Case report: From palliative to potentially curative - the advent of immunotherapy providing hope to advanced gallbladder adenocarcinoma.

Introduction: Biliary tract cancers (BTC) are often diagnosed at an advanced stage where prognosis is poor and curative-intent surgery is infeasible. First-line cisplatin-gemcitabine chemotherapy for advanced gallbladder cancer has remained unchanged over more than a decade, but recent developments in immunotherapy such as durvalumab have highlighted promise as a combination treatment regime with current standard chemotherapy. Methods: In this case description, we present a case of locally-advanced gallbladder adenocarcinoma involving the biliary confluence that was initially planned for an extended right hepatectomy after portal vein embolization. Interval imaging revealed peritoneal metastasis, which was confirmed on diagnostic laparoscopy and biopsy. The patient underwent 8 cycles of cisplatin 25 mg/m2 and gemcitabine 1,000 mg/m2 chemotherapy on days 1 and 8 of each 21-day cycle, with durvalumab (Imfinzi®) 1,500 mg immunotherapy on day 1 of every cycle, in accordance with the treatment protocol of the TOPAZ-1 trial. Repeat imaging demonstrated a stable primary lesion with no further evidence of peritoneal disease. The patient subsequently underwent curative-intent conversion surgery with an extended right hepatectomy and Roux-en-Y hepaticojejunostomy, which were completed through a fully minimally-invasive laparoscopic approach. Results: Final pathological TNM classification was ypT1aN0, with near-complete pathological response to pre-surgical therapy, uninvolved margins (R0 resection) and tumour shrinkage from 2.5 centimetres on pre-operative cross-sectional imaging to 0.5 centimetres on final histology. The patient had an uneventful post-operative course, and was fit for discharge by the fourth post-operative day. He remained well after three months of routine post-operative follow-up, with no significant post-operative complications and biochemical or radiological evidence of disease recurrence. Conclusion: Our case description highlights the immense potential of combination durvalumab immunotherapy with cisplatin-gemcitabine chemotherapy in the treatment of advanced gallbladder adenocarcinoma. The patient's locally advanced disease was initially planned for complex open surgery, prior to discovery of peritoneal metastasis rendering it inoperable. This was successfully down-staged with combination therapy to eventual R0 resection via minimally-invasive surgery. In addition, this case description demonstrates the feasibility of a fully laparoscopic approach with postulated benefits of diagnostic re-evaluation of peritoneal disease, reduced wound pain and shorter length of hospital stay.

A systematic review and meta-analysis of mediastinoscopy-assisted transhiatal esophagectomy (MATHE).

BACKGROUND: Transhiatal esophagectomy (THE) avoids thoracotomy but sacrifices mediastinal lymphadenectomy. Mediastinoscopy-assisted transhiatal esophagectomy (MATHE) allows for visualisation and en-bloc dissection of mediastinal lymph nodes while retaining the benefits of THE. However, given its novel inception, there is a paucity of literature. This study aimed to conduct the first meta-analysis to explore the efficacy of MATHE and clarify its role in the future of esophagectomy. METHODS: Four databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched from inception to May 1, 2023. Studies were included if they reported outcomes for patients with esophageal cancer who underwent MATHE. Meta-analyses of proportions and pooled means were performed for the outcomes of intraoperative blood loss, lymph node (LN) harvest, mean hospital length of stay (LOS), mean operative time, R0 resection, conversion rates, 30-day mortality rate, 5-year OS, and surgical complications (anastomotic leak, cardiovascular [CVS] and pulmonary complications, chyle leak and recurrent laryngeal nerve palsy [RLN]). Sensitivity analyses were performed for outcomes with substantial statistical heterogeneity. RESULTS: The search yielded 223 articles; 28 studies and 1128 patients were included in our analysis. Meta-analyses of proportions yielded proportion rates: 30-day mortality (0 %, 95 %CI 0-0), 5-year OS (60.5 %, 95 %CI 47.6-72.7), R0 resection (100 %, 95 %CI 99.3-100), conversion rate (0.1 %, 95 %CI 0-1.2). Among surgical complications, RLN palsy (14.6 %, 95 %CI 9.5-20.4) were most observed, followed by pulmonary complications (11.3 %, 95 %CI 7-16.2), anastomotic leak (9.7 %, 95 %CI 6.8-12.8), CVS complications (2.3 %, 95 %CI 0.9-4.1) and chyle leak (0.02 %, 95 %CI 0-0.8). Meta-analysis of pooled means yielded means: LN harvest (18.6, 95 %CI 14.3-22.9), intraoperative blood loss (247.1 ml, 95 %CI 173.6-320.6), hospital LOS (18.1 days, 95 %CI 14.4-21.8), and operative time (301.5 min, 95 %CI 238.4-364.6). There was moderate-to-high statistical heterogeneity. Findings were robust to sensitivity analyses. CONCLUSION: MATHE is associated with encouraging post-operative mortality and complication rates, while allowing for radical mediastinal lymphadenectomy with reasonable lymph node harvest.

