Most women unaware of the signs of an aggressive form of breast cancer

 October is National Breast Cancer Awareness Month, and a new national survey commissioned by The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) found that most women are unaware of the unusual symptoms of a particularly aggressive and deadly form of the disease known as inflammatory breast cancer.

The survey – which was conducted online among 1,100 U.S women ages 18 and older – revealed that while 4 in 5 women (78%) recognize a lump in the breast as a sign of breast cancer, less than half of women would flag redness of the breast (44%), pitting/thickening of the skin (44%), or one breast feeling warmer or heavier than the other (34%) as possible symptoms of breast cancer; specifically, the rare and highly aggressive form of the disease known as inflammatory breast cancer. 

The disease can occur in any part of the breast and in any molecular sub-form of the disease. It is often misdiagnosed because it mimics symptoms similar to a breast infection. Those signs include:

• an orange peel-like texture or dimpling of skin; 
• feeling of heaviness; 
• tightening of the skin; 
• engorgement of the breast; and 
• infection-like redness.

“Women should know that radical changes to the breast are not normal, and breast self-exams are still very important. Some 50% of inflammatory breast cancers are diagnosed as stage 4 disease,” said Dr. Ko Un Park, a surgical oncologist who leads a new Inflammatory Breast Cancer Program at the OSUCCC – James’ Stefanie Spielman Comprehensive Breast Center. “It is important for women to recognize changes in both the appearance and feel of their breasts so that changes can be discussed quickly with a physician.”

She notes that even in the medical community, physicians and providers are not accustomed to thinking about a red breast as a sign associated with inflammatory breast cancer because it is such a rare disease.

“Although inflammatory breast cancer only represents 1% to 5% of all breast cancers in the United States, it is a sneaky disease and challenging to diagnose. It is critical that clinicians have a high level of familiarity with its subtle signs and be prepared to take immediate action to avoid belated diagnosis,” Dr. Park said. 

Inflammatory breast cancer clinic launched 

With leadership from Park and breast radiologist Dr. Amy Kerger, the OSUCCC – James has created an inflammatory breast cancer multidisciplinary team that includes surgical, medical and radiation oncologists, as well as breast radiologists, plastic/reconstructive surgeons, physical therapists and nurses. The effort has led to implementation of a formal best-practice clinical decision tree to help the OSUCCC – James medical team triage and rapidly respond to potential inflammatory breast cancer cases.

“Our goal is to push these patients to the front of the line, rapidly mobilizing a treatment plan so that therapy can begin as soon as possible,” Dr. Park said. The team is working with primary care and obstetricians/gynecologists to bring more awareness of this disease and the nuances of diagnosing and treating it.

To learn more about breast cancer treatment at the OSUCCC – James, visit cancer.osu.edu/breastcancer.

Survey methodology:
This survey was conducted online within the United States by The Harris Poll on behalf of The Ohio State University Wexner Medical Center from September 22-26, 2022, among 2,044 U.S. adults ages 18+ among 1,100 of whom are women. The sampling precision of Harris online polls is measured by using a Bayesian credible interval. For this study, the sample data is accurate to within +/- 2.8 percentage points using a 95% confidence level. For complete survey methodology, including weighting variables and subgroup sample sizes, please contact Amanda.Harper2@osumc.edu.

https://www.eurekalert.org/news-releases/967227

U.S. VC firms pull back from late-stage deals amid stormy markets, valuation concerns

 Startups seeking late-stage funding in the United States are failing to attract investors as dour sentiment in the public markets and dull exit conditions make it tougher to justify higher valuations.

U.S. venture capital investments in late-stage deals have plunged 62% to $24.9 billion in the third quarter, according to a report by PitchBook and the National Venture Capital Association (NVCA) on Thursday.

"Right now, the late stage is a much more treacherous market relative to how it has been in the past," Pitchbook's lead VC analyst, Kyle Stanford, said, adding that companies seeking late-stage funding have been relying much more on public market investors.

https://www.marketscreener.com/news/latest/U-S-VC-firms-pull-back-from-late-stage-deals-amid-stormy-markets-valuation-concerns--41994633/

New Covid subvariants could drive wave across Europe, US by end of November

 A “swarm” of new Covid subvariants could drive a fresh wave across Europe and North America by the end of November, experts have warned.

