Efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2-positive breast cancer.

INTRODUCTION: The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer has changed dramatically with the introduction and widespread use of HER2-targeted therapies. There is, however, relatively limited real-world information about the effectiveness and safety of trastuzumab emtansine (T-DM1) in Hong Kong Chinese patients. We assessed the efficacy and toxicity profiles among local patients with HER2-positive advanced breast cancer who had received T-DM1 therapy in the second-line setting and beyond. METHODS: This retrospective study involved five local centres that provide service for over 80% of the breast cancer population in Hong Kong. The study period was from December 2013 to December 2015. Patients were included if they had recurrent or metastatic histologically confirmed HER2+ breast cancer who had progressed after at least one line of anti-HER2 therapy including trastuzumab. Patients were excluded if they received T-DM1 as first-line treatment for recurrent or metastatic HER2+ breast cancer. Patient charts including biochemical and haematological profiles were reviewed for background information, T-DM1 response, and toxicity data. Adverse events were documented during chemotherapy and 28 days after the last dose of medication. RESULTS: Among 37 patients being included in this study, 28 (75.7%) had two or more lines of anti-HER2 agents and 26 (70.3%) had received two or more lines of palliative chemotherapy. Response assessment revealed that three (8.1%) patients had a complete response, eight (21.6%) a partial response, 11 (29.7%) a stable disease, and 12 (32.4%) a progressive disease; three patients could not be assessed. The median duration of response was 17.3 (95% confidence interval, 8.4-24.8) months. The clinical benefit rate (complete response + partial response + stable disease, ≥12 weeks) was 37.8% (95% confidence interval, 22.2%-53.5%). The median progression-free survival was 6.0 (95% confidence interval, 3.3- 9.8) months and the median overall survival had not been reached by the data cut-off date. Grade 3 or 4 toxicities included thrombocytopaenia (13.5%), raised alanine transaminase (8.1%), anaemia (5.4%), and hypokalaemia (2.7%). No patient died as a result of toxicities. CONCLUSIONS: In patients with HER2-positive advanced breast cancer who have been heavily pretreated with anti-HER2 agents and cytotoxic chemotherapy, T-DM1 is well tolerated and provided a meaningful progression-free survival of 6 months and an overall survival that has not been reached. Further studies to identify appropriate patient subgroups are warranted.

Comparison of fluorescence in-situ hybridisation with dual-colour in-situ hybridisation for assessment of HER2 gene amplification of breast cancer in Hong Kong.

OBJECTIVES: To compare the PathVysion fluorescence in-situ hybridisation assay with the INFORM HER2 Dual in-situ hybridisation assay on 104 invasive breast cancers with a broad spectrum of immunohistochemistry scores. METHODS: This case series involved consecutive patients diagnosed with invasive breast carcinoma with equivocal immunohistochemistry score and referred for further HER2 assessment from the departments of Surgery and/or Clinical Oncology of the two hospitals between January 2013 and February 2014. An additional 10 cases with negative HER2 immunohistochemistry and 11 cases with positive HER2 immunohistochemistry were further included. RESULTS: The results of both fluorescence in-situ hybridisation and dual in-situ hybridisation were available in 99 of 104 cases, respectively. Student'st test showed no statistically significant difference in the mean number of HER2 count, CEP17 copies, or HER2/CEP17 ratio between that obtained by fluorescence in-situ hybridisation and that obtained by dual in-situ hybridisation. Pearson's correlation of results for the two assays was strong for HER2/CEP17 signal ratio (R=0.963, P<0.001) and mean HER2 copies per nucleus (R=0.897, P<0.001). Overall agreement was 96.0% (95 out of 99 cases, ĸ0.882). Three of the four discordant cases were equivocal for either fluorescence in-situ hybridisation or dual in-situ hybridisation. The results of immunohistochemistry 0/1+ and 3+ cases showed 100% concordance between the two assays. The failure rate was 0.96% for fluorescence in-situ hybridisation and 3.85% for dual in-situ hybridisation. Cases that failed for fluorescence in-situ hybridisation were successful for dual in-situ hybridisation and vice versa. CONCLUSIONS: Our study showed that dual in-situ hybridisation is a reliable and useful option for HER2 testing in breast cancer.

Novel mRNA isoforms and mutations of uridine monophosphate synthetase and 5-fluorouracil resistance in colorectal cancer.

