A 6-year experience of Zephyr endobronchial valves for severe emphysema in an Australian single-centre cohort.

BACKGROUND: Endobronchial valve (EBV) insertion for lung volume reduction is a management option for patients with severe emphysema. One-way valves cause lobar deflation and improve lung function, exercise capacity and quality of life. AIMS: To retrospectively analyse and compare the outcomes of the first 57 patients treated with EBVs between 2015 and 2021 at the Royal Adelaide Hospital to international standards. METHODS: Clinical outcomes of forced expiratory volume in 1 s (FEV1), residual volume (RV), treated lobe volume reduction (TLVR) and 6-min walk distance (6MWD) at 3, 6 and 12 months after valve insertion were reviewed against established minimally clinically important differences (MCIDs). Complications and subjective breathlessness measured by Borg scores were also reviewed. RESULTS: Fifty-seven patients were included. At 12 months, 77.2% achieved TLVR. FEV1 improved by 170 mL (95% confidence interval (CI): 100-250, P < 0.001), 80 mL (95% CI: 10-150, P = 0.019) and 40 mL (95% CI: -60 to 130, P 0.66) at 3, 6 and 12 months respectively. RV improved by -610 mL (95% CI: -330 to -900, P < 0.0001) at 3 months, -640 mL (95% CI: -360 to -920, P < 0.0001) at 6 months and -360 mL (95% CI: -60 to -680, P = 0.017) at 12 months. 6MWD improved by 57.34 m (95% CI: 36.23-78.45, P < 0.0001) and 44.93 m (95% CI: 7.19-82.67, P = 0.02) at 3 and 6 months. Borg score improved by -0.53 (95% CI: 0.11 to -1.2, P = 0.11) and -0.49 (95% CI: 0.17 to -1.15, P = 0.16) at 3 and 6 months. Complication rates aligned with international standards with mucous/infection (26.3%) and pneumothorax (17.5%) as the most common. Subgroup analysis signalled improved outcomes in patients with heterogeneous emphysema. CONCLUSION: Our study represents the first publicly funded Australian analysis of EBVs. The results align with international prospective trials demonstrating improved lung function and exercise capacity. Australians with severe emphysema and gas trapping should be referred to a multidisciplinary centre for consideration of EBVs.

Synchronous primary malignancies of papillary thyroid carcinoma and Hodgkin lymphoma: Interventions and outcome.

Thyroid carcinoma is uncommon. Papillary thyroid carcinoma (PTC) represents the majority of differentiated thyroid carcinoma and is a recognised complication of prior exposure to ionizing radiation. Even more uncommon is the synchronous occurrence of PTC with Hodgkin lymphoma (HL) as multiple primary malignancies. We report a 33-year-old mother of three who developed asymptomatic thyroid nodule for four years, and neck swelling for the recent ten months. She denied constitutional symptoms or B symptoms, and thyroid profiles were normal. Initially, metastatic thyroid cancer was suspected based on ultrasound scan findings of enlarged left thyroid gland and enlarged supraclavicular lymph nodes (LN). However, fine needle aspiration examinations of the thyroid nodule were inconclusive, and the supraclavicular LN was suspicious of HL. Computerised tomography scan detected a large mass at the thyroid glands and lymphadenopathies in the mediastinal, hilar, subcarinal and axilla with dimensions up to 6 cm. Left hemi-thyroidectomy with left supraclavicular LN biopsy revealed PTC in the left thyroid lobe measuring 38 x 25 x 18 mm, and the left supraclavicular LN was not definitive of HL. Completion thyroidectomy on the right side, bilateral central neck dissection and excision biopsy of the right supraclavicular LN revealed the presence of HL in the right supraclavicular LN, and both HL and metastatic PTC in right central LN. After multidisciplinary discussions, the patient received chemotherapy at four weeks postoperatively and achieved complete remission. This report highlights the importance of patient-centered approach and multidisciplinary consensus within lack of established guidelines, given rarity of the case.

Febrile neutropenia and its associated hospitalization in breast cancer patients on docetaxel-containing regimen: A retrospective cohort study on duration of prophylactic GCSF administration.

