Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy.

BACKGROUND: Single-dose human fibrinogen concentrate (FCH) might have haemostatic benefits in complex cardiovascular surgery. METHODS: Patients undergoing elective aortic surgery requiring cardiopulmonary bypass were randomly assigned to receive FCH or placebo. Study medication was administered to patients with a 5 min bleeding mass of 60-250 g after separation from bypass and surgical haemostasis. A standardized algorithm for allogeneic blood product transfusion was followed if bleeding continued after study medication. RESULTS: 519 patients from 34 centres were randomized, of whom 152 (29%) met inclusion criteria for study medication. Median (IQR) pretreatment 5 min bleeding mass was 107 (76-138) and 91 (71-112) g in the FCH and placebo groups, respectively (P=0.13). More allogeneic blood product units were administered during the first 24 h after FCH, 5.0 (2.0-11.0), when compared with placebo, 3.0 (0.0-7.0), P=0.026. Fewer patients avoided transfusion in the FCH group (15.4%) compared with placebo (28.4%), P=0.047. The FCH immediately increased plasma fibrinogen concentration and fibrin-based clot strength. Adverse event rates were comparable in each group. CONCLUSIONS: Human fibrinogen concentrate was associated with increased allogeneic blood product transfusion, an unexpected finding contrary to previous studies. Human fibrinogen concentrate may not be effective in this setting when administered according to 5-minute bleeding mass. Low bleeding rates and normal-range plasma fibrinogen concentrations before study medication, and variability in adherence to the complex transfusion algorithm, may have contributed to these results. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier no. NCT01475669; EudraCT trial no. 2011-002685-20.

Causal Inference in Oncology: Why, What, How and When.

Oncologists are faced with choosing the best treatment for each patient, based on the available evidence from randomized controlled trials (RCTs) and observational studies. RCTs provide estimates of the average effects of treatments on groups of patients, but they may not apply in many real-world scenarios where for example patients have different characteristics than the RCT participants, or where different treatment variants are considered. Causal inference defines what a treatment effect is and how it may be estimated with RCTs or outside of RCTs with observational - or 'real-world' - data. In this review, we introduce the field of causal inference, explain what a treatment effect is and what important challenges are with treatment effect estimation with observational data. We then provide a framework for conducting causal inference studies and describe when in oncology causal inference from observational data may be particularly valuable. Recognizing the strengths and limitations of both RCTs and observational causal inference provides a way for more informed and individualized treatment decision-making in oncology.

Health-related quality of life in patients with CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: results from the SPOTLIGHT and GLOW clinical trials.

BACKGROUND: First-line zolbetuximab plus chemotherapy (SPOTLIGHT, mFOLFOX6; GLOW, CAPOX) significantly improved progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy in patients with human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors were claudin 18 isoform 2-positive in the phase III SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies. We present patient-reported outcomes (PROs) from these studies. MATERIALS AND METHODS: Health-related quality of life (HRQoL) was measured in the full analysis sets using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Core Questionnaire (QLQ-C30) and Oesophago-Gastric Module (QLQ-OG25), Global Pain, and 5-level EQ-5D (EQ-5D-5L) questionnaires. Analyses focused on key PRO domains: global health status (GHS)/QoL, physical functioning, abdominal pain and discomfort, and nausea/vomiting. Least squares mean (LSM) changes from baseline and time to first definitive deterioration (TTDD) were evaluated combined across SPOTLIGHT and GLOW and for individual studies. Time to confirmed deterioration (TTCD) was evaluated independently for SPOTLIGHT and GLOW. RESULTS: The combined analysis set included 1072 patients (zolbetuximab plus chemotherapy, 537; placebo plus chemotherapy, 535). Compliance rates were similar between treatment arms. Similar trends were observed in the zolbetuximab versus placebo arms for LSM changes from baseline in key PRO domains, with no clinically meaningful deterioration. Nausea/vomiting worsened during the first few zolbetuximab cycles but later returned to baseline levels. Overall TTCD and TTDD results were similar between arms in both studies. CONCLUSIONS: Patients in SPOTLIGHT and GLOW maintained measured HRQoL relative to baseline when treated with first-line zolbetuximab added to chemotherapy. Zolbetuximab plus chemotherapy improved PFS and OS without negatively affecting HRQoL in key PRO domains compared with placebo plus chemotherapy.

Disulfiram-induced combined irreversible anterior ischemic optic neuropathy and reversible peripheral neuropathy: a prospective case report and review of the literature.