The drug fluorouracil (5-FU) is a widely used antimetabolite chemotherapy in the treatment of colorectal cancer. The gene uridine monophosphate synthetase (UMPS) is thought to be primarily responsible for conversion of 5-FU to active anticancer metabolites in tumor cells. Mutation or aberrant expression of UMPS may contribute to 5-FU resistance during treatment. We undertook a characterization of UMPS mRNA isoform expression and sequence variation in 5-FU-resistant cell lines and drug-naive or -exposed primary and metastatic tumors. We observed reciprocal differential expression of two UMPS isoforms in a colorectal cancer cell line with acquired 5-FU resistance relative to the 5-FU-sensitive cell line from which it was derived. A novel isoform arising as a consequence of exon skipping was increased in abundance in resistant cells. The underlying mechanism responsible for this shift in isoform expression was determined to be a heterozygous splice site mutation acquired in the resistant cell line. We developed sequencing and expression assays to specifically detect alternative UMPS isoforms and used these to determine that UMPS was recurrently disrupted by mutations and aberrant splicing in additional 5-FU-resistant colorectal cancer cell lines and colorectal tumors. The observed mutations, aberrant splicing and downregulation of UMPS represent novel mechanisms for acquired 5-FU resistance in colorectal cancer.

Autofluorescence imaging can identify preinvasive or clinically occult lesions in fallopian tube epithelium: a promising step towards screening and early detection.

BACKGROUND: Optical imaging systems are robust, portable, relatively inexpensive, and have proven utility in detecting precancerous lesions in the lung, esophagus, colon, oral cavity and cervix. We describe the use of light-induced endogenous fluorescence (autofluorescence) in identifying preinvasive and occult carcinomas in ex vivo samples of human fallopian tube (FT) epithelium. METHODS: Women undergoing surgery for an i) ovarian mass, ii) a history suggestive of hereditary breast-ovarian cancer, or iii) known serous ovarian cancer following neoadjuvant chemotherapy (NAC) were approached for informed consent. Immediately following surgery, FT's were photographed in reflectance and fluorescence at high resolution. Images included: (1) white-light reflectance of luminal/epithelial surface; (2) narrow-band green reflectance (570 nm) (3) green autofluorescence (405/436 nm excitation); and (4) blue autofluorescence (405 nm excitation). Areas revealing a loss of natural tissue fluorescence or marked increase in tissue microvasculature were recorded and compared to final histopathologic diagnosis (SEE-FIM protocol). RESULTS: Fifty-six cases involving one or both fallopian tubes underwent reflectance and fluorescence visualization. Nine cases were excluded, either secondary to non-ovarian primary pathology (7) or excessive trauma (2) rendering tissue interpretation impossible. Of the 47 cases remaining, there were 11 high grade serous (HGS) and 9 non-serous ovarian carcinomas undergoing primary debulking surgery, 5 serous carcinomas having received NAC, 8 benign ovarian tumors, and 14 women undergoing risk-reducing bilateral salpingo-oophorectomy (RRBSO). Methodology was feasible, efficient, and reproducible. TIC or carcinoma was identified in 7/11 HGS, 3/5 NAC, and 1/14 RRBSO. Optical images were reviewed to determine test positive or negative based on standardized criteria. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the entire cohort (73%; 83%; 57%; 91%) and in a subgroup that excluded non-serous histology (87.5%; 92%; 78%; 96%). CONCLUSIONS: Abnormal FT lesions can be identified using ex vivo optical imaging technologies. With this platform, we will move towards genomic interrogation of identified lesions, and developing in vivo screening modalities via falloposcopy.

Personnel dose reduction in 90Y microspheres liver-directed radioembolization: from interventional radiology suite to patient ward.

OBJECTIVE: To describe a method to reduce the external radiation exposure emitted from the patient after liver-directed radioembolization using 90Y glass microspheres, to quantitatively estimate the occupational dose of medical personnel providing patient care to the patient radioembolized with the use of the method and to discuss radiation exposure to patients who are adjacent if the patient radioembolized needs hospitalization. METHODS: A lead-lined blanket of lead equivalence of 0.5 mm was used to cover the patient abdomen immediately after the 90Y radioembolization procedure, in order to reduce the radiation emitted from the patient. The interventional radiologist used a rod-type puncture site compressor for haemostasis to avoid direct contact with possible residual radioactivity at the puncture site. Dose rates were measured at the interventional radiologist chest and hand positions during puncture site pressing for haemostasis with and without the use of the blanket. The measurement results were applied to estimate the occupational dose of colleagues performing patient care to the patient radioembolized. The exposure to patients adjacent in the ward was estimated if the patient radioembolized was hospitalized. RESULTS: The radiation exposures measured at the radiologist chest and hand positions have been significantly reduced with the lead-lined blanket in place. The radiologist, performing puncture site pressing at the end of radioembolization procedure, would receive an average hand dose of 1.95 µSv and body dose under his own lead apron of 0.30 µSv for an average 90Y microsphere radioactivity of 2.54 GBq. Other medical personnel, nurses and porters, would receive occupational doses corresponding to an hour of background radiation. If the patient radioembolized using 90Y needs hospitalization in a common ward, using the lead-lined blanket to cover the abdomen of the patient and keeping a distance of 2 m from the patient who is adjacent would reduce the exposure by 0.42% of dose limit for the general public. CONCLUSION: By placing a lead-lined blanket on the patient abdominal region after 90Y radioembolization, hospital staff receive minimal radiation exposure in order to comply with the radiation protection "as low as reasonably achievable" principle. There will be no increase in radiation level in ward if the patient radioembolized using 90Y needs to be hospitalized. Therefore, the patient radioembolized can be accommodated alternatively at a corner bed of a common ward if an isolation room with private toilet facility is not available. Advances in knowledge: To reduce exposure to personnel providing patient care to patients radioembolized using 90Y.

