mitochondria in nuclear encapsulation.

Until recently, acquired resistance to cytostatics had mostly been attributed to biochemical mechanisms such as decreased intake and/or increased efflux of therapeutics, enhanced DNA repair, and altered activity or deregulation of target proteins. Although these mechanisms have been widely investigated, little is known about membrane barriers responsible for the chemical imperviousness of cell compartments and cellular segregation in cytostatic-treated tumors. In highly heterogeneous cross-resistant and radiorefractory cell populations selected by exposure to anticancer agents, we found a number of atypical recurrent cell types in (1) tumor cell cultures of different embryonic origins, (2) mouse xenografts, and (3) paraffin sections from patient tumors. Alongside morphologic peculiarities, these populations presented cancer stem cell markers, aberrant signaling pathways, and a set of deregulated miRNAs known to confer both stem-cell phenotypes and highly aggressive tumor behavior. The first type, named spiral cells, is marked by a spiral arrangement of nuclei. The second type, monastery cells, is characterized by prominent walls inside which daughter cells can be seen maturing amid a rich mitochondrial environment. The third type, called pregnant cells, is a giant cell with a syncytium-like morphology, a main nucleus, and many endoreplicative functional progeny cells. A rare fourth cell type identified in leukemia was christened shepherd cells, as it was always associated with clusters of smaller cells. Furthermore, a portion of resistant tumor cells displayed nuclear encapsulation via mitochondrial aggregation in the nuclear perimeter in response to cytostatic insults, probably conferring imperviousness to drugs and long periods of dormancy until nuclear eclosion takes place. This phenomenon was correlated with an increase in both intracellular and intercellular mitochondrial traffic as well as with the uptake of free extracellular mitochondria. All these cellular disorders could, in fact, be found in untreated tumor cells but were more pronounced in resistant entities, suggesting a natural mechanism of cell survival triggered by chemical injury, or a primitive strategy to ensure stemming, self-renewal, and differentiation under adverse conditions, a fact that may play a significant role in chemotherapy outcomes.

Outcome of elderly patients with acute promyelocytic leukemia: results of the German Acute Myeloid Leukemia Cooperative Group.

Despite improvement of prognosis, older age remains a negative prognostic factor in acute promyelocytic leukemia (APL). Reports on disease characteristics and outcome of older patients are conflicting. We therefore analyzed 91 newly diagnosed APL patients aged 60 years or older (30 % of 305 adults with APL) registered by the German AML Cooperative Group (AMLCG) since 1994; 68 patients (75 %) were treated in studies, 23 (25 %) were non-eligible, and 31 % had high-risk APL. Fifty-six patients received induction therapy with all-trans retinoic acid and TAD (6-thioguanine, cytarabine, daunorubicin), and consolidation and maintenance therapy. Treatment intensification with a second induction cycle (high dose cytarabine, mitoxantrone; HAM) was optional (n = 14). Twelve patients were randomized to another therapy not considered in this report. The early death rate was 48 % in non-eligible and 19 % in study patients. With the AMLCG regimen, 7-year overall, event-free and relapse-free survival (RFS) and cumulative incidence of relapse were 45 %, 40 %, 48 %, and 24 %, respectively. In patients treated with TAD-HAM induction, 7-year RFS was superior (83 %; p = 0.006) compared to TAD only, and no relapse was observed. In our registered elderly patients, we see a high rate of non-eligibility for treatment in studies and of high-risk APL. In patients who can undergo a curative approach, intensified chemotherapy is highly effective, but is restricted to a selection of patients. Therefore, new less toxic treatment approaches with broader applicability are needed. Elderly patients might be a particular target group for concepts with arsenic trioxide.

Therapy with antifungals decreases the diagnostic performance of PCR for diagnosing invasive aspergillosis in bronchoalveolar lavage samples of patients with haematological malignancies.

OBJECTIVES: Invasive aspergillosis (IA) is a life-threatening infection in severely immunocompromised patients, especially those receiving intensive chemotherapy or undergoing haematopoietic stem cell transplantation. As the clinical diagnosis of IA is mostly based on biomarkers (galactomannan, ß-d-glucan, PCR assays) indicating Aspergillus as the underlying pathogen, the effect of antifungal treatment on the performance of these parameters is still controversial. We evaluated the effect of antifungal treatment on the performance of an Aspergillus-specific PCR assay in bronchoalveolar lavage (BAL) samples. PATIENTS AND METHODS: Two-hundred-and-twenty-six BAL samples from 226 patients with haematological malignancies at high risk for IA classified according to the 2008 European Organization for the Research and Treatment of Cancer criteria were analysed retrospectively for the diagnostic performance of a nested Aspergillus PCR assay in relation to the number and type of mould-active antifungals received prior to BAL sampling. RESULTS: Sensitivity of BAL PCR for patients without antifungal treatment prior to BAL sampling was 0.69, whereas specificity was 0.87. While no significant change in diagnostic performance by the addition of one antifungal was observed, receiving two or more antifungals prior to BAL sampling led to a significant decrease in the diagnostic performance of BAL PCR testing (P < 0.009). CONCLUSIONS: Treatment with mould-active antifungals prior to BAL sampling significantly decreases the performance of the Aspergillus PCR assay in haematological patients if BAL was performed after administration of more than one antifungal agent. Performing BAL sampling for Aspergillus PCR diagnostic despite pre-treatment with one antifungal or while on prophylaxis is feasible.

Diagnosing pulmonary aspergillosis in patients with hematological malignancies: a multicenter prospective evaluation of an Aspergillus PCR assay and a galactomannan ELISA in bronchoalveolar lavage samples.