Disulfiram is an alcohol-deterring agent with few rare serious adverse effects, usually dose-related, reversible, and more frequent with comorbid alcohol and nicotine dependence. We report a prospective follow-up of such a case with reversible peripheral neuropathy and irreversible optic neuropathy.

An Audit of Breast Conservation Surgery for Breast Cancer - a 7-Year Experience from Southern India.

To audit the use of breast conservation surgery for breast cancer treatment in a tertiary care centre over a 7-year period, and also to chart the clinical, demographic and pathological characteristics of breast cancer patients treated in the setting of a referral centre in a middle income (MDI) group country. A retrospective analysis of the case records of all patients of invasive breast cancer treated at our institute between January 2014 and December 2020 was done after obtaining approval from the Institute Ethics Committee (IEC). The number of patients seen, age, parity, menopausal status, family history of cancer, laterality, site of tumour in the breast, the symptomatology, clinical stage and presence or absence of metastases was the clinical parameters examined. The pathological stage and grade of the tumour, receptor status, treatment offered according to stage and the patterns of failure with respect to the surgery performed were recorded. Statistical analysis was a direct head to head comparison of the percentage proportions of the different variables. A total of 685 patients of breast cancer were treated between January 2014 and December 2020. A total of 53% of the cohort was more than 45 years old and 56.7% were post menopausal. A total of 58.8% of the patients presented with a cancer in the left breast and in the upper outer quadrant. Nearly 41% of the tumours were more than 4 cm in size. The most common receptor profile in our patient population was ER positive, PR positive and HER 2 negative. A total of 27.7% of the patients were offered neo-adjuvant chemotherapy and 63.06% underwent upfront surgery. A total of 19.7% of all surgeries performed (overall) were breast conservation surgeries (BCS). The use of BCS showed an increasing trend over the 7 years studied rising from 16.79 to 25% (annually). The local failure rate for BCS was 11.8% but the incidence of distant metastases was not significantly different compared to the patients who underwent a mastectomy. Breast conservation is safe and feasible in a referral setting even in a middle income nation with multi-disciplinary treatment planning and needs to be adopted widely to preserve the body image and self esteem of patients with breast cancer.

Clinical and pathologic prognostic factors in adult granulosa cell tumors of the ovary.

The objective of this study was to determine the clinicopathologic prognostic factors in adult granulosa cell tumors of the ovary. A retrospective review of the records of patients of granulosa tumors who were treated at our institute over a period of 10 years (1995-2005) was done. Clinical, pathologic, and follow-up data were collected. A total of 34 patients who were treated during this period were subjected to analysis. Cox univariate analysis and Wilcoxon's test for multivariate analysis were used as part of the SPSS software for examining the data. It was found that optimal cytoreduction (P = 0.02), presence of nuclear atypia (P < 0.001), and increased mitoses (P = 0.03) were the three factors that impacted significantly on survival. Age, stage of the tumor, parity, and size of the tumor had no significant effect on survival. Patients who received chemotherapy had a better median disease-free survival than those who did not (60 vs 48 months), but this did not reach statistical significance (P = 0.08). Optimal cytoreduction, nuclear atypia, and increased mitoses are the statistically significant prognostic factors and may be used for selecting patients for adjuvant therapy.

Sarcomatoid carcinoma of the penis: Clinicopathologic features.

Sarcomatoid carcinomas are biphasic tumors, which can occur at any site in the human body. Very few cases have been reported in the literature as arising from the penis. A few studies consider these tumors as a variant of squamous cell carcinoma or a metaplastic differentiation of the mesenchyme. Their clinical behavior is aggressive with both blood borne and lymphatic metastases. Treatment is by surgical excision, and dissected lymph nodes have shown both epithelial and sarcomatous components. We report a 50-year-old gentleman, with a sarcomatoid carcinoma of the penis, which was confirmed immunopathologically. The rarity of this entity makes it a clinicopathologic curiosity.

Asymmetric cell division--how flowering plant cells get their unique identity.

A central question in biology is how cell fate is specified during development of a multicellular organism. Flowering plants use two major pathways of asymmetric cell divisions in a spatio-temporal manner to achieve required cellular differentiation. In the 'one mother--two different daughters' pathway, a mother cell mitotically divides to produce two daughter cells of different size and fate. By contrast, the 'coenocyte-cellularization' pathway involves formation of a coenocyte, nuclear migration to specific locations of the coenocyte and cellularization of these nuclei by unique wall forming processes. Given that cell fate determinants play a key role in establishing cell identity, their allocation to daughter cells in the two pathways needs to be understood in terms of the unique cell cycle regulatory mechanisms involved. Most of the information available on cell fate determination in flowering plants is in the form of genes identified from mutant analysis. Novel techniques of interrogating individual plant cells in vivo are necessary to advance the extant knowledge from genetics to functional genomics data bases.