A Case of Parathyroid Carcinoma in Renal Hyperparathyroidism.

Introduction: Parathyroid carcinoma is a rare malignant endocrine tumor that is usually associated with primary hyperparathyroidism. The coexistence of parathyroid carcinoma and renal hyperparathyroidism is a rare phenomenon. Hence, we present a case of parathyroid carcinoma in a patient with tertiary hyperparathyroidism. Case Presentation: Our patient is a 31-year-old woman with a past medical history of end-stage renal failure (ESRF), on hemodialysis for the past 18 years. She was referred by her nephrologist to the endocrine surgery department for consideration of parathyroidectomy in view of long-standing tertiary hyperparathyroidism complicated by hypercalcemia. Bedside ultrasonography scan (US) of the thyroid revealed three parathyroid glands and a hypoechoic right lower pole thyroid nodule with central calcification. Fine-needle aspiration cytology was performed for the suspected thyroid nodule on the same day, which eventually yielded a follicular lesion of undetermined significance. A right hemithyroidectomy and total parathyroidectomy with deltoid implantation was performed. Intraoperative exploration revealed that the thyroid nodule noted at initial US was found to be the right superior parathyroid gland invading into the right thyroid itself. The right superior parathyroid gland was excised en bloc with the right hemithyroidectomy. Post-operatively, the patient was hypocalcemic but was discharged well on post-operative day 5. Histopathological diagnosis of the right hemithyroidectomy specimen containing the right superior parathyroid gland was consistent with that of parathyroid carcinoma. Conclusion: Parathyroid carcinoma is a rare entity that is difficult to diagnose. In patients with ESRF, the presence of concurrent tertiary hyperparathyroidism makes this even more challenging.

O-Net: A Fast and Precise Deep-Learning Architecture for Computational Super-Resolved Phase-Modulated Optical Microscopy.

We present a fast and precise deep-learning architecture, which we term O-Net, for obtaining super-resolved images from conventional phase-modulated optical microscopical techniques, such as phase-contrast microscopy and differential interference contrast microscopy. O-Net represents a novel deep convolutional neural network that can be trained on both simulated and experimental data, the latter of which is being demonstrated in the present context. The present study demonstrates the ability of the proposed method to achieve super-resolved images even under poor signal-to-noise ratios and does not require prior information on the point spread function or optical character of the system. Moreover, unlike previous state-of-the-art deep neural networks (such as U-Nets), the O-Net architecture seemingly demonstrates an immunity to network hallucination, a commonly cited issue caused by network overfitting when U-Nets are employed. Models derived from the proposed O-Net architecture are validated through empirical comparison with a similar sample imaged via scanning electron microscopy (SEM) and are found to generate ultra-resolved images which came close to that of the actual SEM micrograph.

Systematic Review of the Volume-Outcome Relationship for Radical Prostatectomy.