Covid-19 infections have surged 14 per cent according to latest figures as subvariants of the Omicron family show immune evasive ability according to early data.

According to the Biozentrum research facility at the University of Basel, which has been studying the evolution of the virus since the pandemic started, there is a “collective” of subvariants mutated from the Omicron family’s BA.2 and BA.5, which are showing capability to spread rapidly as many parts of the world approach the colder autumn-winter seasons.

BQ1.1, derived from BA.5 and BA.2.75.2, derived from BA.2 are among the new subvariant scientists fear could drive a “significant wave” as the colder weather persists.

“The trends we’re seeing at the moment are very different from what’s happened in the past,” Cornelius Roemer, a computational biologist with Biozentrum, told The Independent.

“Omicron was maybe the first variant that was good at evading immunity and that’s why it caused such a large wave. Now for the first time, we see many lineages, many variants emerging parallel that all have very similar mutations and that all manage to still evade immunity pretty well.”

Mr Roemer, who analyses Covid sequencing data from different lab databases worldwide and is part of the UK-led Pango Network which names new variants, said the current infection surge presents a new challenge for researchers because for the first time there isn’t a standout variant of concern but instead a collection or “swarm” of subvariants.

He added that the situation with new subvariants is constantly changing, with another immune evasive mutation - XBB - detected in China this week.

When compared to previous waves, Mr Roemer said the new subvariants are showing trends that could match more closely with the unexpected BA.5 led summer wave, but flagged concern that cases are increasing before the new variants have significantly accelerated and made up the majority of new cases.

“The thing now in the northern hemisphere is as temperatures are going down there is already a bit of a wave without the variants having much impact,” Mr Roemer said.

“The variants start accelerating when they reach 50 per cent of cases but we’re very far from that. All together the new variants are only around 5-10 per cent of new vases.

“That’s what’s a bit worrying,” he added, “That we already have cases going up and we know that there will be another surge due to the variants.”

Some 1.1 million people in private households tested positive for coronavirus in the latest survey, which covers the seven days to 17 September in England and the week to 20 September in the other three nations, according to the Office for National Statistics (ONS).

It is the first time the UK-wide total has been above one million since late August, though it is still some way below the 3.8 million weekly infections in early July at the peak of the wave caused by the Omicron BA.4 and BA.5 subvariants of the virus.

Covid cases across parts of Europe are surging also. According to latest data from the European Centre for Disease Prevention and Control, cases among people above 65-years-old rose by 9 per cent in September - the first increase observed across the region since the summer wave.

Based on growth trends of the new subvariants, Mr Roemer forecasts they could drive a wave in Europe and North America by the end of November.

Biozentum research group lead Professor Richard Neher agreed that a wave had already begun driven by the BA.2 and BA.5 offshoots. He insisted that while cases are increasing which could put pressure on health systems if people are hospitalised, a significant portion of populations were vaccinated preventing the likelihood of severe disease.

“It is vaccinations that have led us out of this pandemic. And they will remain an important measure to prevent severe cases in the fall and winter,” Professor Neher said.

Virologist, Professor James Young warned that the UK was blind to these new Covid subvariants that could be dominant in the current wave.

He said that the downscaling of Covid testing laboratories since the unveiling of the government’s Living with Covid plan means the UK is “blind” to the behaviour of new potential variants of concern. Major NHS “Lighthouse” labs closed earlier this year in line with the government’s policy on the infection.

“We’ve really taken our eye off the ball with Covid tests,” Professor Young told The Independent. “We can only detect variants or know what’s coming by doing sequencing from PCR testing, and that’s not going on anywhere near the extent it was a year ago.

“People are going to get various infections over the winter but won’t know what they are because free tests aren’t available – it’s going to be a problem.”

https://news.yahoo.com/swarm-covid-subvariants-could-drive-141414893.html

Philips draws a line under its sleep nightmare

 Philips’ new chief executive does not officially take over until Saturday, and to give him a relatively clean slate the company has finally dealt decisively with the massive issue that has been dogging it for more than a year. 