PURPOSE: To compare febrile neutropenia (FN) incidence and hospitalization among breast cancer patients on docetaxel with no granulocyte colony-stimulating factors (GCSF) primary prophylaxis (PP), 4/5-day PP, or 7-day PP. METHODS: We identified 3916 breast cancer patients using docetaxel-cyclophosphamide (TC), doxorubicin-cyclophosphamide then docetaxel (AC-T), fluorouracil-epirubicin-cyclophosphamide then docetaxel (FEC-T), docetaxel-carboplatin-trastuzumab (TJH), or docetaxel-doxorubicin-cyclophosphamide (TAC) from a hospital pharmacy dispensing database in Hong Kong between 2014 and 2016. Patients were offered GCSF within 5 days since administering docetaxel. Outcomes included FN incidence, time to first hospitalization, hospitalization rate, and duration. RESULTS: In TC regimen, FN incidence (with odds ratio, OR) of patients with no PP, 4/5-day PP, and 7-day PP was 21.69%, 7.95% (OR 0.31, p < 0.001), and 5.33% (OR 0.20, p < 0.001), respectively. In TJH regimen, FN incidence of patients with no PP, 4/5-day PP, and 7-day PP was 38.26%, 8.33% (OR 0.15, p < 0.001), and 8.57% (OR 0.15, p < 0.001), respectively. FN incidence of patients on AC-T regimen with no PP and 4/5-day PP was 20.93% and 6.84%, respectively (OR 0.28, p = 0.005); with FEC-T regimen, the incidence was 9.91% and 4.77%, respectively (OR 0.46, p = 0.035). Only 3.27% FN cases were not hospitalized. Mean (±standard deviation, SD) time to first hospitalization was 8.21 ± 2.44 days. Mean (±SD) duration of hospitalization for patients with no PP, 4/5-day PP, and 7-day PP was 4.66 ± 2.60, 4.37 ± 2.85, and 5.12 ± 2.97 days, respectively. CONCLUSION: GCSF prophylaxis in breast cancer patients on docetaxel could reduce FN incidence and hospitalization. 4/5-day PP demonstrated similar efficacy to 7-day PP with superior saving benefits on healthcare expenditure.

Cytology cell blocks are suitable for immunohistochemical testing for PD-L1 in lung cancer.

Background: PD-L1 immunohistochemistry (IHC) testing is usually carried out on tissue blocks from core needle biopsy or surgical resections. In this study, we assessed the feasibility of using cytology cell blocks for PD-L1 IHC assay. Methods: A total of 1419 consecutive cases of non-small-cell lung cancer (NSCLC), including 371 cytology cell blocks, 809 small biopsies, and 239 surgical specimens, were included in the study. The cytology cell blocks were prepared with formalin only, methanol/alcohol only or both. PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1%-49% and ≥50% tumor cells. A total of 100 viable tumor cells were required for adequacy. Results: Of the cytology cell blocks, 92% of the specimens had an adequate number of tumor cells, not significantly different from small biopsies. The rate of TPS ≥50% differed between sample types and was observed in 42% of cytology cell blocks versus 36% of small biopsies (P = 0.04), and 29% of surgical resections (P = 0.001). The fixative methods did not affect the immunostaining, with overall PD-L1 high expression (TPS ≥50%) rates of 42% in formalin-fixed specimens versus 40% in specimens with combined fixation by methanol/alcohol and formalin (NS). The PD-L1 high expression rate was not associated with EGFR, ALK or KRAS molecular alterations. Higher stage (IV) was associated with higher PD-L1 TPS (P= 0.001). Conclusion: Our results show that when the TPS ≥50% is used as the end point, PD-L1 IHC performs well with cytology cell blocks. Cell blocks should be considered as a valuable resource for PD-L1 testing in advanced NSCLC. The clinical significance of higher PD-L1 IHC scores in cytology specimens needs to be evaluated prospectively.

Interspecies discrimination of A. fumigatus and siblings A. lentulus and A. felis of the Aspergillus section Fumigati using the AsperGenius® assay.

The AsperGenius® assay detects several Aspergillus species and the A. fumigatus Cyp51A mutations TR34/L98H/T289A/Y121F that are associated with azole resistance. We evaluated its contribution in identifying A. lentulus and A. felis, 2 rare but intrinsically azole-resistant sibling species within the Aspergillus section Fumigati. Identification of these species with conventional culture techniques is difficult and time-consuming. The assay was tested on (i) 2 A. lentulus and A. felis strains obtained from biopsy proven invasive aspergillosis and (ii) control A. fumigatus (n=3), A. lentulus (n=6) and A. felis species complex (n=12) strains. The AsperGenius® resistance PCR did not detect the TR34 target in A. lentulus and A. felis in contrast to A. fumigatus. Melting peaks for L98H and Y121F markers differed and those of the Y121F marker were particularly suitable to discriminate the 3 species. In conclusion, the assay can be used to rapidly discriminate A. fumigatus, A. lentulus and A. felis.