Role of programmed cell death in development.

Programmed cell death (PCD) is an integral part of both animal and plant development. In animals, model systems such as Caenorhabditis elegans, Drosophila melanogaster, and mice have shown a general cell death profile of induction, caspase mediation, cell death, and phagocytosis. Tremendous strides have been made in cell death research in animals in the past decade. The ordering of the C. elegans genes Ced-3, 4 and 9, identification of caspase-activated DNase that degrades nuclear DNA during PCD, identification of signal transduction modules involving caspases as well as the caspase-independent pathway, and the involvement of mitochondria are some of the findings of immense value in understanding animal PCDs. Similarly, the caspase inactivation mechanisms of infecting viruses to stall host cell death give a new dimension to the viral infection process. However, plant cell death profiles provide an entirely different scenario. The presence of a cell wall that cannot be phagocytosed, absence of the hallmarks of animal PCDs such as DNA laddering, formation of apoptotic bodies, a cell-death-specific nuclease, a biochemical machinery of killer enzymes such as caspases all point to novel ways of cell elimination. Large gaps in our understanding of plant cell death have prompted speculative inferences and comparisons with animal cell death mechanisms. This paper deals with both animals and plants for a holistic view on cell death in eukaryotes.

Asymmetric cell divisions in flowering plants - one mother, "two-many" daughters.

Plant development shows a fascinating range of asymmetric cell divisions. Over the years, however, cellular differentiation has been interpreted mostly in terms of a mother cell dividing mitotically to produce two daughter cells of different fates. This popular view has masked the significance of an entirely different cell fate specification pathway, where the mother cell first becomes a coenocyte and then cellularizes to simultaneously produce more than two specialized daughter cells. The "one mother - two different daughters" pathways rely on spindle-assisted mechanisms, such as translocation of the nucleus/spindle to a specific cellular site and orientation of the spindle, which are coordinated with cell-specific allocation of cell fate determinants and cytokinesis. By contrast, during "coenocyte-cellularization" pathways, the spindle-assisted mechanisms are irrelevant since cell fate specification emerges only after the nuclear divisions are complete, and the number of specialized daughter cells produced depends on the developmental context. The key events, such as the formation of a coenocyte and migration of the nuclei to specific cellular locations, are coordinated with cellularization by unique types of cell wall formation. Both one mother - two different daughters and the coenocyte-cellularization pathways are used by higher plants in precise spatial and time windows during development. In both the pathways, epigenetic regulation of gene expression is crucial not only for cell fate specification but also for its maintenance through cell lineage. In this review, the focus is on the coenocyte-cellularization pathways in the context of our current understanding of the asymmetric cell divisions. Instances where cell differentiation does not involve an asymmetric division are also discussed to provide a comprehensive account of cell differentiation.

Low-dose Amisulpride for Debilitating Clozapine-induced Sialorrhea: Case Series and Review of Literature.

Clozapine-induced sialorrhea (CIS) affects about one-third of patients treated with clozapine, at times can be stigmatizing, socially embarrassing, disabling, affect quality-of-life, cause poor compliance and can be potentially life-threatening adverse effect. Prompt and effective treatment of CIS may assist treatment tolerability, adherence, and better outcomes in patients with treatment nonresponsive schizophrenia. The beneficial effect of amisulpride augmentation of clozapine therapy for such patients may be enhanced by its anti-salivatory effect on CIS. Current series of five subjects who developed CIS that responded poorly to anticholinergic drugs found drastic improvement in daytime and nocturnal CIS with very low-dose (50-100 mg/day) of amisulpride. Low-dose amisulpride augmentation may also provide strong ameliorating effect on CIS. Nevertheless, a long-term, large-scale study with a broader dose range is warranted to evaluate the stability of this effect across time.

Psychological autopsy and necropsy of an unusual case of suicide by intravenous toluene.