Transcutaneous electrical nerve stimulation for neuropathic pain.

This study examined the clinical effectiveness of high-frequency transcutaneous electrical nerve stimulation for reducing hypersensitivity of the hand. Nineteen patients suffering from hand hypersensitivity were randomly assigned into either a treatment or a placebo group. A visual analogue scale and the Downey Hand Centre Hand Sensitivity Test were used to measure the tactile tolerance of the hand. Grip strength was assessed by a grip dynamometer. Daily applications of electrical stimulation were provided for 2 weeks. Significantly lower pain scores were found in the treatment group than in the placebo group by Day 7 and Day 11. The ranking of ten dowel textures of the Downey Hand Centre Hand Sensitivity Test in the treatment group was significantly higher than in the placebo group by Day 7 and Day 11. However, no significant inter-group difference was found in grip strength.

Formation and control of Turing patterns in a coherent quantum fluid.

Nonequilibrium patterns in open systems are ubiquitous in nature, with examples as diverse as desert sand dunes, animal coat patterns such as zebra stripes, or geographic patterns in parasitic insect populations. A theoretical foundation that explains the basic features of a large class of patterns was given by Turing in the context of chemical reactions and the biological process of morphogenesis. Analogs of Turing patterns have also been studied in optical systems where diffusion of matter is replaced by diffraction of light. The unique features of polaritons in semiconductor microcavities allow us to go one step further and to study Turing patterns in an interacting coherent quantum fluid. We demonstrate formation and control of these patterns. We also demonstrate the promise of these quantum Turing patterns for applications, such as low-intensity ultra-fast all-optical switches.

Radiation dose measurements for personnel performing 90Y-ibritumomab tiuxetan administration: a comparison between two injection methods for dose reduction.

The purpose of this study was to directly measure, using thermoluminescent dosimeters, the radiation doses received by radiation team members performing (90)Y-ibritumomab tiuxetan administration. The occupational doses associated with two injection methods for patient administration - an automatic syringe driver and an injection box - were compared. The associated risks, namely cancer induction and hereditary effect, were also estimated from the results and compared with risk factors recommended by the International Commission on Radiological Protection publication 103. The results showed that the doses received by the index and thumb of the right hand and the index finger of the left hand of the radiation oncologist were significantly reduced by using the injection box method. The difference in the dose received by the medical physicist using the two methods was not statistically significant. It was observed that three pairs of latex gloves could further reduce the dose to the hands. The radiological risks of cancer induction and hereditary effect were negligible: of the order of 10(-6) and 10(-7) per (90)Y-ibritumomab tiuxetan administration, respectively, for both methods. However, the results of our study also showed that it would be possible in a busy centre for pregnant women to receive a dose of (90)Y-ibritumomab tiuxetan that exceeds the recommended annual dose limit for the surface of the abdomen.

Murine monoclonal antibody specific for lipopolysaccharide of Salmonella serogroup A.

To facilitate the routine identification of salmonellae and detailed studies of their lipopolysaccharides, we raised murine monoclonal antibodies against these organisms. We raised an immunoglobulin G1 antibody, MO2, which is specific for factor O2. By immunoblotting following sodium dodecyl sulfate-polyacrylamide gel electrophoresis, MO2 was shown to bind only the lipopolysaccharide of Salmonella paratyphi A, giving a ladderlike reaction pattern with regularly spaced reactive bands. MO2 did not react against lipopolysaccharides of other Salmonella serogroups, including those of serogroups B, C, D, E, and L. Since the lipopolysaccharides of Salmonella serogroups A, B, D, and E are similar except for the presence of paratose in serogroup A organisms, this dideoxyhexose is therefore believed to be the immunodominant epitope for MO2. Consistent with the latter contention was the finding that periodate oxidation of the S. paratyphi A lipopolysaccharide did not destroy its antigenicity for MO2. In a slide agglutination test, MO2 was found to react specifically against all 12 clinical isolates of S. paratyphi A but not against 98 isolates of other salmonellae or 74 isolates of other bacteria and Candida albicans.