CONTEXT: Radical prostatectomy (RP) is one of the most complex urological procedures performed. Higher surgical volume has been found previously to be associated with better patient outcomes and reduced costs to the health care system. This has resulted in some regionalization of care toward high-volume facilities and providers; however, the preponderance of RPs is still performed at low-volume institutions. OBJECTIVE: To provide an updated systematic review of the association of hospital and surgeon volume on patient and system outcomes after RP, including robot-assisted RP. EVIDENCE ACQUISITION: A systematic review of literature was undertaken, searching PubMed (1959-2016) for original articles. Selection criteria included RP, hospital and/or surgeon volumes as predictor variables, categorization of hospital and/or surgeon volumes, and measurable end points. EVIDENCE SYNTHESIS: Overall 49 publications fulfilled the inclusion criteria. Most of the studies demonstrated that higher-volume surgeries are associated with better outcomes including reduced mortality, morbidity, postoperative complications, length of stay, readmission, and cost-associated factors. The volume-outcome relationship is maintained in robotic surgery. Eleven studies assessed hospital and surgeon volume simultaneously, and findings reflect that neither is an independent predictor variable affecting outcomes. The studies varied in how volume cutoffs were categorized as well as how the volume-outcome relationship was methodologically evaluated. CONCLUSIONS: Contemporary evidence continues to support the relationship between high-volume surgeries with improved RP outcomes. Recent studies demonstrate that the volume-outcome relationship applies to robot-assisted RP and may be applied for potential cost savings in health care. An increase in the number of international studies suggests reproducibility of the association. Although regionalization of surgical care remains a contentious issue, there is an increasing body of evidence that short-term outcomes are improved at high-volume centers for RP. PATIENT SUMMARY: This systematic review of the latest literature found that higher surgical volume was associated with improved outcomes for radical prostatectomy.

A pilot study of the utility of choline PET-CT in prostate cancer biochemical relapse following radical prostatectomy.

INTRODUCTION: To evaluate the detection rate of positive choline PET-CT and its clinical role in assisting with management decisions and the correlation between positive choline PET-CT and clinical/pathological parameters in prostate cancer patients with biochemical relapse following radical prostatectomy. METHODS: This was a longitudinal observational pilot study of 34 patients who received choline PET-CT scans with biochemical relapse after radical prostatectomy. Variables including peak PSA, PSA doubling time (DT), Gleason score, age, initial PSA at diagnosis, use of ADT prior to PET and initial clinical staging were statistically analysed to assess for independent predictive factors for positive PET findings. RESULTS: Choline PET-CT was positive in 38.2% of patients (13/34). The only statistically significant predictor for positive PET-CT was the use of ADT prior to PET-CT, with OR 18.7 (95% CI, 2.87-122.45), P < 0.01. Mean peak PSA for patients with positive PET-CT was 5.5 ± 4.8 ng/mL. Patients with positive PET-CT had a mean PSA DT of 5.1 ± 3.8 months and mean total Gleason of 7.6 ± 0.8. Although these variables were not statistically significant, they showed a tendency towards significance. At Receiver Operator Characteristics (ROC) analysis, a peak PSA value of 1.65 ng/mL and PSA DT of 4.4 months were determined to be the optimal cut-off values predicting positive PET-CT. CONCLUSION: Choline PET-CT has its potential as a diagnostic modality enabling the detection of occult prostate cancer recurrence and to differentiate localised disease from systemic disease thus guiding management. Use of ADT prior to PET-CT is a significant predictor of positive PET-CT. Patients with a short PSA DT, high-peak PSA and high Gleason score should also be considered for choline PET-CT.

Referring advanced cancer patients for palliative treatment: a national structured vignette survey of Australian GPs.

BACKGROUND: Although (general practitioners) GPs have a role in managing patients with advanced cancer, little is known about their referral decisions. AIM: The aim of this study was to explore, using structured vignettes, how GPs might manage patients presenting with advanced cancer. DESIGN: A self-administered survey consisting of structured vignettes was administered to GPs in Australia. Fifty-six vignettes describing patients who may benefit from palliative care and/or treatment were constructed encompassing seven advanced cancer diagnoses (cerebral metastasis, lung metastases, renal cancer, bone metastases, ulcerating skin metastases, spinal metastases and stridor) and three clinical variables (age, prognosis and mobility). Seven vignettes were presented to each respondent. Respondents were asked if they would refer the patient and the benefits of different treatment modalities. Participant responses were compared with responses provided by an expert panel. Logistic regression and parametric tests were used to estimate odds of referral. SETTING/PARTICIPANTS: The respondents were GPs, currently registered and practicing in Australia. Participants were selected randomly from a national list of practitioners. RESULTS: Four hundred and seven questionnaires were received. There was wide variation (31%-97%) in the proportion of respondents who agreed with the expert panel. The odds of referral for radiotherapy varied the most. Significant predictive variables included patient age, mobility and prognosis and respondent demographics. CONCLUSION: GPs' referral decisions for patients with advanced cancer appear to deviate from expert opinion and can be predicted using respondent and patient characteristics. If these data were reflected in clinical practice some patients may not be offered helpful palliative treatment options.