OBJECTIVES: Diagnosing invasive pulmonary aspergillosis (IPA) remains a challenge in patients with hematological malignancies. The clinical significance of testing bronchoalveolar lavage (BAL) samples both with polymerase chain reaction (PCR) and Aspergillus galactomannan ELISA (GM) is unclear, and the BAL cutoff for GM has not been clearly evaluated yet. METHODS: Using a validated nested PCR assay and a GM ELISA, we prospectively examined BAL samples from 87 hematological patients at high risk of IPA. Of 76 (87%) evaluable patients, 29 patients had proven or probable disease. RESULTS: The receiver operating characteristic (ROC) analysis of GM optical density (OD) cutoff levels yielded a BAL OD of 0.5 to be optimal. We identified 29 probable or proven cases based on this OD. Sensitivity and specificity for BAL GM were 0.79 (95% CI, 0.62-0.9) and 0.96 (95% CI, 0.86-0.99), respectively. For BAL PCR, sensitivity and specificity were 0.59 (95% CI, 0.41-0.75) and 0.87 (95% CI, 0.75-0.94), respectively. Combining BAL GM and PCR for diagnosis showed a sensitivity and specificity rate of 0.55 (95% CI, 0.38-0.72) and 1.0 (95% CI, 0.93-1.0), respectively, if positivity was defined by positive results for both tests. If either positive BAL GM or positive BAL PCR results defined test positivity, the sensitivity was 0.83 (95% CI, 0.65-0.92), and the specificity was 0.83 (95% CI, 0.70-0.91) CONCLUSIONS: In terms of optimal sensitivity and specificity, a GM OD cutoff of 0.5 was determined for BAL samples. Positivity for both GM and Aspergillus PCR in BAL makes a pulmonary aspergillosis highly likely.

Regorafenib for cancer.

INTRODUCTION: Regorafenib (BAY 73-4506) is a novel, orally active, diphenylurea multikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-ß, FGFR-1, RET, RAF-1, BRAF and p38 MAP kinase. AREAS COVERED: This review covers the preclinical development of regorafenib as well as the pivotal Phase I studies. The safety profile of regorafenib is discussed in context with other oral multikinase inhibitors bearing a similar target profile. Current clinical developments, especially in colorectal cancer (CRC) and gastrointestinal stromal tumor (GIST), are addressed. Open questions on clinically useful biomarkers predicting response with regard to a personalized therapy strategy are also being discussed. EXPERT OPINION: Regorafenib (BAY 73-4506) is a novel, orally active multikinase inhibitor that is well tolerated in preclinical mouse models as well as clinically according to Phase I - III trials performed. The toxicity profile is comparable with other oral multikinase inhibitors with similar molecular targets. Regorafenib has promising antineoplastic activity in various tumor types. Two large, randomized Phase III pivotal registration studies in patients with GIST and CRC, respectively, already completed enrolment, with final results being awaited. Further extensive clinical development as a single agent or in combination with standard chemotherapeutic agents in various malignant tumors is ongoing. Moreover, regorafenib has recently been granted Orphan Drug Status for GIST tumors and 'fast track' status for both GIST and CRC by the FDA.

Phase II study of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients with locally advanced or metastatic pancreatic cancer.

INTRODUCTION: Nimotuzumab is a humanized monoclonal antibody that binds to the EGFR. Based on phase I data, the recommended dose has been established at 200 mg weekly. This study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic pancreatic cancer. METHODS: Pts who failed first line standard chemotherapy for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given intravenously at 200 mg once weekly for 6 weeks (wks). Follow up by CT scan was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), progression-free survival (PFS), and safety. RESULTS: A total of 56 pts were enrolled for treatment (ECOG status of 1 [n = 41] or 0 [n = 15]), the majority (47 pts) had metastatic disease. Nearly half of the pts [n = 26] received ≥2 regimens. Pts evaluable for response: n = 36; CR: 0; PR: 0; SD: 6 pts. Median PFS for pts with SD was 19.2 weeks, for all pts 6.7 weeks (95% CI: 6.43-7.14 weeks). PFS after 1 year was 10.3% with a median overall survival of 18.1 weeks. Treatment-related adverse events were generally mild including rash grade 1 in 5 pts. After a single dose of 200 mg, the t(1/2) was calculated to 45 h. CONCLUSION: These data confirm that nimotuzumab is safe and very well tolerated. To improve efficacy, a randomized, placebo-controlled trial with Gem has been initiated.

Results of a phase II trial of S-1 as first-line treatment of metastatic pancreatic cancer (CESAR-study group).

PURPOSE: S-1, an oral fluoropyrimidine derivative, has previously demonstrated anticancer efficacy in pancreatic cancer (PC), predominantly in Asian populations. This study evaluated the antitumor effect and safety of S-1 in Caucasian patients with metastatic PC. METHODS: Chemotherapy-naïve patients received S-1 orally at 30 mg/m(2) twice daily (BID) for 2 weeks, repeated every 3 weeks. Primary endpoint was ORR. Secondary endpoints included PFS, OS and safety assessment. The trial had a Simon's two-stage design with 22 patients evaluable for efficacy in stage 1 and an additional 18 patients in stage 2, if ≥3/22 patients had a confirmed response at the first stage. RESULTS: Three out of 27 patients showed PR, however, detection of asymptomatic brain metastases in one of them prevented this study from proceeding to stage 2. The median PFS and OS for all patients was 3.5 and 9.1 months, respectively. The median duration of disease control for patients with SD or PR (n = 17) was 4.3 months. S-1 was well tolerated; fatigue was the most frequent grade 3/4 adverse event. CONCLUSIONS: Efficacy data of PFS and OS are at least comparable to gemcitabine, the current standard of care. S-1 is active in Caucasian patients with metastatic PC.