Today the Dutch group said it would write off the value of its sleep and respiratory care business by €1.3bn ($1.3bn), following three major device recalls and thousands of reports to the FDA suggesting that its sleep apnoea devices might have contributed to a death or serious injury. The stock is down 12% today, and 68% since the first recall last June.

And the woes don’t stop there. Philips also issued a profit warning, blaming “more significant than anticipated” supply chain problems. Its third-quarter operating profit will come in at around €210m, it said, a sharp drop from the €512m seen a year earlier. 

Philips will report earnings on October 24, by which time Roy Jakobs will have assumed control of the business from the current chief executive, Frans Van Houten. 

In June 2021 Philips voluntarily withdrew some of its ventilators, bi-level positive airway pressure and continuous positive airway pressure machines. The FDA issued a safety alert about the devices the same month, and in July designated the recall class 1, the most serious kind.

The problem was with the polyester-based polyurethane foam used to make the devices quieter. It was found to be liable to breaking down, forming potentially toxic particles that could be ingested or inhaled by the user. The foam was also suspected of producing potentially dangerous gas as it degraded. 

A further disaster hit in November, when a replacement silicone-based foam failed a safety test for the release of volatile chemicals. A second major recall occurred in June of this year. 

By July 31, 2022 the FDA had received more than 69,000 reports of dangerous events, including 168 reports of deaths, associated with the breakdown or suspected breakdown of the polyurethane foam. All in all Philips promised to replace or repair some 5.5 million sleep apnoea machines, a process that had been hampered by supply chain problems.

Sleep no more

The impairment on the sleep care business incorporated the group’s “best estimate” of the likely upshot of a settlement proposed by the US Department of Justice on behalf of the FDA, following the inspection of some of Philips Respironics’ facilities in the US in 2021. The agreement is still being negotiated.

To help mitigate the loss of value of the sleep franchise the company says it is “accelerating productivity initiatives”, details on which will come at the end of the month. It has already decided to shift the focus of its R&D activities to “fewer and better resourced projects”.

Philips has long been one of medtech’s biggest spenders on in-house research as a proportion of its sales, particularly since Mr Van Houten oversaw its transition to a pure-play device company. 

The graph below shows consensus forecast sales for the top-five developers of respiratory technologies, pre-dating today’s news. However, any investors hoping that Philips’ competitors in this space might benefit from the company’s catastrophe are in for a disappointment; shares in Resmed and Fisher & Paykel are down slightly, and Medtronic’s stock is flat. 

Kinnate is the latest Raf player to trip up

 Kinnate Biopharma floated two years ago on the promise of novel small molecules able to hit mutations other kinase inhibitors could not, but it is finding the going tough. Yesterday brought news of a second delay to its lead project, KIN-2787, and some analysts fear the worst.

However, the problem might not lie in the logic of what Kinnate is trying to do; KIN-2787 is a Raf kinase inhibitor with activity in class 2 and 3 Braf alterations, and thus said to work beyond Tafinlar’s class 1-restricted label. Rather, Kinnate might have designed the phase 1 study badly or recruited the wrong patients, or its molecule lacks potency.

Whatever the reason, the markets did not take kindly to the delay, which will see initial phase 1 data pushed into 2023; results had first been expected in the third and then the fourth quarter of this year. Kinnate was yesterday trading just above half its IPO price, and today the shares fell 27%.

Raf inhibitors approved for cancers with Braf class 1 (V600) mutations
			Sales ($m)
Product	Company	Approved uses	2021	2028e
Tafinlar (dabrafenib)	Novartis (ex GSK)	Melanoma (incl adjuvant), NSCLC & anaplastic thyroid cancer	1,693	1,875
Braftovi (encorafenib)	Pfizer (ex Array)	Melanoma & colorectal cancer	231	576
Zelboraf (venmurafenib)	Roche	Melanoma & Erdheim-Chester disease	86*	83
Note: *estimate as Roche has not split out sales since 2017. Source: US prescribing information & Evaluate Pharma sellside consensus.