Toluene (methylbenzene; volatile hydrocarbon) is an industrial solvent that causes major injury to the lungs; the organ being the first capillary bed encountered. We report an unusual case of suicide by a 24-year-old male, paramedical professional, with fatal outcome within 16 h of intentional, intravenous self-administration of toluene, with clinical presentation of acute respiratory distress syndrome. Psychological autopsy revealed severe depressive disorder and solvent (inhalant) abuse, with marital disharmony as the precipitating stressor for suicide. Necropsy revealed diffuse congestion of internal organs like lungs and liver, epicardial petechial hemorrhages, and gastric hemorrhages. Treatment of toluene poisoning includes supportive care as no specific antidote is available. Early and aggressive management may be conducive to a favorable outcome with minimal residual pulmonary sequelae. Relevant literature of toluene poisoning was identified via PubMed, PubChem, ToxNet, Hazardous Substances Data Bank (HSDB), Embase, and PsycINFO. To our knowledge, this is the first case of suicide by intravenous administration of toluene in the literature.

Harnessing the developmental potential of nucellar cells: barriers and opportunities.

Angiosperm nucellar cells can either use or avoid meiosis in vivo, depending on the developmental context. This unique ability contrasts with the conditions required in vitro, either for a reconstituted oocyte to avoid meiosis and produce clones by somatic cell nuclear transfer (SCNT), or for mammalian stem cells to undergo meiosis and produce synthetic sex cells (gametes). Current biotechnological initiatives to harness the potential of nucellar cells are based on the transfer of apomixis genes to sexual crop plants with the aim of producing clones through seeds. The elusive genetic basis of apomixis compels us to examine whether this process involves epigenetic factors. The elegant and versatile developmental platform available in nucellar cells should be explored as a genome-scale science and compared with mammalian stem cell biology for a holistic understanding of developmental programming and reprogramming in eukaryotes.

Organic Depression and Terson's Syndrome in Adult Polycystic Kidney Disease: Case Report and Review of Literature.

Depressive symptoms are common in neurological diseases, at times posing dilemma in organic or functional origin. Cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes that resemble primary depressions both clinically and therapeutically in about half of the patients following acute stroke. Terson's syndrome is the direct occurrence of vitreous hemorrhage following subarachnoid/subdural hemorrhage, often overlooked in the acute setting. Autosomal dominant (adult) polycystic kidney disease may be associated with berry aneurysms and hypertension, and may lead to intracranial bleeds. We report an unusual case of organic depression and Terson's syndrome in a 50-year-old female with polycystic kidney disease and hypertension, following anterior communicating artery aneurysmal subarachnoid bleed with bilateral subdural extension. Management included anti-hypertensives, antiepileptics, neodymium: YAG laser photocoagulation, and aneurysmal clipping.

Disulfiram-induced reversible hypertension: a prospective case series and review of the literature.

Disulfiram (DSF) is one of the recommended aids in the management of selected patients with alcohol dependence. Hypertension (HTN) as an adverse effect of DSF therapy is less understood. In our prospective case series of 7 subjects with co-morbid alcohol and nicotine dependence, a temporal, dose-dependent, and reversible grade 1-3 HTN within 1-6 weeks of initiation of DSF therapy (125-500 mg/day) with no other detectable causes of HTN was noted. Challenges and strategies surrounding diagnosis and treatment along with mean change and percentage rise in blood pressure are described. Literature review and clinical description of case series may suggest neurobiological role in its causation. HTN may be a clinically significant, dose-dependent, and reversible adverse effect of DSF therapy, especially in co-morbid alcohol and nicotine-dependent patients. Awareness amongst clinicians may render better health care delivery to subjects with alcohol dependence.

Disulfiram induced reversible hypertension: a prospective case study and brief review.

Disulfiram (DSF) is one of the recommended aids in the management of alcohol dependence. Hypertension may be a clinically significant, dose-dependent, and usually reversible adverse event of DSF therapy. We report 6 month prospective study of normotensive case of comorbid alcohol and tobacco dependence that developed reversible stage-II hypertension within 2-4 weeks of DSF therapy. We suggest that regular monitoring of blood pressure at least fortnightly for 1(st) 3 months, followed by monthly for next 3 months, and later once in 3 months, may possibly detect "silent" adverse event of DSF - hypertension.

Linezolid-induced near-fatal serotonin syndrome during escitalopram therapy: case report and review of literature.

Linezolid is a synthetic antimicrobial agent of the oxazolidinone class with weak, nonspecific inhibitor of monoamine oxidase enzymes. Concomitant therapy with an adrenergic or serotonergic agent or consuming tyramine (>100 mg/day) may induce serotonin syndrome (SS). We present a case report of near-fatal adverse interaction between linezolid and escitalopram inducing SS in a 65-year-old woman with sepsis, under empirical antibiotic treatment. This report also summarizes the current relevant literature as identified via PubMed, EMBASE, and PsycINFO, supplemented with a manual search of cross references.