Racial variations in booking haemoglobin of primigravidae in Malaysia: a prospective study.

BACKGROUND: Variations in racial haemoglobin had been previously described in multiple studies locally and abroad. This study was conducted to quantify the differences in haemoglobin of booking primigravidae amongst the three major races in Malaysia at the antenatal clinic of University Malaya Medical Centre, Kuala Lumpur. FINDINGS: One year prospective study of booking full blood count sample of primigravidae taken in one centre was conducted. Multiple comparative analyses of the booking haemoglobin were performed using the One-way ANOVA comparative mean test in each trimester. 622 primigravidae without any known history of haematological disorders were recruited into the study. The mean haemoglobin for the Indian race was the lowest compared to the two other races in the second and the third trimesters, and it was found to be statistically significant lower (p- value 0.001) than the Malay race in the second trimester. It was also found that the Indian race had a significantly higher incidence of moderate to severe anaemia (p- value: 0.029). The prevalence of anaemia in our study population is also significantly higher in the Indian population (p- value: 0.01). CONCLUSIONS: The findings from this study have established that there is racial preponderance to anaemia in pregnancy. The Indian race is at a higher risk of having anaemia in pregnancy particularly in the second trimester.

Tensile and Compressive Responses of Ceramic and Metallic Nanoparticle Reinforced Mg Composites.

In the present study, room temperature mechanical properties of pure magnesium, Mg/ZrO2 and Mg/(ZrO2 + Cu) composites with various compositions are investigated. Results revealed that the use of hybrid (ZrO2 + Cu) reinforcements in Mg led to enhanced mechanical properties when compared to that of single reinforcement (ZrO2). Marginal reduction in mechanical properties of Mg/ZrO2 composites were observed mainly due to clustering of ZrO2 particles in Mg matrix and lack of matrix grain refinement. Addition of hybrid reinforcements led to grain size reduction and uniform distribution of hybrid reinforcements, globally and locally, in the hybrid composites. Macro- and micro- hardness, tensile strengths and compressive strengths were all significantly increased in the hybrid composites. With respect to unreinforced magnesium, failure strain was almost unchanged under tensile loading while it was reduced under compressive loading for both Mg/ZrO2 and Mg/(ZrO2 + Cu) composites.

The influence of testosterone suppression and recovery on sexual function in men with prostate cancer: observations from a prospective study in men undergoing intermittent androgen suppression.

PURPOSE: We investigated the effects of testosterone change on the sexual function of men with prostate cancer undergoing intermittent maximal androgen deprivation therapy. MATERIALS AND METHODS: We conducted a phase II cohort study of 250 patients with prostate cancer undergoing intermittent maximal androgen deprivation therapy. Flutamide (Eulexin®) 250 mg 3 times daily and leuprolide (Lucrin®) 22.5 mg were given during a 9-month treatment phase (ONPhase). Therapy was ceased provided that prostate specific antigen was 4 ng/ml or less. Monitoring continued every 3 months for a further 2 years (OFFPhase) unless re-treatment occurred. Sexual function was assessed with the QLQ-PR25 version 3.0 prostate module in conjunction with the QLQ-C30 questionnaire at baseline and every 3 months thereafter. RESULTS: At baseline 46% of patients reported sexual activity with almost half (43%) reporting mild or no erectile problems. Of the men 63% reported an interest in sex (libido), with 28% reporting moderate to high libido. In addition, 26% felt less masculine as a result of illness or treatment. By 3 months of ONPhase all parameters deteriorated, worsening to a low at 9 months. Only 13% of the men reported sexual activity and 10% reported moderate to high libido. The proportion of men feeling less masculine increased to 50%. During the OFFPhase recovery was observed. Of those previously sexually active men 52% resumed sexual activity. Of these patients all reported erectile function returning to baseline. Levels of libido, masculinity and sexual activity recovered but not to baseline levels. CONCLUSIONS: Libido, sexual activity and perceptions of masculinity deteriorate during ONPhase. Of the sexually active men at baseline half will resume sexual activity despite 9 months of androgen deprivation therapy.