First-generation Raf inhibitors are approved in melanoma and several other cancers, all of which must carry a class 1 (also known as V600) Braf mutation. Novartis’s Tafinlar is the best-seller, but the market also includes Pfizer’s Braftovi and Roche’s Zelboraf.

Kinnate, however, says KIN-2787 additionally targets class 2 and 3 Braf mutations, and wants to position it as a first-line targeted therapy. It designed its phase 1 monotherapy trial in two parts, first a dose escalation in class 1, 2 or 3 tumours or Nras-positive melanoma, and then dose-expansion cohorts in class 2 and 3 cancers only.

However, the dose-escalation phase, the subject of the delays, allowed pretreated patients. This brings up the first possible problem, namely that this has resulted in too heterogeneous a population. 

In a statement after market close yesterday Kinnate said KIN-2787 had achieved “meaningful exposures” with the 300mg twice-daily dose that preclinical models suggested would be efficacious. “Encouraging initial clinical responses” have been seen, it claimed, but crucially it did not say whether these included clinical remissions.

Thus it seems that actual response rates so far have been low – worrying given that target dosing has been achieved, though Stifel analysts caution that preclinical models might have been misleading. A 400mg dose is now being tested, and going up to 500mg is possible.

Kinnate also blames Covid on the trial delay, but Stifel does not buy this, citing the fact that enrolment has been sufficient to reach dose level five. Perhaps too many subjects with difficult tumours (ie, not melanoma) have been recruited, but surely Kinnate has had enough time to rectify this and enrol more of the right patients.

So maybe KIN-2787 just does not work very well. As well as claiming activity beyond class 1 Braf mutations Kinnate has argued that KIN-2787 is more selective than two other second-generation projects, Novartis’s naporafenib and Hanmi/Roche’s belvarafenib, claims that are now in doubt.

Developmental Raf inhibitors with possible activity beyond class 1 Braf mutations
Porject	Company	Activity	Clinical trial
Tovorafenib (DAY101)	Day One (ex Sunesis/ Biogen/ Takeda)	Pan-Raf	Ph3 1st-line Raf+ve glioma
FORE-8394	Fore (ex Daiichi Sankyo)*	Class 1 & 2	Ph2 in Braf-altered cancers
Naporafenib (LXH-254)	Novartis	Pan-Raf	Ph2 in 2nd-line melanoma
Belvarafenib (HM95573)	Hanmi/ Roche	Pan-Raf	Ph2 in class 2 mutant or fusion +ve tumours
LUT014	Lutris Pharma	Unclear	Ph2 in colorectal cancer
Avutometinib (VS-6766)	Verastem (ex Roche)	Dual Raf/Mek inhibitor	Ph2 in low-grade serous ovarian cancer
XP-102	Xynomic (ex Boehringer Ingelheim)	Pan-Raf	Ph1/2 is in V600 only
BGB-3245	Beigene/ Springworks**	Unclear	Ph1, incl class 2 & 3
KIN-2787	Kinnate	Class 1, 2 & 3	Ph1 in various cancers
PF-07284890	Pfizer	Unclear	Ph1 includes substudy in class 2 Braf
Note: *Fore was earlier known as Novellusdx, and Daiichi rights stem from acquisition of Plexxikon; **via the Mapkure JV. Source: company information.

Kinnate is not the only Raf player to trip up recently. Verastem is active in a slightly different sphere, with the Roche-derived dual Raf/Mek inhibitor avutometinib, but earlier this month discontinued a study in Kras G12V-mutant NSCLC.

Avutometinib had shown promise in a separate setting, Kras-mutated low-grade serous ovarian cancer. However, that trial also tests wild-type disease, and lack of clarity on whether this too might be addressable, combined with Verastem’s decision not to release further data, seemed to upset investors.

One notable win has come courtesy of Day One Pharmaceuticals with tovorafenib, another molecule with a convoluted ownership history, said to have pan-Raf activity. The success came this year in the Firefly-1 study in paediatric glioma, and the project is now in phase 3.