Durable remission of both multicentric Castleman's disease and Kaposi's sarcoma with valganciclovir, rituximab and liposomal doxorubicin in an HHV-8-positive, HIV-negative patient.

WHAT IS KNOWN AND OBJECTIVE: Human herpesvirus-8 (HHV-8)-positive, HIV-negative multicentric Castleman's disease is a rare lymphoproliferative disorder with no standardized treatment. Concurrent Kaposi's sarcoma, another HHV-8-related disease, is uncommon in HIV-negative patients. The role of antiviral therapy and rituximab in HIV-negative patients is not well established. CASE DESCRIPTION: We report a case of a 5-year, durable remission of HHV-8-positive, HIV-negative comorbid multicentric Castleman's disease and Kaposi's sarcoma treated with long-term valganciclovir, following initial rituximab and liposomal doxorubicin. WHAT IS NEW AND CONCLUSION: Currently, there is no defined role for antiviral therapy in the treatment of HIV-negative HHV-8-positive multicentric Castleman's disease and Kaposi's sarcoma. Ganciclovir followed by indefinite, continuous valganciclovir is thought to have contributed significantly to the durable response in this case.

Diagnostic Performance of Galactomannan Antigen Testing in Cerebrospinal Fluid.

Testing cerebrospinal fluid (CSF) for the presence of galactomannan (GM) antigen may help in diagnosing cerebral aspergillosis (CA). However, the use of the CSF GM test as a diagnostic test has been little studied. We evaluated its diagnostic performance by comparing the CSF GM optical density indexes (ODI) at different cutoffs in patients with probable and proven CA to those in patients without CA. Patients from 2 tertiary referral hospitals with suspected CA between 2004 and 2014 and in whom CSF GM ODI had been determined were selected. European Organization for Research and Treatment of Cancer/Invasive Infectious Diseases Study Mycoses Group (EORTC/MSG) definitions of invasive aspergillosis and CA were used, but with the exclusion of the test to be validated (i.e., the CSF GM test) as a microbiological EORTC/MSG criterion. The study population consisted of 44 patients (4 with proven CA, 13 with probable CA, and 27 with no CA). Of the 17 patients with CA, 15 had a CSF GM ODI of ≥2.0. Of 27 patients without CA, 26 had a CSF GM ODI of <0.5 and 1 had a CSF GM ODI of 8.2. When a GM CSF ODI cutoff of 1.0 was used, the sensitivity, specificity, and positive and negative predictive values were 88.2%, 96.3%, 93.8%, and 92.9%, respectively. The same results were found when a CSF GM ODI cutoff of 0.5 or 2.0 was used. Testing GM in CSF has a high diagnostic performance for diagnosing CA and may be useful to diagnose or virtually rule out the infection without the need for a cerebral biopsy.

Using a family history questionnaire to identify adult patients with increased genetic risk for sarcoma.

BACKGROUND: Sarcomas in adults can be associated with hereditary cancer syndromes characterized by early-onset predisposition to numerous types of cancer. Because of variability in familial presentation and the largely unexplained genetic basis of sarcomas, ascertainment of patients for whom a genetics evaluation is most indicated poses challenges. We assessed the utility of a Sarcoma Clinic Genetic Screening (scgs) questionnaire in facilitating that task. METHODS: Between 2008 and 2012, 169 patients (median age: 53 years; range: 17-88 years) completed a self-administered scgs questionnaire. A retrospective chart review was completed for all respondents, and descriptive statistics were reported. Probands were divided into two groups depending on whether they did or did not report a family history of Li-Fraumeni syndrome-type cancers. RESULTS: A family history of cancer (as far as 3rd-degree relatives) was reported in 113 of 163 sarcoma patients (69%). Eeles Li-Fraumeni-like (lfl) criteria were fulfilled in 46 probands (28%), Chompret lfl in 21 (13%), Birch lfl in 8 (5%), and classic Li-Fraumeni in none. In the 10 probands tested for TP53 mutations, 1 pathogenic mutation was found. Further investigation of selected families led to the discovery of germline mutations in MLH1, MSH2, and APC genes in 3 individuals. CONCLUSIONS: The scgs questionnaire was useful for ascertaining probands with sarcoma who could benefit from a genetic assessment. The tool allowed us to identify high-risk families fitting the criteria for lfl and, surprisingly, other hereditary cancer syndromes. Similar questionnaires could be used in other cancer-specific clinics to increase awareness of the genetic component of these cancers.