Outcomes from combined chemoradiotherapy in unresectable and locally advanced resected cholangiocarcinoma.

PURPOSE: Whilst surgery is the only potentially curative treatment for cholangiocarcinoma, many patients are either unfit for major surgery or have unresectable disease. Patients who undergo attempted curative resective surgery often have involved resection margins. The role of radiotherapy in these settings has not been clarified and is often not considered because of fears of late complications, especially liver and gastrointestinal toxicity. We present our experience of treating cholangiocarcinoma, either unresectable or locally advanced, with conformal radiotherapy and concurrent chemotherapy, examining survival, toxicity, patterns of failure and details of radiotherapy and chemotherapy administered. METHODS: Between 1995 and 2005, 20 patients, median age 60.5 years (range 45-78 years) with cholangiocarcinoma received radical conformal radiotherapy (median dose 46 Gy in 1.8-2.0 Gy fractions) with concurrent cisplatin/5-FU and sequential gemcitabine chemotherapy. RESULTS: Overall median survival was 20.4 months, 2 year survival, 43% and relapse-free survival, 9.6 months. 19/20 patients (95%) have died. One patient remains alive with liver and bone metastases. First site of failure was local and within radiotherapy field in 9/20 (45%) patients. No patient required interruption of radiotherapy for radiation toxicity, and none experienced subsequent late liver toxicity. CONCLUSIONS: The survival of this group of historically poor prognosis patients is encouraging. Durable local control was achieved in a majority of patients having chemoradiotherapy and toxicity was not severe. Although most patients still succumbed to disease, treatment delayed onset of progression. Conformal radiotherapy should be considered as an integral component in new investigative approaches to treatment in this rare cancer.

Lamotrigine adjunctive therapy for refractory generalized tonic-clonic seizures.

BACKGROUND: Primary generalized tonic-clonic seizures are one of a number of generalized seizure types which also includes absence, myoclonic and atonic seizures. Effective control of tonic-clonic seizures is required to reduce the risk of injury and death and to improve quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not and usually take a combination of antiepileptic drugs. OBJECTIVES: To assess the effectiveness of adjunctive lamotrigine for refractory primary generalized tonic-clonic seizures. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE (Ovid) 1950 to June 2010. No language restrictions were imposed. We also contacted GlaxoSmithKline, manufacturers of lamotrigine. SELECTION CRITERIA: Randomised parallel or cross-over add-on trials of add-on lamotrigine for refractory primary generalized tonic-clonic seizures. DATA COLLECTION AND ANALYSIS: Outcome measures were: proportion of people (1) with 50% or greater reduction in frequency; (2) with cessation of seizures; (3) who had treatment withdrawn; (4) with adverse effects; and (5) cognitive effects; (6) quality of life outcome measures. Data were independently extracted by review authors. MAIN RESULTS: Two small trials were found that met the inclusion criteria. Due to differences in study design we decided not to undertake a meta-analysis. One placebo controlled cross-over trial (26 participants) showed a significant 50% reduction in tonic-clonic seizure frequency with lamotrigine. Rash was the only adverse effect causing discontinuation (N = 7). A placebo controlled parallel trial comparing 117 participants found a significant median percent reduction in tonic-clonic seizure frequency of 66.5% with lamotrigine compared with 34.2% with placebo (P = 0.006). The most common adverse events were dizziness, somnolence and nausea. AUTHORS' CONCLUSIONS: Two short term trials indicate that lamotrigine has efficacy against primary generalized tonic-clonic seizures; however, this evidence is insufficient to inform clinical practice and longer term active controlled trials are required.