Interestingly, tovorafenib’s previous owner, Takeda, had studied and discontinued the molecule in melanoma. Day One has a phase 1/2 trial that includes melanoma, but this use has clearly taken a back seat.

https://www.evaluate.com/vantage/articles/news/trial-results/kinnate-latest-raf-player-trip

Thousands Of US Officials Trade Shares Of Companies They Regulate

More than 2,600 executive branch officials have bought and sold shares of companies whose fortunes rise and fall on the policies their agencies enact, a Wall Street Journal investigation has found. 

While controversy about insider trading by members of Congress has occasionally stirred major headlines, this phenomenon has quietly endured across Democratic and Republican administrations alike -- and it involves more than 20% of senior officials among the 50 agencies covered by the Journal's research so far.

The findings are based on the Journal's study of more than 31,000 disclosure forms filed between 2016 and 2021 by 12,000 senior career employees, presidential appointees and political staffers.  

Some riskier trades -- involving options and short sales, for example -- were valued between $5 million and $25 million. 

Though it's illegal for officials to work on issues in which they have a direct financial interest -- and though regulations even prohibit the mere appearance of conflicts of interest -- the Journal found many such instances. For example: 

"A top official at the Environmental Protection Agency reported purchases of oil and gas stocks. The Food and Drug Administration improperly let an official own dozens of food and drug stocks on its no-buy list. A Defense Department official bought stock in a defense company five times before it won new business from the Pentagon."

Often, ethics officials have simply waived the rules, or certified that an official's trade qualifies for an exception.  

More than 40% of the Treasury Department's senior officials traded in companies touched by their agency -- the highest among the 50 agencies studies by the Journal. Treasury was followed by the Environmental Protection Agency, the Department of Defense, the IRS, SEC and the Fed -- each of which had an above-average percentage of officials implicated.  

Some agencies sought to thwart the Journal's scrutiny, and at least one is still stonewalling completely: 

"Some [agencies] made it difficult to obtain the forms, and several agencies haven’t turned over all of them. The Department of Homeland Security hasn’t provided any financial records," the Journal reports.

The Journal has indicated these initial revelations are just the start of an investigative series. For a deep dive into several examples of questionable trading by federal officials, read the Journal's first installment here.   

https://www.zerohedge.com/political/thousands-us-officials-trade-shares-companies-they-regulate-wsj

Shanghai shuts down schools, gyms, bars as Covid-19 returns

 Shanghai is quietly shutting down schools and a raft of other venues as officials try to rein in a Covid-19 flare-up that has hit the financial hub just days before one of China's most important political events.

Several schools dotted throughout the city have suspended in-person classes as the fear of infection spread grows, according to parents and social media posts.

At least five districts have closed entertainment venues, including cinemas, bars and gyms, in an effort to stamp out transmission, according to statements issued by Covid-19 prevention offices.

The authorities said on Sunday there is no citywide school shutdown after speculation rippled through social media that the measure would be rolled out.

But the creeping suspensions, as well as a ramp up in other restrictions such as the lockdown of neighbourhoods and individual residential compounds, have left Shanghai's 25 million residents on edge.

As well as schools, venues such as gyms and bars have shut in the Shanghai districts of Changning, Putuo, Jiading, Yangpu, and Qingpu.

Shanghai Disney Resort said last Saturday that some facilities have been shut and performances cancelled to follow the Covid-19 control requirements.

Social media users lamented the never-ending cycle of shutdowns and reopenings that is a feature of China's Covid-Zero policy.

Others speculated whether they may face another lockdown just months after a two-month ordeal that saw many in Shanghai struggle to access food and medical care.

The tightening comes as Shanghai reported 38 new infections, all of which were found in its quarantine system.

While small by international standards, the flareup is occurring just days before China's once-in-five-years Party Congress, when President Xi Jinping is expected to secure a precedent-breaking third term in power.

Mr Xi has made Covid-Zero a cornerstone of his leadership, despite its growing social and economic cost, and China's propaganda machine has ramped up its defence of the policy this week, in a sign that there will be no shift towards living with the virus any time soon.

https://www.straitstimes.com/asia/east-asia/shanghai-shuts-down-schools-gyms-bars-as-covid-19-returns