New method: Are tumor markers in vaginal-washing fluid significant in the diagnosis of primary ovarian carcinoma?

OBJECTIVE: Ovarian cancer is the seventh most common cancer in women worldwide, with nearly a quarter of a million women diagnosed every year. The serum tumor markers cancer antigens CA 125, CA 19-9, and carcinoembryonic antigen (CEA) are potentially of clinical value for the diagnosis of ovarian cancer. A diagnostic tool that is noninvasive, simple to perform, and specific is needed to predict primary ovarian cancer. The purpose of this study was to evaluate the diagnostic sensivitity and specificity of vaginal-washing tumor markers CA 125, CA 19-9, and CEA for diagnosis of primary ovarian cancer. MATERIALS AND METHODS: In the current prospective study, 30 patients with advanced primary ovarian cancer and 30 patients with benign ovarian cysts were enrolled. The vaginal-washing fluid samples were obtained the day before surgery and were immediately centrifuged and stored at -80 degrees C until analysis. Measurements of CA 125, CA 19-9, and CEA were determined using fully-automated chemiluminescent microparticle immunoassays. RESULTS: The vaginal fluid concentrations of CA 125, CA 19-9, and CEA in patients with primary ovarian carcinoma were significantly higher (p < 0.001) compared to those in patients with benign adnexal masses (p < 0.001). In the ROC curve analysis, the optimal cut-off values for the detection of primary ovarian cancer were >295 for CA 125 (p < 0.001), > 101 for CA 19-9 (p < 0.001), and >135 for CEA (p < 0.001). CONCLUSION: Vaginal-washing tumor markers CA 125, CA 19-9, and CEA are simple, noninvasive, and reliable diagnostic tests for the detection of primary ovarian cancer.

Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population.

We identified an MSH6 mutation (c.10C>T, p.Gln4*) causing Lynch syndrome (LS) in 11 French Canadian (FC) families from the Canadian province of Quebec. We aimed to investigate the molecular and clinical implications of this mutation among FC carriers and to assess its putative founder origin. We studied 11 probands and 27 family members. Additionally 6433 newborns, 187 colorectal cancer (CRC) cases, 381 endometrial cancer (EC) cases and 179 additional controls, all of them from Quebec, were used. Found in approximately 1 of 400 newborns, the mutation is one of the most common LS mutations described. We have found that this mutation confers a greater risk for EC than for CRC, both in the 11 studied families and in the unselected cases: EC [odds ratio (OR) = 7.5, p < 0.0001] and CRC (OR = 2.2, p = 0.46). Haplotype analyses showed that the mutation arose in a common ancestor, probably around 430-656 years ago, coinciding with the arrival of the first French settlers. Application of the results of this study could significantly improve the molecular testing and clinical management of LS families in Quebec.

Is gastrointestinal stromal tumor (GIST) originating from the rectovaginal septum GIST or extra-GIST (EGIST)? A case report with literature review.

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal (GI) tract that arise from primitive mesenchymal cells. Extragastrointestinal stromal tumors (EGISTs) are extremely rare tumors that show the features of GISTs outside the GI tract. Their most common locations are the omentum, mesentery, and retroperitoneum. The authors report herein a case of a 54-year-old woman with GIST in rectovaginal septum. The patient underwent low anterior resection of the rectum, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and partial resection of the posterior vagina. She received adjuvant therapy with an oral tyrosine-kinase inhibitor. She is presently healthy without any evidence of recurrence at 26 months after surgery. For GISTs arising in the rectovaginal septum, it is difficult to ascertain whether the tumor origin site is the rectum, rectovaginal septum, or vagina. In other words, it is difficult to classify these tumors as GISTs or EGISTs. More consideration for the exact origin should be given to the GIST in the rectovaginal septum for the precise diagnosis (GIST or EGIST) and risk classification in future.

The correlation between expression of synuclein-gamma, glucose transporter-1, and survival outcomes in endometrioid endometrial carcinoma.

PURPOSE: To evaluate the correlation between immunohistochemical expression of synuclein-gamma, glucose transporter-1, and survival outcomes in endometrioid endometrial carcinoma. MATERIALS AND METHODS: A tissue microarray was constructed using formalinfixed, paraffin-embedded tissue that included 23 early and 18 advanced cases. The intensity and area of the immunohistochemical reactions were evaluated using the semi-quantitative scoring system. RESULTS: Synuclein-y expression was higher in the advanced stage, although it was not statistically significant (p = 0.51). Glucose transporter-1 was overexpressed in the advanced stage (p = 0.01). Synuclein-gamma (score = 0 vs > 0) and glucose transporter-1 (score < or = 7 vs > 7) did not show any differences in overall survival (p = 0.54, p = 0.48) and disease-free survival (p = 0.61, p = 0.14). CONCLUSION: In this study the expression of synuclein-y and glucose transporter-1 were not considered to be a prognostic factor and were not related with survival outcomes in endometrioid endometrial carcinoma.

EGFR and K-ras gene mutation status in squamous cell anal carcinoma: a role for concurrent radiation and EGFR inhibitors?

BACKGROUND: There is a growing appreciation for radio-sensitiser use in multi-modal cancer treatment models. Squamous cell anal carcinoma (SCAC) is a rare gastrointestinal tumour traditionally treated with concurrent chemotherapy and radiation. Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, has demonstrated significant efficacy when combined with radiation in squamous cell carcinoma of the head and neck (SccH&N). We wanted to assess EGFR and Kirsten-ras (K-ras) status in SCAC to see whether it compares with SccH&N. METHODS: Over 90 SCAC paraffin-embedded biopsies were mounted onto a tissue microarray and were assessed for EGFR expression by immunohistochemistry. These samples were also assessed for the most frequently mutated K-ras and EGFR exons by high-resolution melting analysis. RESULTS: The EGFR was present in over 90% of samples tested. The K-ras and EGFR mutations were absent in all samples tested, although a synonymous single-nucleotide polymorphism was found in 3 out of 89 samples tested for EGFR exon 19. CONCLUSION: The low rate of K-ras and EGFR mutations, coupled with the high surface expression of EGFR, suggests similarity in the EGFR signalling pathway between SCAC and SccH&N, and thus a potential role for EGFR inhibitors in SCAC. To our knowledge this is the largest cohort of invasive SCAC samples investigated for EGFR and K-ras mutations reported to date.

EGFR tyrosine kinase mutation testing in the treatment of non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (nsclc) tumours with activating mutations of the epidermal growth factor receptor (efgr) tyrosine kinase are highly sensitized to the effects of oral tyrosine kinase inhibitors such as gefitinib and erlotinib, suggesting the possibility of targeted treatment of nsclc based on EFGR mutation status. However, no standardized method exists for assessing the EGFR mutation status of tumours. Also, it is not known if available methods are feasible for routine screening. To address that question, we conducted a validation study of methods used for detecting EGFR mutations in exons 19 and 21 at molecular laboratories located in five specialized Canadian cancer centres. METHODS: The screening methods were first optimized using cell lines harbouring the mutations in question. A validation phase using anonymized patient samples followed. RESULTS: The methods used at the sites were highly specific and sensitive in detecting both mutations in cell-line dna (specificity of 100% and sensitivity of at least 1% across all centres). In the validation phase, we observed excellent concordance between the laboratories for detecting mutations in the patient samples. Concordant results were obtained in 26 of 30 samples (approximately 87%). In general, the samples for which results were discordant were also less optimal, containing small amounts of tumour. CONCLUSIONS: Our results suggest that currently available methods are capable of reliably detecting exon 19 and exon 21 mutations of EFGR in tumour samples (provided that sufficient tumour material is available) and that routine screening for those mutations is feasible in clinical practice.

Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome.

Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case­control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984_3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2­78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95% CI = 1.8­217.2, p = 0.0006). MSH6*c.3959_3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients.

A case of ovarian endometrioid adenocarcinoma with yolk sac tumor in a 35-year-old woman.

Ovarian yolk sac tumor (YST) is a malignant ovarian neoplasm differentiated from primordial germ cells that occur in young age, while endometrioid carcinoma (ECA) is a müllerian epithelial tumor that usually occurs in older patients. The coexistence of an ovarian ECA and YST component is very rare. Only 12 cases have been reported until now according to a Medline search of the English literatures. We present a case of a simultaneous ECA and a YST component in a 35-year-old woman. Exploratory laparotomy was performed. The parts of both ovaries that showed an endometrioid-like glandular pattern were positive for cytokeratin 7 and negative for AFP, but the YST component was negative for cytokeratin 7 and positive for AFP. After completion of four courses of BEP chemotherapy, two courses of taxane and carboplatin chemotherapy were added. The patient failed to respond and succumbed to the disease after 12 months of follow-up.